1. 慢性炎症与癌症关联的理论基础
1.1 炎症-癌症转化的经典模型
慢性炎症是癌症发生发展的重要驱动因素之一，其核心在于炎症能够作为癌症的启动因子，通过持续的组织损伤-修复循环破坏基因组稳定性，进而促进肿瘤的形成。Correa级联反应是胃癌发生发展中一个经典的炎症-癌症转化模型，清晰阐述了慢性炎症如何逐步导致恶性病变1。这一模型描述了胃黏膜从正常状态，经历慢性非萎缩性胃炎、慢性萎缩性胃炎、胃黏膜肠化生（GIM）、异型增生（或称不典型增生），最终发展为胃癌的过程2。
具体来说，幽门螺杆菌（Hp）感染是启动Correa级联反应的主要因素。Hp感染导致持续的胃黏膜炎症，引起胃腺体萎缩，正常胃黏膜细胞被肠型上皮细胞取代，形成肠化生3。肠化生被认为是胃癌的重要癌前病变，其异质性（完全型或不完全型）与癌变风险密切相关。在肠化生基础上，持续的炎症刺激进一步导致细胞异常增殖和分化，形成异型增生，这被认为是更晚期的癌前病变，具有更高的恶变风险。最终，异型增生可能进展为原位癌，直至侵袭性胃癌。研究表明，在肠化生或异型增生阶段，p53基因和p21(WAF1/CIP1)基因的变异可能影响胃癌的发生发展进程4。
这种炎症驱动的癌变过程不仅限于胃癌。普遍认为，慢性炎症通过诱导持续的组织损伤和随后的修复尝试，创造了一个有利于肿瘤发生的微环境。反复的损伤-修复循环导致细胞增殖加速，增加了DNA复制错误的几率，从而积累基因突变和表观遗传改变。例如，在炎症环境中，脂质过氧化产生的二羰基亲电试剂（如异亮腺甘酸，isoLGs）可以与DNA形成共价加合物，导致DNA损伤和体细胞突变，从而连接了炎症和基因组改变，成为癌症化学预防的关键靶点5。此外，持续的炎症也可能导致细胞衰老，虽然细胞衰老在短期内可以作为肿瘤抑制机制阻止细胞无限增殖6，但长期存在的衰老细胞会通过分泌衰老相关分泌表型（SASP）因子，如细胞因子、趋化因子和蛋白酶，改变组织微环境，反而可能促进邻近细胞的增殖和恶性转化7。这些因素共同作用，导致基因组不稳定性（genomic instability），包括单碱基替换、插入/缺失以及染色体水平的改变（如拷贝数变异和结构变异）8，这是肿瘤发生发展的一个标志性特征910。细胞可塑性（cellular plasticity）理论指出，成熟的分化细胞在损伤修复过程中可能重新获得干细胞样特性，这种可塑性在癌症发生中也发挥作用，可能使细胞在累积致癌突变后，通过再分化进入恶性增殖通路1112。
1.2 炎症微环境的关键组分
炎症微环境是慢性炎症驱动癌症发生发展的核心舞台，其复杂组分间的精密交互作用决定了肿瘤的命运。在这一微环境中，免疫细胞、基质细胞以及可溶性因子扮演着至关重要的角色，共同调控细胞增殖、凋亡和上皮间质转化（EMT）等关键癌变过程。
免疫细胞中，巨噬细胞是肿瘤微环境（TME）中最丰富的免疫细胞之一，其表型和功能具有高度异质性13。肿瘤相关巨噬细胞（TAMs）在肿瘤进展中发挥关键作用，它们通过促进肿瘤生长、血管生成和免疫逃逸来影响预后1314。TAMs的起源和分化复杂，既可以来源于局部自我更新的组织驻留巨噬细胞，也可以来源于单核细胞衍生的巨噬细胞，这些细胞在肿瘤形成早期便在肿瘤细胞附近聚集，促进EMT和侵袭性，同时诱导调节性T细胞反应以保护肿瘤细胞免受适应性免疫攻击15。在胰腺导管腺癌（PDAC）中，IL-1β表达的TAMs与肿瘤细胞之间存在炎症循环，这种IL-1β巨噬细胞是由前列腺素E（PGE）和肿瘤坏死因子（TNF）局部协同作用所诱导，它们的物理接近与PDAC细胞的炎症重编程和致病特性获得相关，导致疾病进展和不良预后16。
基质细胞，特别是癌相关成纤维细胞（CAFs），是炎症微环境的重要组成部分。CAFs通过分泌多种细胞因子和生长因子，直接或间接影响肿瘤细胞的行为。例如，转化生长因子-β（TGF-β）就是由基质成纤维细胞（特别是CAFs）分泌的主要生长因子之一17，它在晚期癌症中是EMT的主要诱导剂，并与肿瘤细胞转移、癌症干细胞自我更新和耐药性相关1819。内皮细胞在炎症微环境中也发挥作用，通过促进血管生成为肿瘤提供营养和氧气。
可溶性因子在炎症微环境的细胞间通讯中起着核心作用：
- 细胞因子：
- IL-6：IL-6是一种重要的促炎细胞因子，其水平升高与多种癌症的进展和不良预后相关2021。它通过激活下游信号通路（如STAT3）促进细胞增殖、抑制凋亡并诱导EMT。
- IL-1β：作为NLRP3炎性体活化的关键产物，IL-1β是动脉粥样硬化等疾病中的重要血管和全身炎症介质22。在癌症中，IL-1β被认为在肿瘤侵袭、进展和转移中扮演重要角色23。临床试验CANTOS（Canakinumab Anti-inflammatory Thrombosis Outcomes Study）的探索性结果显示，使用IL-1β中和抗体卡那单抗（canakinumab）可显著降低肺癌发生率和死亡率，这提示IL-1β在炎症驱动的肿瘤发生中具有潜在的治疗靶点价值23。
- 趋化因子：
- 生长因子：
这些组分共同编织了一个复杂的网络，炎症因子和生长因子通过自分泌或旁分泌的方式作用于肿瘤细胞和基质细胞，驱动细胞增殖失控、抑制细胞凋亡、诱导EMT，进而促进肿瘤的侵袭和转移。EMT是一个生理过程，在上皮细胞转化为间充质细胞以迁移和定植到次级组织时发生，但在癌症晚期，TGF-β是EMT的主要诱导剂，与肿瘤细胞转移、癌症干细胞自我更新和耐药性有关19。这些机制共同揭示了慢性炎症微环境如何从多方面推动癌症的发生和发展。
2. 慢性病毒性肝炎与肝癌的病理进程
2.1 病毒持续感染与肝脏炎症的恶性循环
慢性病毒性肝炎，尤其是由乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）引起的感染，是全球肝细胞癌（HCC）发生的最主要原因，约占全球HCC病例的70%以上 2627。这两种病毒的持续感染会在肝脏内引发长期的炎症反应，进而形成一个恶性循环，最终导致肝纤维化、肝硬化并显著增加HCC的风险。
乙型肝炎病毒（HBV）持续感染的机制
HBV感染对肝细胞癌的贡献涉及直接和间接机制 2829。HBV DNA整合到宿主基因组中是肿瘤克隆早期扩张的步骤之一，这不仅会导致基因组不稳定，还能直接引起多种癌症相关基因的插入诱变 262829。病毒调节蛋白HBx和/或前S/S包膜蛋白的异常版本持续表达，会扰乱细胞转录和增殖控制，并使肝细胞对致癌因子敏感 262829。HBx蛋白在肝细胞癌发展中扮演重要角色，它被招募到细胞染色质上，调节特定基因座的染色质动态，导致表观遗传改变，进而影响抑癌基因的表达 2829。
HBV引起的持续炎症和肝脏再生反应会促进感染肝细胞中遗传变异的积累 26。在慢性HBV感染的不同阶段，肝内炎症程度存在差异。研究显示，与健康对照组相比，慢性HBV感染患者肝脏中的免疫基因表达和频率均增加 30。特别是免疫活跃期（IA）和HBeAg阴性肝炎期（ENEG）的肝脏表现出更显著的转录组失调，干扰素刺激基因、免疫激活和耗竭基因（如ICOS, CTLA4, PDCD1）以及趋化因子基因（如CXCL9, CXCL10）均显著上调 30。这表明HBV感染通过诱导持续的免疫应答和炎症来推动肝脏损伤。近期研究也揭示了HBV感染可能通过上调SEMA6B等蛋白，诱导巨噬细胞介导的全身炎症反应和肝细胞凋亡，从而加剧肝衰竭进程 31。
HBV特异性CD8+ T细胞功能障碍在慢性HBV感染中普遍存在，这被认为是病毒持续存在和疾病进展的关键因素 3233。虽然在成人中，约90%的急性HBV感染患者能够清除病毒，但持续感染的患者则面临更高的纤维化、肝硬化和HCC风险 32。CD8+ T细胞耗竭是慢性病毒性肝炎中T细胞功能丧失的主要机制之一，表现为抑制性受体（如PD-1, TIM-3, LAG-3）的过表达，这些耗竭的T细胞无法有效清除病毒 323334。此外，HBV还可能通过IL-33/调节性T细胞（Treg）轴增强肝脏对环境致癌物的敏感性，进一步促进肝细胞癌变。CD4+ T细胞通过与枯否细胞（Kupffer cells）的CD40-CD40L相互作用，触发IL-12和IL-27的产生，从而挽救CD8+ T细胞的功能障碍，这一发现为HBV治疗提供了新的免疫治疗靶点 35。
丙型肝炎病毒（HCV）持续感染的机制
HCV感染也极易导致持续感染，并在很大比例的慢性HCV感染患者中发展为HCC 363738。与HBV类似，HCV引起的慢性肝脏炎症是HCC发展的重要驱动因素。HCV的复制或病毒蛋白可以扰乱细胞稳态，诱导活性氧（ROS）的产生，并作为激动剂触发先天免疫应答，导致慢性炎症 37。HCV感染引发的复杂细胞因子网络，最初旨在控制病毒和减轻肝损伤，但HCV会干扰这些细胞因子，通过诱导Th2/T细胞毒性2型细胞因子谱来逃避免疫应答 39。这种免疫控制的失效导致炎症浸润物进入肝实质，并通过干扰素-γ诱导的CXC趋化因子（CXCL9, -10, -11）持续损伤肝脏，最终导致肝硬化 39。
在HCV感染相关肝癌中，Wnt/β-catenin信号通路异常激活也较为常见 40。HCV感染诱导的microRNA-155（miR-155）水平显著升高，miR-155的转录受NF-κB调控，并促进肝细胞增殖和致瘤性，机制是通过激活Wnt信号通路，并抑制Wnt通路抑制因子APC 36。这表明HCV感染通过促进炎症因子释放和表观遗传调控，激活了癌前信号通路。肝星状细胞（HSC）在HCV感染时被激活，是细胞外基质的主要来源，并在纤维化发生中发挥关键作用 37。慢性肝脏炎症、纤维化和肝硬化是HCV相关HCC的典型背景，但并非所有持续感染都会进展为HCC，病毒和宿主免疫因素的组合可能共同促进癌变 38。尽管直接抗病毒药物（DAAs）能够有效清除HCV，但对于已发展为HCC的患者，其影响数据有限，且HCV清除并不能完全消除HCC的风险 2737。这强调了持续监测和深入理解HCV致癌机制的重要性。
总结来说，HBV和HCV通过多种复杂机制，包括病毒蛋白对宿主细胞信号通路的直接干扰（如HBV的HBx蛋白影响p53和Wnt/β-catenin通路，HCV诱导的miR-155激活Wnt信号）、病毒逃逸宿主免疫系统、氧化应激、以及持续的炎症微环境（包括激活肝星状细胞导致肝纤维化），共同驱动肝细胞发生恶性转化，最终导致肝癌的发生发展 2829323637。这些过程的深入理解对于开发更有效的预防和治疗策略至关重要。
2.2 肝炎相关肝癌的分子机制
肝炎病毒感染促进肝细胞癌（HCC）的分子机制复杂而多样，涉及氧化应激、表观遗传修饰以及代谢重编程等多个层面，这些机制共同驱动肝细胞向恶性转化。
氧化应激（ROS积累）
慢性病毒性肝炎感染会诱导持续的氧化应激，导致活性氧（ROS）在肝细胞内大量积累，这是肝细胞癌变的关键驱动因素之一 4142。ROS的过度积累会直接损伤DNA，引起基因突变、染色体不稳定和细胞周期的异常。例如，HCV感染能够通过其病毒蛋白扰乱细胞稳态，诱导ROS的产生 42。这种损伤-修复循环不仅促进了遗传变异的累积，还激活了促炎信号通路，进一步加剧了炎症反应。研究表明，肝脏作为重要的靶向和清除病毒、细菌等异物的器官，通过免疫耐受和抗炎机制维持其功能 42。然而，病毒感染引起的应激会导致线粒体功能障碍，增加ROS表达，并消耗ATP，这些变化进一步触发促炎、免疫抑制的微环境，以及细胞凋亡和坏死机制，破坏肝脏形态的完整性 42。最终，这些通路共同促进肝脏脂肪变性、炎症、纤维化、肝硬化和肝癌的发生 42。
表观遗传修饰
病毒感染通过诱导多种表观遗传修饰来促进肝癌发生，包括DNA甲基化、组蛋白修饰和非编码RNA的表达异常 43。这些改变能够影响基因表达，从而调控细胞增殖、凋亡和分化等过程。
- USP26介导的SIRT1去泛素化：虽然直接证据关联USP26介导的SIRT1去泛素化与肝炎相关肝癌的发生机制尚未在提供的材料中详细阐述，但可以推断，去泛素化酶（DUBs）如USP26在维持蛋白质稳定性中发挥关键作用，而SIRT1作为重要的脱乙酰酶，参与调控细胞代谢、炎症和衰老。SIRT1功能的异常可能影响抑癌基因或促癌基因的表达，从而为癌变创造条件。在肝癌中，表观遗传学异常是普遍存在的现象，包括染色质重塑、组蛋白改变、DNA甲基化和非编码RNA表达，这些都与HCC的进展和转移相关 43。例如，WTAP（Wilms tumor 1-associated protein）在HCC中高表达，并通过m6A修饰和HuR-ETS1-p21/p27轴促进肝癌发展，表明m6A修饰作为一种表观遗传机制在肝癌发生中的重要性 44。
代谢重编程
癌细胞通常在缺氧和低营养条件下生存，这迫使它们进行适应性改变，以满足其对能量和生物合成物质的高需求，这种现象被称为“代谢重编程” 4546。病毒性肝炎诱导的慢性炎症会促进肝细胞的代谢重编程，从而为癌细胞的生长提供有利条件。
- ANGPTL8促进炎症-纤维化：血管生成素样蛋白8（ANGPTL8）是一种与肝纤维化相关的炎症因子。研究发现，ANGPTL8水平在肝硬化和HCC患者中均与肝纤维化相关 47。高脂肪饮食（HFD）诱导的非酒精性脂肪肝病（NAFLD）通过促进慢性炎症来诱导ANGPTL8的表达。肝细胞来源的ANGPTL8作为促炎因子，通过与LILRB2受体相互作用，激活ERK信号通路，增加促进肝纤维化的基因表达，从而活化肝星状细胞（HSC），加速HFD诱导的肝纤维化 47。虽然该研究主要关注HFD诱导的NAFLD，但慢性病毒性肝炎同样引起持续炎症，ANGPTL8可能在病毒性肝炎介导的炎症-纤维化-癌变链条中扮演类似角色。
- 其他代谢改变：HCC细胞表现出显著的代谢异质性 45。例如，激活β-catenin的HCC肿瘤依赖于脂肪酸分解代谢，而由脂肪肝引起的HCC肿瘤则避免使用脂肪酸 45。此外，肝癌细胞中通常存在糖酵解途径的增强和乳酸生成增加（Warburg效应） 45。低氧环境（缺氧）是实体瘤，特别是HCC的一个标志，通过缺氧诱导因子（HIF）介导的代谢重编程，促进癌细胞的耐药性 48。p300/CBP作为表观遗传的中心调节因子，在HCC进展中发挥重要作用，其抑制剂B029-2能通过表观遗传调控代谢，减少HCC细胞的糖酵解功能和核苷酸合成，表明表观遗传机制对代谢重编程的调控 49。最新的研究发现，乳酸诱导的IGF2BP3蛋白乳酰化修饰，通过捕获PCK2和NRF2 mRNA并增强其表达，重编程丝氨酸代谢并强化抗氧化防御系统，从而促进HCC对乐伐替尼的耐药性 50。此外，肝癌中精氨酸水平升高，通过与RNA结合基序蛋白39（RBM39）结合，进一步重编程葡萄糖、氨基酸、核苷酸和脂肪酸代谢，促进肿瘤生长 51。
HBV通过IL-33/调节性T细胞轴增强环境致癌物敏感性
2025年的新发现表明，HBV本身不直接导致肝脏炎症或癌症，而是通过改变化学致癌物诱导的慢性炎症来促进肝脏癌变 52。HBV基因组在小鼠肝脏中的长期表达，会增加致癌物（如二乙基亚硝胺，DEN）引起的肝脏炎症和癌症倾向 52。HBV联合DEN激活了IL-33/调节性T细胞（Treg）轴，这一轴在肝脏癌变中是必需的 52。IL-33是一种报警素，在肝脏炎症和损伤中发挥作用。HBV患者的IL-33水平显著升高，而IL-33抑制剂匹伐他汀（Pitavastatin）可以抑制HBV加DEN诱导的肝癌 52。此外，匹伐他汀的使用与患者肝炎及其相关HCC风险的降低显著相关 52。这揭示了环境致癌物是HBV与HCC风险之间的联系，为HBV携带者的癌症预防提供了新的机会 52。
综上所述，肝炎病毒感染通过多种分子机制协同作用，包括持续的氧化应激引发基因损伤、多种表观遗传修饰调控癌基因和抑癌基因表达、以及全面的代谢重编程为癌细胞提供生长优势，同时病毒与环境因素相互作用，共同推动了肝炎相关肝癌的发生发展。对这些复杂机制的深入理解，对于开发针对HCC的精准治疗和预防策略至关重要。
3. 幽门螺杆菌相关胃炎与胃癌的级联转化
3.1 幽门螺杆菌感染的胃黏膜损伤机制
幽门螺杆菌（Helicobacter pylori, Hp）感染是引起慢性胃炎、消化性溃疡以及胃癌的主要病因之一。Hp通过其独特的毒力因子及其诱导的持续炎症反应，对胃黏膜造成损伤，并启动Correa级联反应，最终可能导致胃癌 53。
Hp毒力因子对宿主细胞的直接作用：
Hp感染的致病性与细菌的毒力因子密切相关，其中细胞毒素相关基因A (CagA) 和空泡细胞毒素A (VacA) 是最重要的两种 54。
- CagA蛋白：CagA是Hp感染中最重要的致癌蛋白之一，编码于Cag致病岛（cagPAI）上。携带cagPAI的Hp菌株通过IV型分泌系统（Type IV Secretion System, T4SS）将CagA蛋白注入宿主胃上皮细胞内 55。一旦进入细胞，CagA会在宿主酪氨酸激酶（如Src和Abl）的作用下发生酪氨酸磷酸化，磷酸化的CagA能够模拟或干扰多种宿主细胞信号通路，包括与细胞增殖、凋亡、黏附和迁移相关的信号 56。CagA通过与宿主蛋白αPix相互作用，激活PAK1、ERK和NF-κB等信号通路，进而诱导IL-8的表达 57。IL-8是一种重要的趋化因子，能够吸引中性粒细胞和其他免疫细胞到感染部位，加剧炎症反应 58。此外，CagA的转运能够破坏细胞-细胞连接和细胞骨架重排，引发炎症、细胞周期相关、增殖、抗凋亡和DNA损伤应答等一系列宿主信号网络改变 55。近期研究还发现，CagA通过干扰端粒酶逆转录酶（TERT）与其E3连接酶SYVN1的相互作用，提高TERT的丰度，从而激活TERT/Wnt/β-Catenin通路，促进痉挛性多肽表达性化生（SPEM）和贲门腺萎缩的发生 59。
- VacA蛋白：VacA是Hp分泌的另一种重要毒力因子，可以诱导宿主细胞形成空泡，并对免疫细胞产生抑制作用。虽然VacA对IL-8表达的影响不如CagA显著，但它通过多种机制协同CagA促进胃黏膜损伤。
信号通路的激活与炎症因子释放：
Hp感染引起的持续炎症主要通过激活宿主细胞内的关键信号通路来介导，包括NF-κB和MAPK通路：
- NF-κB通路：Hp（尤其是CagA阳性菌株）通过T4SS注入宿主细胞的CagA以及脂多糖等成分，能够激活核因子-κB（NF-κB）通路 6061。NF-κB是多种炎症和免疫反应基因转录的关键调节因子。NF-κB的激活导致IL-8、TNF-α、IL-1β等促炎细胞因子和趋化因子的表达上调，这些因子进一步吸引和活化免疫细胞，导致胃黏膜持续炎症 62。
- MAPK通路：丝裂原活化蛋白激酶（MAPK）通路，包括ERK、JNK和p38，也在Hp感染过程中被激活 57。例如，HP99菌株能够通过Ras和MAPK级联反应激活AP-1和NF-κB，进而诱导IL-8和MCP-1等趋化因子的表达 61。MAPK通路的激活对细胞增殖、分化和凋亡具有重要调控作用，其异常活化参与了癌前病变的发生 62。
Hp对胃酸分泌的抑制与胃微生态失调：
除了直接损伤作用，Hp感染还能通过影响胃酸分泌来改变胃内环境。虽然胃酸被认为是Hp生存的障碍，但Hp具有多种机制来适应和调节胃酸环境，例如产生尿素酶将尿素水解为氨和二氧化碳以中和胃酸。长期Hp感染，特别是伴随萎缩性胃炎，常导致胃酸分泌减少，甚至出现胃酸缺乏 63。胃酸分泌的长期抑制，无论是由Hp感染还是长期使用质子泵抑制剂（PPIs）引起，都会导致胃内pH值升高，从而为非Hp细菌的生长创造有利条件，导致胃微生态失调 6364。
- 胃微生态失调：正常情况下，胃是相对无菌的环境。但Hp感染后，尤其是伴随胃酸减少，胃内细菌多样性显著增加，非Hp的革兰氏阴性菌（如_Streptococcus_、Veillonella、Lactobacillus、Prevotella_和_Rothia_等）以及一些肠道细菌（如_Escherichia_和_Enterobacter）开始在胃内定植并增殖 6566。这种菌群失调进一步促进炎症反应，产生致癌物质（如亚硝胺），并影响宿主细胞的信号通路。例如，在Hp阳性个体中，根除治疗成功后，胃黏膜菌群的丰富度和Shannon指数均显著增加，并恢复到与Hp阴性个体相似的水平，这表明Hp感染导致了胃黏膜菌群的失调，并且根除治疗能够逆转这一过程 67。一些研究表明，_Fusobacterium_在胃癌进展过程中显著富集，可能在胃癌发生中发挥重要作用 6566。
这些复杂的相互作用——Hp毒力因子直接损伤宿主细胞，激活促炎信号通路，诱导炎症因子释放，同时通过抑制胃酸分泌导致胃微生态失调——共同加速了胃黏膜的萎缩和肠化生进程，为胃癌的发生奠定了病理基础。
3.2 慢性萎缩性胃炎到胃癌的关键节点
慢性萎缩性胃炎（CAG）是幽门螺杆菌（Hp）感染引起的胃癌发生级联反应中的一个重要阶段。在这个阶段，胃黏膜腺体萎缩并常伴有胃黏膜肠化生（Gastric Intestinal Metaplasia, GIM），GIM被认为是胃癌的癌前病变，其进展至胃癌是Hp感染相关胃癌级联转化的关键环节 6869。
肠化生（GIM）的异质性与癌变风险的关联
GIM的异质性是评估其癌变风险的重要因素。GIM根据其形态学和组织学特征可分为完全型和不完全型。完全型GIM表现为小肠绒毛状结构和杯状细胞、吸收细胞、潘氏细胞等，而不完全型GIM则呈现结肠型上皮细胞，缺乏小肠特有的细胞类型，且常伴有异型增生。研究普遍认为，不完全型GIM具有更高的癌变风险 68。
近期对肠化生的时空基因组分析揭示了胃癌进展中的克隆动态。通过对1256份胃样本（其中1152份为IM）进行为期10年的前瞻性研究，研究人员识别出26个IM驱动基因，涉及染色质调控（如ARID1A）和肠道稳态（如SOX9）等多个通路。单细胞和空间分析突出了组织生态学和IM谱系异质性的变化，其中一个以肠道干细胞为主的细胞区室与早期恶性肿瘤相关联。扩展的转录组分析揭示了与不完全型组织学、胃窦/肠型细胞类型、ARID1A突变、炎症以及通常与健康口腔相关的微生物群落相关的IM表达分子亚型 68。这些研究强调了整合临床-基因组模型在预测IM患者癌变风险方面的优越性，并指出微生物失调在IM进展中的作用，为胃癌的精准预防和干预提供了机会 68。
Hp感染后持续炎症驱动异型增生的机制
Hp感染导致的持续炎症通过多种分子机制驱动胃黏膜从肠化生向异型增生，最终发展为胃癌：
DNA甲基化异常：
DNA甲基化是一种重要的表观遗传修饰，在基因表达调控中发挥关键作用。Hp感染诱导的慢性炎症会引起DNA甲基化异常，特别是抑癌基因启动子区域的高甲基化，从而导致这些基因的沉默，促进癌变 70717273747576。- 抑癌基因启动子高甲基化：在胃癌中，多种抑癌基因被发现存在启动子区域的高甲基化，例如：
- RUNX3：Runt相关转录因子3 (RUNX3) 是一个在胃癌中扮演抑癌基因角色的转录因子。多项研究表明，RUNX3启动子高甲基化与胃癌的发生密切相关 77。
- CDH1 (E-cadherin)：CDH1基因编码E-钙粘蛋白，是上皮细胞间黏附的关键分子，其失活与肿瘤的侵袭和转移密切相关。CDH1基因启动子的高甲基化在胃癌，特别是弥漫型胃癌中常见 78。
- APC：腺瘤性息肉病结肠基因（APC）是一个重要的抑癌基因，其启动子甲基化与胃癌的发生风险增加有关 79。
- p16：p16基因编码细胞周期抑制蛋白p16INK4a，其启动子高甲基化与胃癌的发生和进展显著相关，包括肠化生、较差的组织学分化、局部浸润、淋巴结播散和更晚期的TNM分期 80。
- Hp感染与甲基化：Hp感染是异常DNA甲基化的重要诱因，无论是通过其致病性CagA蛋白还是通过诱导慢性炎症，都可导致DNA甲基化改变 707173747576。Hp感染引发的活性氧/氮物种（ROS/RNS）不仅损伤DNA，还可激活DNA甲基转移酶（DNMTs）活性，导致DNA胞嘧啶甲基化，进一步促进表观遗传改变 7275。根除Hp感染可以部分逆转某些基因的异常甲基化，提示其在预防胃癌中的潜在作用。
- 抑癌基因启动子高甲基化：在胃癌中，多种抑癌基因被发现存在启动子区域的高甲基化，例如：
干细胞异常增殖（如LGR5+胃干细胞活化）：
胃黏膜的持续损伤和修复循环会刺激干细胞的异常增殖，从而增加致癌突变的累积。在胃肠道中，LGR5（Leucine-rich repeat-containing G protein-coupled receptor 5）被认为是重要的干细胞标志物。在Hp感染和慢性炎症的背景下，胃黏膜干细胞（包括LGR5+干细胞）的异常活化和增殖可能导致克隆扩张，并增加发生异型增生的风险。这些异常增殖的干细胞更容易积累基因突变，并产生对恶劣环境具有抵抗力的细胞克隆，这些克隆最终可能演变为肿瘤。微RNAs失调：
慢性炎症还导致微RNAs（miRNAs）表达的异常。miRNAs是小的非编码RNA分子，通过调控基因表达在多种细胞过程中发挥作用，包括细胞增殖、分化和凋亡。在Hp感染相关的胃癌发生过程中，一些miRNAs的表达上调或下调，例如miR-30a在Hp感染的胃癌模型中被发现作为肿瘤抑制因子，通过双重靶向COX-2和BCL9来抑制肿瘤生长和迁移 81。miRNA的失调可以促进致癌基因的表达或抑制抑癌基因的功能，从而加速异型增生向胃癌的转化 70717276。微生物群落失调：
如前所述，Hp感染不仅直接引起炎症，还可能导致胃微生态失调，促进其他致病菌的定植和增殖 6882。这些非Hp细菌也可以通过产生致癌代谢物或激活炎症信号通路，协同Hp驱动胃黏膜损伤和癌变进程。胃癌发生过程中，微生物群落的变化与炎症、ARID1A突变等因素相互作用，共同促进疾病进展 68。
综上所述，从慢性萎缩性胃炎发展到胃癌是一个多阶段、多因素参与的复杂过程。GIM的异质性及其相关风险，以及Hp感染后持续炎症通过DNA甲基化、干细胞异常增殖和miRNA失调等关键分子机制，共同推动了异型增生的发生和发展，最终导致胃癌的形成。对这些关键节点的深入理解，对于胃癌的早期诊断、风险评估和精准预防具有重要意义。
4. 慢性胰腺炎与胰腺癌的转化机制
4.1 慢性胰腺炎的病理特征与致癌微环境
慢性胰腺炎（Chronic Pancreatitis, CP）是一种进行性炎症性疾病，其特征是胰腺组织结构和功能的不可逆性破坏，是胰腺癌（Pancreatic Ductal Adenocarcinoma, PDAC）发生发展的重要危险因素。CP的病理进程伴随着腺泡细胞损伤、炎症浸润、纤维化和腺泡-导管化生（Acinar-to-Ductal Metaplasia, ADM）等一系列复杂病理变化，这些变化共同营造了一个有利于癌细胞生长的致癌微环境。
腺泡-导管化生（ADM）
ADM是CP早期发生的关键病理事件之一，指胰腺腺泡细胞在持续炎症刺激下，发生表型转化，获得导管样细胞的特征。这一过程被认为是胰腺癌的起始步骤，因为ADM灶常常伴随有致癌基因突变，尤其是KRas基因突变，是胰腺导管内乳头状黏液性肿瘤（IPMN）和胰腺上皮内瘤变（PanIN）等癌前病变的前兆 8384。在体外三维培养和基因工程小鼠模型中，糖原合酶激酶-3β（GSK-3β）被证明能促进TGF-α诱导的ADM发展，而敲除GSK-3β则能减弱ADM形成和PanIN进展，这表明GSK-3β可能成为治疗CP和预防PDAC进展的靶点 83。此外，基底膜（BM）中的细胞外基质受体dystroglycan在正常胰腺腺泡细胞中高表达，但在ADM和胰腺癌前病变的所有阶段，其表达均显著下调。在致癌性Kras表达的背景下条件性删除dystroglycan，可加速胰腺疾病进展，包括促进异型增生发展和缩短生存期，表明dystroglycan是胰腺异型增生发展的抑制因子 85。
纤维化与肌成纤维细胞增殖
慢性胰腺炎的另一个显著特征是胰腺间质中大量纤维组织的增生，这一过程主要由胰腺星状细胞（Pancreatic Stellate Cells, PSCs）的活化和增殖驱动。PSCs是胰腺微环境中主要的基质细胞，在正常生理条件下处于静止状态，但在炎症、损伤和肿瘤微环境中会被激活，转变为肌成纤维细胞样表型。活化的PSCs分泌大量的细胞外基质（Extracellular Matrix, ECM）成分，如胶原蛋白、纤连蛋白等，导致胰腺组织纤维化，形成坚硬的肿瘤间质。这种致密的纤维化间质不仅限制了药物渗透，也为肿瘤细胞提供了生长支架和保护屏障。磷脂酰肌醇3-激酶（PI3K）家族的成员在肿瘤细胞、PSCs和肿瘤浸润性炎症细胞中均被激活，以促进癌症生长。促炎细胞因子和趋化因子可以激活PSC和炎症细胞中的PI3K通路 86。
癌前病变：导管内黏液性乳头状肿瘤（IPMN）和胰腺上皮内瘤变（PanIN）
慢性胰腺炎患者发生胰腺癌的风险显著高于普通人群，这与CP引起的反复炎症促进IPMN和PanIN等癌前病变的形成密切相关。IPMN是一种起源于胰腺导管上皮的囊性肿瘤，具有不同程度的异型增生，并有进展为浸润性癌的潜能。PanIN则是导管上皮内的一种非浸润性病变，通常发生在小导管，被认为是PDAC最常见的癌前病变。这些病变在组织学上呈现出从低级别异型增生到高级别异型增生再到浸润性癌的连续性进展。
炎症微环境中的关键细胞与分子
CP诱导的炎症微环境是PDAC发生发展的“土壤”，其中巨噬细胞和CXCL12/CXCR4轴扮演着重要角色。
- M2型巨噬细胞：肿瘤相关巨噬细胞（TAMs）在PDAC微环境中高度富集，其中M2型巨噬细胞是主要亚型。M2型巨噬细胞具有免疫抑制和促肿瘤的特性，它们通过分泌多种细胞因子（如TGF-β、IL-10）和生长因子，促进肿瘤细胞增殖、血管生成、侵袭和转移，并抑制抗肿瘤免疫反应。在CP和PDAC中，炎症介质诱导巨噬细胞向M2型极化，这些M2型巨噬细胞进一步促进PSCs的活化和ECM的沉积，从而加剧纤维化和肿瘤进展。
- CXCL12/CXCR4轴对PSCs活化的促进作用：趋化因子CXCL12（也称为SDF-1）及其受体CXCR4在CP和PDAC的进展中发挥关键作用。CXCL12由活化的PSCs和肿瘤细胞分泌，而PSCs、肿瘤细胞以及各种免疫细胞均表达CXCR4。CXCL12-CXCR4轴的激活能够促进PSCs的增殖、迁移和ECM的合成，从而加剧胰腺纤维化。同时，该轴还诱导肿瘤细胞的增殖、侵袭和转移，并通过招募免疫抑制细胞（如调节性T细胞和髓源性抑制细胞）来抑制抗肿瘤免疫。在炎症微环境中，CXCL12-CXCR4轴作为一个重要的信号通路，连接了炎症、纤维化和肿瘤发生发展。
- p38 MAPK通路：p38 MAPK通路的激活在急性胰腺炎早期发生，抑制p38 MAPK可能减轻胰腺炎症。研究表明，在胰腺腺泡细胞（PACs）和星状细胞（PSCs）的共培养环境中，细胞微环境对p38 MAPK和糖皮质激素受体（GR）的激活具有重要作用。氢化可的松能够抑制PACs和PSCs中由共培养引起的磷酸化p38 MAPK的上调，并增加GR的核转位。这提示p38 MAPK通路在胰腺炎症中扮演关键角色，可能成为药物干预的靶点 87。
- 其他通路：SNAIL相关蛋白Slug（Snai2）意外地被发现能通过抑制ADM发展，从而抑制胰腺癌的发生。在Kras表达小鼠中，Slug可以减弱Kras诱导的ADM发展、ERK1/2磷酸化和细胞增殖。Slug与Kras共表达还能减轻慢性胰腺炎诱导的ADM发展和纤维化。这表明Slug可能在ADM中发挥肿瘤抑制作用，通过阻止ADM，从而抑制胰腺癌的发生 88。此外，Akt1信号通路在急性胰腺炎发展中也扮演关键角色，其特异性失活可减少腺泡细胞增殖并加剧ADM形成，提示Akt1活化剂可能有助于促进胰腺再生 89。
综上所述，慢性胰腺炎通过ADM、纤维化、癌前病变以及由M2型巨噬细胞和CXCL12/CXCR4轴等组成的致癌微环境，为胰腺癌的发生发展提供了肥沃的土壤。深入理解这些病理特征和分子机制，对于开发有效的预防和治疗PDAC的策略至关重要。
4.2 遗传与环境因素的协同致癌效应
胰腺癌（PDAC）的发生发展是遗传、环境因素与慢性炎症协同作用的复杂过程。特定基因的突变可以降低胰腺对炎症的耐受性，而吸烟、高脂饮食等环境因素则能加剧炎症反应，共同促进致癌事件的发生，其中KRas突变是胰腺癌中最常见的致癌基因突变。
遗传突变降低胰腺对炎症的耐受性
多种遗传基因突变与慢性胰腺炎（CP）的发生和PDAC风险升高密切相关，这些突变影响胰腺的蛋白酶平衡和离子通道功能，使胰腺对炎症刺激更为敏感 9091。
- PRSS1基因突变：阳离子胰蛋白酶原基因（PRSS1）的突变是遗传性慢性胰腺炎（HCP）最主要的遗传基础 9091。PRSS1突变，如R122H，导致胰蛋白酶原在胰腺内过早激活，生成具有活性的胰蛋白酶。正常情况下，胰腺通过胰蛋白酶抑制剂（如SPINK1）维持蛋白酶的平衡。然而，PRSS1突变导致胰蛋白酶活性失衡，诱发自身消化，进而引起反复的胰腺炎症和损伤 90。长期来看，这种持续的炎症和损伤增加了胰腺癌的风险 9192。虽然PRSS1突变直接导致CP，但其与胰腺癌风险的直接关联在一些研究中并未显著发现，德国患者的研究显示PRSS1突变未显著增加胰腺癌风险 93。但另有研究指出，PRSS1基因的内含子突变（如IVS 3+36 A>G）在胰腺癌和CP患者中均有发现，提示其可能作为胰腺癌和CP的特殊共同病因 92。
- CFTR基因突变：囊性纤维化跨膜传导调节因子（CFTR）基因编码一种氯离子通道蛋白，其功能障碍会导致黏液分泌异常，进而引起导管堵塞和慢性炎症。CFTR基因突变是囊性纤维化的病因，也是一些特发性CP患者的遗传风险因素 90。研究表明，CFTR基因突变患者发生胰腺癌的风险显著升高，尤其是在伴有吸烟等风险因素时 94。这提示CFTR功能异常通过影响胰腺液的正常分泌和清除，使得胰腺更容易受到炎症的侵袭，从而增加了癌变的几率。然而，也有研究指出，CFTR突变频率在胰腺癌患者中与健康对照组相比无显著差异 93。这种差异可能与研究人群的遗传背景和环境暴露有关。
- 其他基因：丝氨酸蛋白酶抑制剂Kazal型1（SPINK1）和胰凝乳蛋白酶C（CTRC）基因突变也与CP的发生相关 9093。SPINK1编码一种胰蛋白酶抑制剂，其突变可能导致抑制功能下降，进而促进胰蛋白酶的异常激活。虽然这些突变增加了CP风险，但其与胰腺癌风险的直接关联仍需更多研究证实 93。
环境因素的协同致癌效应
吸烟和高脂饮食是公认的胰腺癌环境风险因素，它们通过多种机制加剧胰腺炎症，并与遗传因素协同作用，促进癌变 95。
- 吸烟：吸烟是胰腺癌最明确、最一致的危险因素之一，可使胰腺癌风险增加约两倍 9495。吸烟中的致癌物质，如亚硝胺，可以直接损伤胰腺细胞DNA，并诱导慢性炎症。对于携带遗传性胰腺炎基因突变（如CFTR突变）的个体，吸烟的致癌效应更为显著，进一步提高了胰腺癌的风险 94。
- 高脂饮食：高脂饮食，特别是西方饮食模式，与多种癌症的发生发展相关，包括胰腺癌 95。高脂饮食可能通过多种途径促进胰腺炎症和癌变：
- 肠道菌群失调：高脂饮食可以改变肠道微生物群落的组成和功能，导致肠道菌群失调。这种失调可能增加肠道通透性，使细菌产物（如脂多糖, LPS）进入血液循环，进而通过门静脉系统到达胰腺，激活胰腺细胞的炎症反应。
- TLR4/NF-κB通路：TLR4（Toll样受体4）是识别LPS的重要模式识别受体。肠道来源的LPS可以激活胰腺细胞上的TLR4，进而触发NF-κB信号通路。NF-κB是炎症反应的核心转录因子，其激活导致多种促炎细胞因子和趋化因子（如TNF-α、IL-6、IL-1β）的释放，加剧胰腺炎症。持续的NF-κB激活不仅直接促进炎症，还可能诱导细胞增殖、抑制凋亡，为KRas突变等致癌事件创造有利条件。
- 氧化应激与代谢异常：高脂饮食还可引起氧化应激和胰岛素抵抗，这些代谢异常进一步加剧胰腺炎症，并通过复杂的信号网络促进胰腺上皮细胞的恶性转化。
- 其他环境因素：酗酒是慢性胰腺炎的主要病因之一，虽然与胰腺癌的直接关联不如吸烟显著，但重度饮酒者胰腺癌风险增加 95。2025年的一项研究发现，一位伴有高脂肪饮食和大量吸烟习惯的复发性高甘油三酯血症性急性胰腺炎（HTG-AP）患者，体内存在 novel GPD1基因错义变异p.K327N。虽然该变异对GPD1功能影响相对较小，但与高脂肪饮食和大量吸烟共同作用，可能触发了HTG-AP，这提示了基因-环境交互作用在胰腺疾病发生中的重要性 96。
Kras突变等致癌事件的促进
KRas基因突变是胰腺癌中最常见的驱动突变 97。慢性胰腺炎所造成的持续炎症微环境，包括ROS积累、DNA损伤和细胞增殖加速，为KRas突变的发生和克隆选择提供了机会。
- 炎症促进KRas突变：炎症微环境中产生的活性氧和氮物种，以及细胞增殖过程中DNA复制的错误，都会增加KRas基因发生突变的可能性。一旦KRas发生突变，它便诱导ADM向PanINs和浸润性癌进展 9899。
- 基因-环境交互作用加速进展：有研究表明，组织损伤（如胰腺炎）与KRas致癌突变协同作用，显著加速早期肿瘤病变（如PanIN）的形成和进展 100。在这种基因-环境交互作用下，胰腺上皮细胞中会形成一种独特的染色质状态，区分于正常再生过程，并贯穿于整个恶性演变过程。这种癌症相关表观遗传状态在胰腺损伤后48小时内即可出现，涉及“腺泡-肿瘤”染色质转换，导致早期与人类胰腺癌相关的基因失调 100。此外，IL-33这种报警素细胞因子在组织损伤后被迅速激活，与突变型KRas协同作用，引发早期肿瘤和新生物转化的表观遗传重塑程序 100。
- HBP1在PanIN进展中的作用：HMG盒包含蛋白1（HBP1）在人慢性胰腺炎和鼠急性胰腺炎中均上调，并且其在人慢性胰腺炎中的表达与癌症的存在相关。虽然HBP1上调可能减轻胰腺炎症损伤，但在KRas致癌突变存在的情况下，HBP1却促进PanIN的进展。这提示HBP1在胰腺炎和早期胰腺肿瘤形成中都扮演着关键角色，可能成为干预胰腺炎和PanIN进展的潜在治疗靶点 101。
总之，遗传因素（如PRSS1、CFTR突变）通过影响胰腺对炎症的敏感性，降低其耐受性，而吸烟、高脂饮食等环境因素则通过肠道菌群失调、TLR4/NF-κB通路激活以及氧化应激等机制加剧胰腺炎症，两者协同作用，共同促进KRas突变等致癌事件的发生，最终驱动慢性胰腺炎向胰腺癌转化。深入理解这些协同机制，对于制定胰腺癌的风险评估、早期预防和靶向治疗策略至关重要。
5. 慢性炎症相关癌症的共同分子机制
5.1 关键信号通路的异常激活
慢性炎症通过多种信号通路的异常激活，深刻影响细胞增殖、凋亡、分化和迁移等基本生物学过程，从而驱动癌症的发生和发展。在不同的炎症-癌症模型中，NF-κB、STAT3和HIF-1α等信号通路表现出共性激活模式，并在调节细胞周期和凋亡方面发挥关键作用。
1. NF-κB (核因子-κB) 通路
NF-κB是炎症和免疫反应中的核心转录因子，其异常激活是连接慢性炎症与癌症的关键分子环节。自首次发现NF-κB在连接持续感染和慢性炎症与癌症风险增加中发挥分子核心作用以来，炎症与癌症领域已日趋成熟，炎症被广泛认为是癌症的标志和原因 102。
- 激活机制：在炎症微环境中，多种促炎因子（如TNF-α、IL-1β、LPS等）或感染因子（如Hp毒力因子CagA）能激活NF-κB通路。通常，非激活状态的NF-κB与抑制蛋白IκB结合，存在于细胞质中。当IκB被磷酸化并泛素化降解后，NF-κB释放并转位入核，与靶基因启动子结合，启动相关基因的转录。
- 功能：激活的NF-κB促进促炎细胞因子和趋化因子的表达，吸引更多的免疫细胞到炎症部位，形成恶性循环。此外，NF-κB还直接调控细胞增殖、存活和血管生成相关的基因，例如：
- 细胞周期调控：NF-κB可以通过调控细胞周期蛋白（如cyclin D1）和细胞周期抑制因子（如p21）的表达来影响细胞周期进程。
- 凋亡抑制：NF-κB可上调抗凋亡蛋白的表达，抑制癌细胞的程序性死亡，从而促进肿瘤细胞的存活和积累 103。
- 在癌症中的作用：在多种癌症中，包括肝癌、胃癌和胰腺癌，NF-κB的持续激活与肿瘤的发生、进展和转移密切相关。例如，在胶质瘤中，敲低Trem2可以抑制NF-κB p50信号通路，促进促炎性小胶质细胞的产生，从而抑制胶质瘤的生长和血管生成 104。在肝癌中，NF-κB可与STAT3协同，共同上调HIF-1α和CD133的表达，促进肝癌的发生发展 105。胰腺癌中，NF-κB通路的持续激活促进CXCL1的产生，进而促进免疫抑制 106。
2. STAT3 (信号转导与转录激活因子3) 通路
STAT3是JAK/STAT信号通路的关键成员，在炎症和癌症中扮演着多功能角色。
- 激活机制：多种细胞因子（尤其是IL-6）和生长因子可以激活JAK（Janus激酶），进而使STAT3磷酸化，形成二聚体并转位入核，调控靶基因的表达 107。IL-6/STAT3通路是慢性炎症相关癌症中一个核心的促癌通路。
- 功能：激活的STAT3促进细胞增殖、抑制凋亡、诱导血管生成和免疫抑制，并且与干细胞特性和耐药性相关 108。具体而言：
- 细胞增殖与存活：STAT3能够上调细胞周期蛋白（如cyclin D1、c-Myc）和抗凋亡蛋白（如Bcl-2、Survivin）的表达，促进癌细胞的无限增殖和存活。
- EMT和转移：STAT3通过调控EMT相关转录因子（如Snail、Slug）的表达，促进癌细胞获得间充质表型，增强侵袭和转移能力。
- 在癌症中的作用：STAT3在多种炎症相关癌症中普遍激活。例如，在肝癌中，IL-6/STAT3信号通过功能性协同NF-κB和HIF-1α，诱导CD133的表达，从而促进肝癌进展 105。早期研究也表明，RB（视网膜母细胞瘤）肿瘤抑制基因的失活通过刺激IL-6/STAT3通路增强促炎信号，直接促进癌细胞的多种恶性特征 107。在血管瘤中，IL-6通过激活STAT3/HIF-1α/VEGFA信号，促进血管瘤细胞的恶性增殖和迁移 109。中药复方M-BJJW可通过调节HIF-1α/STAT3/NF-κB信号通路，抑制PD-L1介导的免疫逃逸，从而发挥抗肝癌作用 110。
3. HIF-1α (缺氧诱导因子-1α) 通路
肿瘤组织内普遍存在的缺氧微环境是HIF-1α激活的主要因素，HIF-1α在炎症和癌症的交界处扮演着关键角色。
- 激活机制：在常氧条件下，HIF-1α被脯氨酰羟化酶（EGLN）羟基化，随后被VHL蛋白泛素化并降解。在缺氧条件下，EGLN活性受抑制，导致HIF-1α稳定并积累，随后与HIF-1β结合形成HIF-1，转位入核调控下游靶基因 111。长时间缺氧通过调节脯氨酰羟化来促进RIPK1激酶的激活，独立于TNFα-TNFR1通路，进而介导细胞死亡和炎症 111。
- 功能：HIF-1α调控多种基因的表达，这些基因参与细胞代谢重编程（如Warburg效应）、血管生成、细胞增殖和存活等过程。
- 在癌症中的作用：HIF-1α在多种实体瘤中高表达，与肿瘤的恶性程度和预后不良相关。例如，在肝癌中，HIF-1α通过调节PD-L1的表达促进免疫逃逸 110。在胃癌前病变中，HIF-1α介导的糖酵解在病程进展中表现出动态变化，而中药复方改良左金丸可通过靶向HIF-1α通路缓解胃癌前病变 115。
通路间的交叉对话与协同作用
NF-κB、STAT3和HIF-1α通路之间并非独立作用，而是存在复杂的交叉对话，共同增强促癌效应。例如：
- NF-κB与STAT3：NF-κB可以促进IL-6的表达，从而激活STAT3通路，形成正反馈循环 103。
- HIF-1α与NF-κB/STAT3：在缺氧条件下，HIF-1α与NF-κB和STAT3之间存在协同作用，共同促进肿瘤细胞的增殖、存活和免疫逃逸 105110113。缺氧和循环缺氧两种类型的缺氧都与HIF-1和NF-κB的激活有关，并诱导基因表达的变化 113。持续缺氧和循环缺氧通过HIF-1和NF-κB激活，诱导各种细胞因子和趋化因子的表达，促进肿瘤的慢性低度炎症 113。
这些关键信号通路的异常激活及其复杂的交互作用，共同构成了慢性炎症驱动癌症发生发展的分子基础。深入理解这些机制，对于开发靶向炎症-癌症转化的新型治疗策略具有重要意义。
5.2 表观遗传与代谢重编程的交叉作用
慢性炎症驱动癌症的发生发展，不仅涉及关键信号通路的异常激活，更深层次地体现在表观遗传修饰和代谢重编程的复杂交叉作用中。炎症因子能够通过调控表观遗传酶来影响基因表达，而炎症诱导的代谢改变则为癌细胞的生长和增殖提供必要的物质和能量，两者相互促进，共同推动肿瘤进展。
1. 炎症因子对表观遗传修饰的影响
表观遗传修饰，如DNA甲基化、组蛋白修饰（乙酰化、甲基化等）以及非编码RNA的调控，在不改变DNA序列的前提下，深刻影响基因的表达模式。炎症因子作为微环境中的重要信号分子，可以直接或间接地调控这些表观遗传酶的活性，进而塑造癌细胞的基因表达景观。
IL-6与组蛋白去乙酰化酶（HDAC）：
IL-6作为一种重要的促炎细胞因子，在慢性炎症驱动的癌症中扮演核心角色。研究表明，IL-6可以通过多种机制影响组蛋白去乙酰化酶（HDACs）的表达和活性。HDACs通过去除组蛋白上的乙酰基，使染色质结构变得紧密，从而抑制基因转录。例如，在卵巢癌细胞中，H1.0连接组蛋白通过调节HDAC5来影响IL-6的表达和紫杉醇耐药性。H1.0的沉默可提高HDAC5水平，而HDAC5过表达能显著抑制IL-6的mRNA和蛋白表达，这与H3K9Ac组蛋白乙酰化水平的降低以及NF-κB在IL-6启动子上的结合减少有关 116。这表明IL-6本身可以被HDACs调控，同时也可能反过来影响HDACs的活性，形成一个复杂的调控网络。另一个例子是，Tet2在炎症消退过程中通过招募HDAC2特异性抑制IL-6的表达 117，这提示HDACs在炎症反应的精细调控中发挥着重要作用。
此外，HDACs，特别是HDAC3，在炎症相关的癌症中发挥着关键作用。例如，在吸烟诱导的胰腺癌模型中，吸烟通过减少组蛋白乙酰化并招募巨噬细胞，刺激胰腺导管内瘤变（PanIN）的发展。这种促癌作用可被HDAC I/II抑制剂Saha所阻断。机制研究发现，IL-6的产生受到癌细胞中HDAC3核转位的调控，而IL-6又进一步刺激巨噬细胞向促肿瘤表型转化 118。这表明HDACs在炎症因子诱导的癌变过程中充当了重要的介质，通过调控炎症因子的表达和免疫细胞的极化来影响肿瘤微环境。DNA甲基转移酶（DNMT）与炎症：
DNA甲基化由DNA甲基转移酶（DNMTs）催化，主要发生在CpG二核苷酸上，通常导致基因沉默。慢性炎症，特别是幽门螺杆菌（Hp）感染，被认为是异常DNA甲基化的重要诱因。Hp感染可以通过其致病性CagA蛋白或持续诱导的慢性炎症来影响DNA甲基化 70。非编码RNA与炎症：
非编码RNA，如microRNA（miRNA）和长链非编码RNA（lncRNA），也在炎症相关的表观遗传调控中发挥重要作用。炎症因子可以改变miRNA的表达谱，进而调控靶基因。例如，肠毒素产气荚膜梭菌（ETBF）通过下调exosome封装的miR-149-3p来促进肠道炎症和恶性肿瘤 119。miR-149-3p的下调依赖于METTL14介导的N6-甲基腺苷（m6A）甲基化，这表明RNA甲基化作为一种表观遗传修饰在炎症和癌症中的作用。
2. 炎症诱导的代谢重编程
癌细胞表现出显著的代谢重编程，以满足其快速增殖、生长和存活的巨大生物能量和生物合成需求 120。炎症微环境是代谢重编程的重要驱动力，通过诱导癌细胞采取独特的代谢策略，为其恶性行为提供支持。
Warburg效应：
Warburg效应是癌细胞代谢重编程的标志性特征，指癌细胞即使在有氧条件下也倾向于通过糖酵解而非氧化磷酸化来产生能量 121。这种代谢模式虽然效率较低，但能快速产生生物合成所需的中间产物（如核苷酸、氨基酸和脂质），以支持细胞的快速增殖 120。HIF-1α在Warburg效应中扮演关键角色，即使在有氧条件下，癌细胞也能激活HIF信号，确保糖酵解的增强以合成大分子 120。炎症因子，如IL-6和TNF-α，可以促进HIF-1α的稳定和活性，从而间接增强Warburg效应。此外，丙酮酸激酶M2（PKM2）作为糖酵解途径中的关键酶，在癌细胞的代谢重编程中具有多重功能，除了其经典的糖酵解作用外，还参与免疫调节、炎症、DNA修复和mRNA加工等非糖酵解过程 122。谷氨酰胺依赖：
许多癌细胞对谷氨酰胺具有高度依赖性，将其作为碳源和氮源来合成蛋白质、核酸和脂质，并维持氧化还原平衡。炎症微环境可以通过多种机制影响谷氨酰胺代谢。例如，谷氨酰胺合成酶（GS）通过从谷氨酸合成谷氨酰胺来控制重要的细胞事件，包括炎症介质的释放和mTOR激活。抑制GS可以将M2极化巨噬细胞转向M1样表型，表现为细胞内谷氨酰胺减少，琥珀酸增加，并通过HIF1α激活增强糖酵解。这种代谢变化使得被抑制GS的巨噬细胞诱导T细胞募集能力增强，T细胞抑制潜力降低，并削弱其促进内皮细胞分支或癌细胞迁移的能力 123。这表明谷氨酰胺代谢的调控对免疫细胞功能和肿瘤进展至关重要。
在胃癌中，谷氨酰胺代谢也是治疗靶点 121。一些癌细胞，特别是在腹膜转移中，会利用谷氨酰胺作为替代能源底物 124。氧化应激与代谢：
慢性炎症往往伴随着活性氧（ROS）的产生和氧化应激。ROS不仅直接损伤DNA，还可以作为信号分子影响细胞代谢。例如，ROS可以诱导HIF-1α的稳定，从而增强糖酵解和Warburg效应。同时，癌细胞通过代谢重编程来提高其抗氧化能力，以应对高水平的ROS。
3. 表观遗传与代谢重编程的互作
表观遗传和代谢重编程并非孤立发生，而是紧密交织，形成复杂的调控网络。
- 代谢产物作为表观遗传修饰的底物或辅因子：
细胞内的代谢产物，如乙酰辅酶A（作为组蛋白乙酰化的底物）、S-腺苷甲硫氨酸（作为DNA和组蛋白甲基化的甲基供体），直接影响表观遗传酶的活性。炎症诱导的代谢重编程，特别是Warburg效应和谷氨酰胺分解代谢，改变了这些代谢产物的水平，从而直接影响表观遗传修饰。例如，细胞因子（如IL-6）可以调控HDACs和DNMTs的活性，进而影响基因表达。而这些表观遗传修饰又可以反过来调控参与代谢的基因，形成一个正反馈或负反馈环路。 - 染色质重塑影响代谢基因：
表观遗传修饰能够改变染色质结构，影响代谢相关基因的转录。例如，组蛋白甲基化转移酶EZH2的异常表达，可能会影响代谢酶的基因表达，从而重塑癌细胞的代谢特征 125。
综上所述，慢性炎症通过诱导多种表观遗传改变和代谢重编程，共同为癌细胞的生长和恶性转化创造了有利条件。炎症因子直接或间接调控表观遗传酶的活性，改变基因表达谱；而代谢重编程则为癌细胞提供能量和生物合成前体，并与表观遗传修饰紧密互作，形成一个复杂的致癌网络。深入理解这些机制有助于发现新的诊断标志物和治疗靶点，以应对慢性炎症相关的癌症。
6. 临床干预与预防策略
6.1 炎症相关癌症的一级预防
癌症的一级预防旨在通过消除或减少致癌风险因素来阻止癌症的发生。针对慢性炎症驱动的癌症，一级预防策略主要包括疫苗接种、病原体根除治疗以及健康生活方式的干预。
1. HBV疫苗接种
乙型肝炎病毒（HBV）感染是全球肝细胞癌（HCC）的主要病因之一。HBV疫苗的问世是癌症预防领域的重大突破，它是第一个被证实具有预防癌症作用的疫苗 126。世界卫生组织推荐将乙型肝炎疫苗纳入所有国家的常规婴幼儿免疫计划 127。
- 有效性与影响：HBV疫苗接种对预防HBV相关HCC具有显著效果。普遍的HBV免疫接种项目已使儿童、青少年和年轻成人中的HBV感染流行率大幅降低 127128。例如，在HBV高流行地区，如台湾，通过实施新生儿普遍免疫接种计划，HBV慢性感染的发生率显著下降，并进一步导致儿童和年轻成人HCC发病率的降低，预防HCC的有效性约为70% 126127128。HBV疫苗通过诱导针对表面抗原HBs的免疫应答，有效阻止了病毒感染，从而切断了慢性炎症向肝癌发展的路径。
- 挑战：尽管HBV疫苗效果显著，但仍需进一步努力以避免疫苗失败，并提高全球覆盖率，特别是在一些HBV高流行地区 126。此外，疫苗接种后的HBs抗体水平会随时间降低，但新生儿疫苗接种项目仍能导致年轻成人慢性HBV感染率下降 128。
2. Hp根除治疗
幽门螺杆菌（H. pylori, Hp）感染是慢性胃炎、消化性溃疡和胃癌的主要病因 129。Hp根除治疗被认为是预防胃癌的重要策略之一 130131。
- 预防胃癌的证据：基于Hp感染与胃癌的强关联性，根除Hp被视为降低胃癌风险的有效手段。多项研究表明，成功根除Hp可以显著降低胃癌的发病率 132。一项在台湾进行的随机临床试验评估了Hp筛查对胃癌发病率和死亡率的影响。结果显示，虽然仅凭邀请筛查未能显著降低胃癌发病率或死亡率，但在校正了筛查参与率和随访时间等因素后，邀请进行Hp抗原筛查并进行相应治疗与较低的胃癌发病率相关 133。这支持了Hp根除在胃癌预防中的作用，尽管其对死亡率的影响仍需进一步观察。
- 根除后胃黏膜逆转的局限性：Hp根除后，胃黏膜的炎症和萎缩可能得到改善甚至逆转，但对于已经发生肠化生或异型增生的患者，其逆转程度有限，且胃癌风险仍高于正常人群。因此，对于存在癌前病变的患者，即使Hp已根除，仍需要定期随访监测。
- 长期PPI使用的潜在风险：质子泵抑制剂（PPIs）是治疗胃食管反流病和消化性溃疡的常用药物。长期使用PPIs会导致持续性高胃泌素血症，这被认为可能增加胃神经内分泌肿瘤（g-NETs）的风险 134135。虽然有研究发现长期PPI使用与g-NETs的发生有关，但其风险相对较低，且PPI相关的g-NETs通常属于低级别、预后较好的类型（被称为“第四型”），与散发性或因其他疾病引起的高级别g-NETs不同 135136。然而，也有研究未发现长期PPI使用与g-NETs发展之间的显著关联，而是将其与胃萎缩和自身免疫性萎缩性胃炎相关联 137。鉴于此，临床上建议权衡长期PPI使用的风险与益处，并对高风险患者进行监测。
3. 戒烟限酒
吸烟和酗酒是多种癌症，包括肝癌、胰腺癌和胃癌的重要危险因素 131138139140。
- 吸烟：吸烟会增加多种癌症的风险，包括肝细胞癌 139、胃癌 131和胰腺癌 140。烟草中的致癌物质可直接损伤DNA，诱导炎症，并影响细胞的修复机制。戒烟是预防这些癌症的有效一级预防措施 138141。
- 限酒：酒精摄入，特别是过量饮酒，与酒精性肝病、肝硬化以及肝癌的发生密切相关 139。对于胰腺癌，酗酒是慢性胰腺炎的主要原因之一，进而增加胰腺癌的风险 140。减少或戒除酒精摄入对于降低相关癌症风险至关重要。
4. 健康饮食与体重管理
不良饮食习惯和肥胖是多种癌症的风险因素 138139142143。
- 地中海饮食：地中海饮食富含蔬菜、水果、全谷物、豆类、坚果和橄榄油，被认为具有抗炎和抗氧化的作用，可能有助于降低癌症风险 138。
- 避免高脂饮食：高脂饮食，尤其是西方饮食模式，与胰腺癌等多种癌症的发生发展相关 140。高脂饮食可能通过肠道菌群失调、TLR4/NF-κB通路激活以及氧化应激等机制加剧炎症反应，促进癌变。
- 体重管理：肥胖是许多癌症（如胰腺癌、子宫癌、卵巢癌、肝癌）的独立风险因素，它通过引起激素失衡、慢性炎症和氧化应激来促进癌症发展 138139142。通过均衡饮食和适度运动维持健康的体重，是预防多种癌症的重要策略。例如，肥胖是胰腺癌少数可改变的风险因素之一，持续的体重减轻可能是一种有效的预防措施 142。
- 肠道微生物群：饮食通过影响肠道微生物群的组成和功能，在癌症风险中发挥作用 143。健康饮食有助于维持健康的肠道微生物群，从而降低癌症风险。
总之，一级预防通过针对病因和可改变的风险因素，在癌症发生之前进行干预，是降低癌症负担最根本和最有效的策略。
6.2 早期筛查与精准治疗
早期筛查和精准治疗是改善慢性炎症相关癌症患者预后的关键策略。通过高敏感度和特异性的筛查手段发现早期病变，并根据分子特征选择个体化治疗方案，能够显著提高治愈率和生存期。
1. 早期筛查策略
早期诊断对于慢性炎症驱动的癌症至关重要，特别是肝癌、胃癌和胰腺癌，由于其早期症状不明显，发现时往往已处于晚期。
肝癌（HCC）：
高危人群（如乙肝/丙肝病毒感染者、肝硬化患者）的HCC筛查指南通常推荐每6个月进行一次超声检查 144。- 超声检查：腹部超声是HCC筛查的首选方法，因为它无创、经济且易于普及 144。然而，超声单独检测早期HCC的敏感性较低，仅为47%（95% CI 33%-61%）145。
- 甲胎蛋白（AFP）：AFP是常用的血清肿瘤标志物，但其敏感性和特异性有限。研究表明，将AFP与超声检查结合使用，可以显著提高早期HCC的检测敏感性。一项荟萃分析指出，超声联合AFP检测早期HCC的敏感性可达63%（95% CI 48%-75%），明显高于单独超声的45%（95% CI 30%-62%）145。尽管如此，单独使用超声的特异性高于超声联合AFP检测 145。
- CT/MRI：对于超声或AFP提示异常的患者，CT或MRI可用于进一步确诊和分期。增强CT和增强MRI在HCC诊断中具有更高的敏感性和特异性，能够发现更小的病灶 146。其中，MRI在肝脏病变检出方面具有优势，尤其是对于早期HCC 146。
- 新型生物标志物：液体活检技术，特别是基于循环游离DNA（cfDNA）的检测，显示出在HCC早期筛查中的巨大潜力。例如，一项多中心、大规模研究开发了一种基于cfDNA五个特征的筛选模型（PreCar Score），在早期/超早期HCC（巴塞罗那分期A/0）的检测中显示出显著高于超声的敏感性（PreCar Score为51.32%，超声为23.68%）。PreCar Score联合超声进一步将敏感性提高到60.53% 147。此外，甲基化cfDNA作为新兴的液体活检生物标志物，在HCC的早期检测中也具有前景 146。
胃癌（GC）：
胃癌的早期筛查主要依赖高质量的内镜检查。欧洲消化内镜学会（ESGE）、欧洲幽门螺杆菌与微生物群研究组（EHMSG）和欧洲病理学会（ESP）建议，在高危地区（年龄标准化发病率>20/10万人年）每2-3年进行一次内镜筛查，在经济效益允许的情况下，中危地区（发病率10-20/10万人年）可每5年进行一次，而低危地区（发病率<10/10万人年）不推荐常规筛查 148。- 高清内镜与靶向活检：高质量的内镜检查，结合虚拟染色内镜（VCE）等图像增强技术，能够更好地识别胃黏膜萎缩、肠化生和异型增生等癌前病变以及早期胃癌病灶 148。内镜医师应在VCE引导下对可疑病灶进行靶向活检，并在内镜下未见明显病变时进行随机活检 148。建议从至少两个解剖部位（胃窦/胃角和胃体）采集活检样本，并分别标记，以进行准确的组织学分期 148。对于可疑的早期胃部肿瘤病变，应详细描述其位置、大小、巴黎分型和血管/黏膜模式，并进行光照记录和两次靶向活检 148。
- Hp根除后的随访：对于已进行Hp根除治疗的胃癌前病变患者，仍需定期内镜监测。美国胃肠病学会（AGA）建议，对于患有严重的萎缩性胃炎和/或多灶性或不完全性GIM的个体，特别是伴有其他GC危险因素（如家族史）的，应每3年考虑一次内镜监测 149。
胰腺癌（PDAC）：
胰腺癌的早期诊断极具挑战性，因为其早期症状不明显，且缺乏有效的筛查标志物。目前，胰腺癌的筛查主要针对高危人群，如具有家族史或遗传综合征的个体 150。- CA19-9联合MRI/EUS：糖类抗原19-9（CA19-9）是目前临床上最常用的胰腺癌血清标志物，但其敏感性和特异性不足以用于早期筛查，主要用于监测治疗效果和疾病复发 151。在对高危人群进行筛查时，通常联合MRI和内镜超声（EUS）150152。
- DNA甲基化标志物：2024年的研究进展表明，DNA甲基化标志物在区分慢性胰腺炎和胰腺癌方面具有应用潜力。例如，PKCβ基因CpG岛的甲基化状态可能成为鉴别慢性胰腺炎和胰腺癌的生物标志物，有助于提高早期诊断的准确性。这为胰腺癌的早期诊断提供了新的方向。磁共振弹性成像（MRE）也被证明在鉴别胰腺导管腺癌与其他胰腺实体肿块方面具有良好潜力，通过测量肿瘤硬度，对PDAC的诊断具有较高的诊断性能，AUC可达0.7895，与CA19-9联合可进一步提高诊断性能 153。
2. 精准治疗
精准治疗通过识别肿瘤特异性分子靶点或免疫特征，选择最适合患者的个体化治疗方案，以提高疗效并减少毒副作用。
免疫检查点抑制剂：
免疫检查点抑制剂（ICIs）通过解除肿瘤对免疫系统的抑制，激活T细胞对肿瘤的杀伤作用，已在多种癌症治疗中取得突破。- 肝细胞癌（HCC）：对于不可切除的HCC，双重程序性细胞死亡-1（PD-1）和血管内皮生长因子（VEGF）通路抑制已成为新的标准治疗方案 154。
- Sintilimab联合贝伐珠单抗（IBI-305）：信迪利单抗（一种PD-1抑制剂）联合贝伐珠单抗生物类似药（抗VEGF单抗IBI-305）的组合疗法在不可切除HCC的一线治疗中显示出前景 154155。有研究显示，信迪利单抗联合贝伐珠单抗生物类似药和传统经动脉化疗栓塞（c-TACE）治疗不可切除HCC患者，即便出现免疫相关不良事件（如吉兰-巴雷综合征），仍可能通过替代PD-1抑制剂进行免疫检查点抑制剂再挑战，并取得良好疗效，甚至实现病理学上的主要缓解，最终成功进行转化手术 156。
- 阿替利珠单抗（Atezolizumab）联合贝伐珠单抗（Bevacizumab）：阿替利珠单抗（抗PD-L1）联合贝伐珠单抗（抗VEGF）是HCC一线治疗的另一种重要组合，已显著改善患者的总生存期和无进展生存期 154。网络荟萃分析显示，阿替利珠单抗联合贝伐珠单抗相比索拉非尼、乐伐替尼等传统靶向药物，显著降低了死亡风险 154。
- 其他组合：特瑞普利单抗联合度伐利尤单抗（Tremelimumab plus Durvalumab, STRIDE方案）也是HCC治疗的重要进展 154。卡瑞利珠单抗（Camrelizumab）联合阿帕替尼（Rivoceranib）在不可切除HCC的一线治疗中，在中国患者中显示出更具成本效益的潜力 157。
- 肝细胞癌（HCC）：对于不可切除的HCC，双重程序性细胞死亡-1（PD-1）和血管内皮生长因子（VEGF）通路抑制已成为新的标准治疗方案 154。
靶向成纤维细胞亚型：
肿瘤微环境中的基质细胞，特别是癌相关成纤维细胞（CAFs），在癌症进展和免疫抑制中发挥关键作用。- LRRC15+肌成纤维细胞：单细胞RNA测序研究揭示了胰腺导管腺癌（PDAC）肿瘤微环境中存在一类独特的癌相关成纤维细胞，表达富含亮氨酸重复序列的蛋白15（LRRC15）。这些LRRC15+ CAFs受TGF-β编程，围绕在肿瘤岛周围，在正常胰腺组织中不存在 158。在PDAC中，LRRC15+ CAFs的存在与对免疫检查点抑制剂治疗的应答不佳相关 158。这表明LRRC15+ CAFs通过在肿瘤微环境中形成免疫抑制微环境，可能阻碍T细胞的抗肿瘤活性。
- 临床意义：靶向LRRC15+ CAFs有望增强癌症免疫疗法的效果 158159。阻断或消除这些促肿瘤成纤维细胞，可以改善T细胞浸润和功能，逆转肿瘤免疫抑制，从而提高免疫检查点抑制剂的疗效。这为开发新的联合治疗策略提供了靶点，通过同时靶向肿瘤细胞和肿瘤微环境中的关键组分，实现更有效的抗癌作用。
综上所述，早期筛查和精准治疗策略是应对慢性炎症相关癌症的关键。通过结合传统影像学、血清标志物和新型液体活检技术进行早期诊断，并利用免疫检查点抑制剂和靶向肿瘤微环境等创新疗法进行个体化治疗，有望显著改善患者的预后。
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参考文献
1Artificial intelligence-guided discovery of gastric cancer continuum.PubMed
Daniella Vo, Pradipta Ghosh, Debashis Sahoo
Gastric Cancer. 2023 Mar;26(2):286-297. doi: 10.1007/s10120-022-01360-3. Epub 2023 Jan 24.
BACKGROUND: Detailed understanding of pre-, early and late neoplastic states in gastric cancer helps develop better models of risk of progression to gastric cancers (GCs) and medical treatment to intercept such progression. METHODS: We built a Boolean implication network of gastric cancer and deployed machine learning algorithms to develop predictive models of known pre-neoplastic states, e.g., atrophic gastritis, intestinal metaplasia (IM) and low- to high-grade intestinal neoplasia (L/HGIN), and GC. Our approach exploits the presence of asymmetric Boolean implication relationships that are likely to be invariant across almost all gastric cancer datasets. Invariant asymmetric Boolean implication relationships can decipher fundamental time-series underlying the biological data. Pursuing this method, we developed a healthy mucosa → GC continuum model based on this approach. RESULTS: Our model performed better against publicly available models for distinguishing healthy versus GC samples. Although not trained on IM and L/HGIN datasets, the model could identify the risk of progression to GC via the metaplasia → dysplasia → neoplasia cascade in patient samples. The model could rank all publicly available mouse models for their ability to best recapitulate the gene expression patterns during human GC initiation and progression. CONCLUSIONS: A Boolean implication network enabled the identification of hitherto undefined continuum states during GC initiation. The developed model could now serve as a starting point for rationalizing candidate therapeutic targets to intercept GC progression.
2ROLE OF INCISURA ANGULARIS BIOPSY IN GASTRITIS STAGING AND RISK ASSESSMENT OF GASTRIC CÂNCER.PubMed
Fangio Ferrari, Daniel Cury Ogata, Celso Abdon Lopes de Mello
Arq Gastroenterol. 2023 Oct-Dec;60(4):478-489. doi: 10.1590/S0004-2803.23042023-120.
BACKGROUND: Gastric atrophy (GA) and intestinal metaplasia (IM) are early stages in the development of gastric cancer. Evaluations are based on the Updated Sydney System, which includes a biopsy of the incisura angularis (IA), and the Operative Link on Gastritis Assessment (OLGA) and Operative Link on Gastritis Assessment using Intestinal Metaplasia (OLGIM) gastric cancer risk staging systems. OBJECTIVE: To compare the OLGA and OLGIM classifications with and without IA biopsy. In addition, to determine the prevalence of Helicobacter pylori (HP) and pre-neoplastic changes (GA and IM) in different biopsied regions and to identify the exclusive findings of IA. METHODS: Observational, prospective, descriptive, unicentric study with 350 patients without a diagnosis of gastric cancer, who underwent upper digestive endoscopy with biopsies at Gastroclínica Itajaí, from March 2020 to May 2022. The histopathological classification of gastritis followed the Updated Sydney System, and the gastric cancer risk assessment followed the OLGA and OLGIM systems. The methodology applied evaluated the scores of the OLGA and OLGIM systems with and without the assessment of the IA biopsy. Statistical analysis was performed using descriptive measures (frequencies, percentages, mean, standard deviation, 95% confidence interval). Ranks were compared using the Kruskal-Wallis or Wilcoxon tests. To analyze the relationship between the frequencies, the bilateral Fisher’s exact test was used. Wilson’s score with continuity correction was applied to the confidence interval. RESULTS: The median age was 54.7 years, with 52.57% female and 47.43% male patients. The comparison between the used biopsies protocol (corpus + antrum [CA] vs corpus + antrum + incisura angularis [CAI]) and the OLGA and OLGIM stages showed a significant decrease in both staging systems when the biopsy protocol restricted to the corpus and antrum was applied (OLGA CAI vs CA; P=0.008 / OLGIM CAI vs CA; P=0.002). The prevalence of pre-malignant lesions (GA, IM and dysplasia) of the gastric mucosa was (33.4%, 34% and 1.1%, respectively) in the total sample. The antrum region exhibited significantly higher numbers of alteration (P<0.001), except for HP infection, which was present in 24.8% of the patients. CONCLUSION: Incisura angularis biopsy is important because it increased the number of cases diagnosed in more advanced stages of intestinal metaplasia and atrophy. The study had limitations, with the main one being the relatively small sample size, consisting mostly of healthy individuals, although mostly elderly.
3Is there any association between colonic polyps and gastric intestinal metaplasia?PubMed
Gülhan Kanat Ünler, Gülsüm Teke Özgür, Hüseyin Savaş Göktürk, et al.
Turk J Gastroenterol. 2016 May;27(3):221-6. doi: 10.5152/tjg.2016.15212.
BACKGROUND/AIMS: Chronic gastritis progression is a multistep process of atrophy, intestinal metaplasia (IM), and dysplasia, which may lead to invasive carcinoma. In this study, we identified an association of colonic polyps with gastric IM in patients undergoing colonoscopy. MATERIALS AND METHODS: This retrospective case-control, cross-sectional study was conducted in a tertiary-care institution in Turkey. Pathology and endoscopy reports were reviewed. The study group comprised 400 patients with colonic adenomatous polyps, and the control group comprised 360 patients without colonic adenomatous polyps on colonoscopy. RESULTS: The risk of gastric IM was 1.42-fold higher in the study group (p<0.05). The risk of IM in patients aged ≥50 years with colonic polyps was 3.35-fold higher than in those aged <50 years (p<0.05). The risk of Helicobacter pylori infection in the study group was 1.07-folder higher than that in the control group (p<0.05). H. pylori infection prevalence was higher only in patients with high-grade colonic polyp dysplasia (p<0.05). There were no statistically significant differences in the proportion of incomplete IM between the groups (p<0.05). CONCLUSION: This study observed increased rates of gastric IM with colonic polyps. An increased risk of gastric IM was associated with higher grades of polyp dysplasia.
4p53 polymorphism and p21WAF1/CIP1 haplotype in the intestinal gastric cancer and the precancerous lesions.PubMed
Ya-Guang Xi, Ke-Yue Ding, Xiu-Lan Su, et al.
Carcinogenesis. 2004 Nov;25(11):2201-6. doi: 10.1093/carcin/bgh229. Epub 2004 Jul 7.
The development of intestinal gastric carcinoma involves several precancerous stages. The environmental factor plays an important role in gastric carcinogenesis, while the host's genetic makeup may influence the susceptibility to cancer. In this study we investigated correlations of the p53 variations at codon 72 and p21(WAF1/CIP1) haplotype with the risk of intestinal gastric carcinoma. Forty-eight intestinal gastric carcinoma cases (GC), 96 chronic atrophic gastritis (CAG), 96 intestinal metaplasia (IM) and 96 dysplasia (DYS) controls were enrolled in this study. The p53 codon 72 proline allele carriers were found to be more susceptible to progress to GC than to IM (OR = 2.22, 95%CI = 1.05-4.70, P = 0.038). Patients carrying homozygous p21(WAF1/CIP1) haplotype A, which contains the serine at codon 31, the cytidine at the 16th base of the second intron, and the cytidine at the 70th base of the exon 3 were more prone to develop GC than to reach the IM or DYS stage (IM versus GC, OR = 3.35, 95%CI = 1.11-10.15; DYS versus GC, OR = 3.27, 95%CI = 1.09-9.80, P = 0.035). The combination of p53 codon 72 variation with the p21(WAF1/CIP1) haplotype further distinguished the risk of GC from IM precancerous lesion (OR = 9.31, 95% CI = 1.77-48.85, P = 0.08). These results suggest that p53 and/or p21(WAF1/CIP1) genotype may influence the progression during gastric tumorigenesis.
5Dicarbonyl Electrophiles Mediate Inflammation-Induced Gastrointestinal Carcinogenesis.PubMed
Alain P Gobert, Olivier Boutaud, Mohammad Asim, et al.
Gastroenterology. 2021 Mar;160(4):1256-1268.e9. doi: 10.1053/j.gastro.2020.11.006. Epub 2020 Nov 13.
BACKGROUND & AIMS: Inflammation in the gastrointestinal tract may lead to the development of cancer. Dicarbonyl electrophiles, such as isolevuglandins (isoLGs), are generated from lipid peroxidation during the inflammatory response and form covalent adducts with amine-containing macromolecules. Thus, we sought to determine the role of dicarbonyl electrophiles in inflammation-associated carcinogenesis. METHODS: The formation of isoLG adducts was analyzed in the gastric tissues of patients infected with Helicobacter pylori from gastritis to precancerous intestinal metaplasia, in human gastric organoids, and in patients with colitis and colitis-associated carcinoma (CAC). The effect on cancer development of a potent scavenger of dicarbonyl electrophiles, 5-ethyl-2-hydroxybenzylamine (EtHOBA), was determined in transgenic FVB/N insulin-gastrin (INS-GAS) mice and Mongolian gerbils as models of H pylori-induced carcinogenesis and in C57BL/6 mice treated with azoxymethane-dextran sulfate sodium as a model of CAC. The effect of EtHOBA on mutations in gastric epithelial cells of H pylori-infected INS-GAS mice was assessed by whole-exome sequencing. RESULTS: We show increased isoLG adducts in gastric epithelial cell nuclei in patients with gastritis and intestinal metaplasia and in human gastric organoids infected with H pylori. EtHOBA inhibited gastric carcinoma in infected INS-GAS mice and gerbils and attenuated isoLG adducts, DNA damage, and somatic mutation frequency. Additionally, isoLG adducts were elevated in tissues from patients with colitis, colitis-associated dysplasia, and CAC as well as in dysplastic tumors of C57BL/6 mice treated with azoxymethane-dextran sulfate sodium. In this model, EtHOBA significantly reduced adduct formation, tumorigenesis, and dysplasia severity. CONCLUSIONS: Dicarbonyl electrophiles represent a link between inflammation and somatic genomic alterations and are thus key targets for cancer chemoprevention.
6Cellular Senescence: Aging, Cancer, and Injury.PubMed
Arianna Calcinotto, Jaskaren Kohli, Elena Zagato, et al.
Physiol Rev. 2019 Apr 1;99(2):1047-1078. doi: 10.1152/physrev.00020.2018.
Cellular senescence is a permanent state of cell cycle arrest that occurs in proliferating cells subjected to different stresses. Senescence is, therefore, a cellular defense mechanism that prevents the cells to acquire an unnecessary damage. The senescent state is accompanied by a failure to re-enter the cell cycle in response to mitogenic stimuli, an enhanced secretory phenotype and resistance to cell death. Senescence takes place in several tissues during different physiological and pathological processes such as tissue remodeling, injury, cancer, and aging. Although senescence is one of the causative processes of aging and it is responsible of aging-related disorders, senescent cells can also play a positive role. In embryogenesis and tissue remodeling, senescent cells are required for the proper development of the embryo and tissue repair. In cancer, senescence works as a potent barrier to prevent tumorigenesis. Therefore, the identification and characterization of key features of senescence, the induction of senescence in cancer cells, or the elimination of senescent cells by pharmacological interventions in aging tissues is gaining consideration in several fields of research. Here, we describe the known key features of senescence, the cell-autonomous, and noncell-autonomous regulators of senescence, and we attempt to discuss the functional role of this fundamental process in different contexts in light of the development of novel therapeutic targets.
7The ECM path of senescence in aging: components and modifiers.PubMed
Naama Levi, Nurit Papismadov, Inna Solomonov, et al.
FEBS J. 2020 Jul;287(13):2636-2646. doi: 10.1111/febs.15282. Epub 2020 Mar 20.
The extracellular matrix (ECM) is a key noncellular component in all organs and tissues. It is composed of a large number of proteins including collagens, glycoproteins (GP), and ECM-associated proteins, which show diversity of biochemical and biophysical functions. The ECM is dynamic both in normal physiology of tissues and under pathological conditions. One cellular phenomenon associated with changes in both ECM components expression and in ECM remodeling enzymes secretion is cellular senescence. It represents a stable state form of cell cycle arrest induced in proliferating cells by various forms of stress. Short-term induction of senescence is essential for tumor suppression and tissue repair. However, long-term presence of senescent cells in tissues may have a detrimental role in promoting tissue damage and aging. Up to date, there is insufficient knowledge about the interplay between the ECM and senescence cells. Since changes in the ECM occur in many physiological and pathological conditions in which senescent cells are present, a better understanding of ECM-senescence interactions is necessary. Here, we will review the functions of the different ECM components and will discuss the current knowledge about their regulation in senescent cells and their influence on the senescence state.
8Widespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosis.PubMed
Sriram Vijayraghavan, Thomas Blouin, James McCollum, et al.
Nat Commun. 2024 Oct 15;15(1):8889. doi: 10.1038/s41467-024-53332-z.
Systemic sclerosis is a connective tissue disorder characterized by excessive fibrosis that primarily affects women, and can present as a multisystem pathology. Roughly 4-22% of patients with systemic sclerosis develop cancer, which drastically worsens prognosis. However, the mechanisms underlying systemic sclerosis initiation, propagation, and cancer development are poorly understood. We hypothesize that the inflammation and immune response associated with systemic sclerosis can trigger DNA damage, leading to elevated somatic mutagenesis, a hallmark of pre-cancerous tissues. To test our hypothesis, we culture clonal lineages of fibroblasts from the lung tissues of controls and systemic sclerosis patients and compare their mutation burdens and spectra. We find an overall increase in all major mutation types in systemic sclerosis samples compared to control lung samples, from small-scale events such as single base substitutions and insertions/deletions, to chromosome-level changes, including copy-number changes and structural variants. In the genomes of patients with systemic sclerosis, we find evidence of somatic hypermutation or kategis (typically only seen in cancer genomes), we identify mutation signatures closely resembling the error-prone translesion polymerase Polη activity, and observe an activation-induced deaminase-like mutation signature, which overlaps with genomic regions displaying kataegis.
9Intratumoural microbiota: a new frontier in cancer development and therapy.PubMed
Yaqi Cao, Hui Xia, Xueyun Tan, et al.
Signal Transduct Target Ther. 2024 Jan 10;9(1):15. doi: 10.1038/s41392-023-01693-0.
Human microorganisms, including bacteria, fungi, and viruses, play key roles in several physiological and pathological processes. Some studies discovered that tumour tissues once considered sterile actually host a variety of microorganisms, which have been confirmed to be closely related to oncogenesis. The concept of intratumoural microbiota was subsequently proposed. Microbiota could colonise tumour tissues through mucosal destruction, adjacent tissue migration, and hematogenic invasion and affect the biological behaviour of tumours as an important part of the tumour microenvironment. Mechanistic studies have demonstrated that intratumoural microbiota potentially promote the initiation and progression of tumours by inducing genomic instability and mutations, affecting epigenetic modifications, promoting inflammation response, avoiding immune destruction, regulating metabolism, and activating invasion and metastasis. Since more comprehensive and profound insights about intratumoral microbiota are continuously emerging, new methods for the early diagnosis and prognostic assessment of cancer patients have been under examination. In addition, interventions based on intratumoural microbiota show great potential to open a new chapter in antitumour therapy, especially immunotherapy, although there are some inevitable challenges. Here, we aim to provide an extensive review of the concept, development history, potential sources, heterogeneity, and carcinogenic mechanisms of intratumoural microorganisms, explore the potential role of microorganisms in tumour prognosis, and discuss current antitumour treatment regimens that target intratumoural microorganisms and the research prospects and limitations in this field.
10DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons.PubMed
Therese Wilhelm, Maha Said, Valeria Naim
Genes (Basel). 2020 Jun 10;11(6):642. doi: 10.3390/genes11060642.
Chromosomal instability (CIN) is associated with many human diseases, including neurodevelopmental or neurodegenerative conditions, age-related disorders and cancer, and is a key driver for disease initiation and progression. A major source of structural chromosome instability (s-CIN) leading to structural chromosome aberrations is "replication stress", a condition in which stalled or slowly progressing replication forks interfere with timely and error-free completion of the S phase. On the other hand, mitotic errors that result in chromosome mis-segregation are the cause of numerical chromosome instability (n-CIN) and aneuploidy. In this review, we will discuss recent evidence showing that these two forms of chromosomal instability can be mechanistically interlinked. We first summarize how replication stress causes structural and numerical CIN, focusing on mechanisms such as mitotic rescue of replication stress (MRRS) and centriole disengagement, which prevent or contribute to specific types of structural chromosome aberrations and segregation errors. We describe the main outcomes of segregation errors and how micronucleation and aneuploidy can be the key stimuli promoting inflammation, senescence, or chromothripsis. At the end, we discuss how CIN can reduce cellular fitness and may behave as an anticancer barrier in noncancerous cells or precancerous lesions, whereas it fuels genomic instability in the context of cancer, and how our current knowledge may be exploited for developing cancer therapies.
11Plasticity of differentiated cells in wound repair and tumorigenesis, part I: stomach and pancreas.PubMed
Joseph Burclaff, Jason C Mills
Dis Model Mech. 2018 Jul 23;11(7):dmm033373. doi: 10.1242/dmm.033373.
For the last century or so, the mature, differentiated cells throughout the body have been regarded as largely inert with respect to their regenerative potential, yet recent research shows that they can become progenitor-like and re-enter the cell cycle. Indeed, we recently proposed that mature cells can become regenerative via a conserved set of molecular mechanisms ('paligenosis'), suggesting that a program for regeneration exists alongside programs for death (apoptosis) and division (mitosis). In two Reviews describing how emerging concepts of cellular plasticity are changing how the field views regeneration and tumorigenesis, we present the commonalities in the molecular and cellular features of plasticity at homeostasis and in response to injury in multiple organs. Here, in part 1, we discuss these advances in the stomach and pancreas. Understanding the extent of cell plasticity and uncovering its underlying mechanisms may help us refine important theories about the origin and progression of cancer, such as the cancer stem cell model, as well as the multi-hit model of tumorigenesis. Ultimately, we hope that the new concepts and perspectives on inherent cellular programs for regeneration and plasticity may open novel avenues for treating or preventing cancers.
12Plasticity of differentiated cells in wound repair and tumorigenesis, part II: skin and intestine.PubMed
Joseph Burclaff, Jason C Mills
Dis Model Mech. 2018 Aug 31;11(9):dmm035071. doi: 10.1242/dmm.035071.
Recent studies have identified and begun to characterize the roles of regenerative cellular plasticity in many organs. In Part I of our two-part Review, we discussed how cells reprogram following injury to the stomach and pancreas. We introduced the concept of a conserved cellular program, much like those governing division and death, which may allow mature cells to become regenerative. This program, paligenosis, is likely necessary to help organs repair the numerous injuries they face over the lifetime of an organism; however, we also postulated that rounds of paligenosis and redifferentiation may allow long-lived cells to accumulate and store oncogenic mutations, and could thereby contribute to tumorigenesis. We have termed the model wherein differentiated cells can store mutations and then unmask them upon cell cycle re-entry the 'cyclical hit' model of tumorigenesis. In the present Review (Part II), we discuss these concepts, and cell plasticity as a whole, in the skin and intestine. Although differentiation and repair are arguably more thoroughly studied in skin and intestine than in stomach and pancreas, it is less clear how mature skin and intestinal cells contribute to tumorigenesis. Moreover, we conclude our Review by discussing plasticity in all four organs, and look for conserved mechanisms and concepts that might help advance our knowledge of tumor formation and advance the development of therapies for treating or preventing cancers that might be shared across multiple organs.
13Decoding the spatiotemporal heterogeneity of tumor-associated macrophages.PubMed
Xiangyuan Chu, Yu Tian, Chao Lv
Mol Cancer. 2024 Jul 27;23(1):150. doi: 10.1186/s12943-024-02064-1.
Tumor-associated macrophages (TAMs) are pivotal in cancer progression, influencing tumor growth, angiogenesis, and immune evasion. This review explores the spatial and temporal heterogeneity of TAMs within the tumor microenvironment (TME), highlighting their diverse subtypes, origins, and functions. Advanced technologies such as single-cell sequencing and spatial multi-omics have elucidated the intricate interactions between TAMs and other TME components, revealing the mechanisms behind their recruitment, polarization, and distribution. Key findings demonstrate that TAMs support tumor vascularization, promote epithelial-mesenchymal transition (EMT), and modulate extracellular matrix (ECM) remodeling, etc., thereby enhancing tumor invasiveness and metastasis. Understanding these complex dynamics offers new therapeutic targets for disrupting TAM-mediated pathways and overcoming drug resistance. This review underscores the potential of targeting TAMs to develop innovative cancer therapies, emphasizing the need for further research into their spatial characteristics and functional roles within the TME.
14Macrophage Polarization States in the Tumor Microenvironment.PubMed
Ava J Boutilier, Sherine F Elsawa
Int J Mol Sci. 2021 Jun 29;22(13):6995. doi: 10.3390/ijms22136995.
The M1/M2 macrophage paradigm plays a key role in tumor progression. M1 macrophages are historically regarded as anti-tumor, while M2-polarized macrophages, commonly deemed tumor-associated macrophages (TAMs), are contributors to many pro-tumorigenic outcomes in cancer through angiogenic and lymphangiogenic regulation, immune suppression, hypoxia induction, tumor cell proliferation, and metastasis. The tumor microenvironment (TME) can influence macrophage recruitment and polarization, giving way to these pro-tumorigenic outcomes. Investigating TME-induced macrophage polarization is critical for further understanding of TAM-related pro-tumor outcomes and potential development of new therapeutic approaches. This review explores the current understanding of TME-induced macrophage polarization and the role of M2-polarized macrophages in promoting tumor progression.
15Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells.PubMed
María Casanova-Acebes, Erica Dalla, Andrew M Leader, et al.
Nature. 2021 Jul;595(7868):578-584. doi: 10.1038/s41586-021-03651-8. Epub 2021 Jun 16.
Macrophages have a key role in shaping the tumour microenvironment (TME), tumour immunity and response to immunotherapy, which makes them an important target for cancer treatment. However, modulating macrophages has proved extremely difficult, as we still lack a complete understanding of the molecular and functional diversity of the tumour macrophage compartment. Macrophages arise from two distinct lineages. Tissue-resident macrophages self-renew locally, independent of adult haematopoiesis, whereas short-lived monocyte-derived macrophages arise from adult haematopoietic stem cells, and accumulate mostly in inflamed lesions. How these macrophage lineages contribute to the TME and cancer progression remains unclear. To explore the diversity of the macrophage compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we performed single-cell RNA sequencing of tumour-associated leukocytes. We identified distinct populations of macrophages that were enriched in human and mouse lung tumours. Using lineage tracing, we discovered that these macrophage populations differ in origin and have a distinct temporal and spatial distribution in the TME. Tissue-resident macrophages accumulate close to tumour cells early during tumour formation to promote epithelial-mesenchymal transition and invasiveness in tumour cells, and they also induce a potent regulatory T cell response that protects tumour cells from adaptive immunity. Depletion of tissue-resident macrophages reduced the numbers and altered the phenotype of regulatory T cells, promoted the accumulation of CD8 T cells and reduced tumour invasiveness and growth. During tumour growth, tissue-resident macrophages became redistributed at the periphery of the TME, which becomes dominated by monocyte-derived macrophages in both mouse and human NSCLC. This study identifies the contribution of tissue-resident macrophages to early lung cancer and establishes them as a target for the prevention and treatment of early lung cancer lesions.
16IL-1β macrophages fuel pathogenic inflammation in pancreatic cancer.PubMed
Nicoletta Caronni, Federica La Terza, Francesco M Vittoria, et al.
Nature. 2023 Nov;623(7986):415-422. doi: 10.1038/s41586-023-06685-2. Epub 2023 Nov 1.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with high resistance to therapies. Inflammatory and immunomodulatory signals co-exist in the pancreatic tumour microenvironment, leading to dysregulated repair and cytotoxic responses. Tumour-associated macrophages (TAMs) have key roles in PDAC, but their diversity has prevented therapeutic exploitation. Here we combined single-cell and spatial genomics with functional experiments to unravel macrophage functions in pancreatic cancer. We uncovered an inflammatory loop between tumour cells and interleukin-1β (IL-1β)-expressing TAMs, a subset of macrophages elicited by a local synergy between prostaglandin E (PGE) and tumour necrosis factor (TNF). Physical proximity with IL-1β TAMs was associated with inflammatory reprogramming and acquisition of pathogenic properties by a subset of PDAC cells. This occurrence was an early event in pancreatic tumorigenesis and led to persistent transcriptional changes associated with disease progression and poor outcomes for patients. Blocking PGE or IL-1β activity elicited TAM reprogramming and antagonized tumour cell-intrinsic and -extrinsic inflammation, leading to PDAC control in vivo. Targeting the PGE-IL-1β axis may enable preventive or therapeutic strategies for reprogramming of immune dynamics in pancreatic cancer.
17TGF-β1 dominates stromal fibroblast-mediated EMT via the FAP/VCAN axis in bladder cancer cells.PubMed
Qinrong Ping, Chunhui Wang, Xin Cheng, et al.
J Transl Med. 2023 Jul 17;21(1):475. doi: 10.1186/s12967-023-04303-3.
BACKGROUND: Bladder cancer is one of the most common malignant tumors of the urinary system and is associated with a poor prognosis once invasion and distant metastases occur. Epithelial-mesenchymal transition (EMT) drives metastasis and invasion in bladder cancer. Transforming growth factor β1 (TGF-β1) and stromal fibroblasts, especially cancer-associated fibroblasts (CAFs), are positive regulators of EMT in bladder cancer. However, it remains unclear how TGF-β1 mediates crosstalk between bladder cancer cells and CAFs and how it induces stromal fibroblast-mediated EMT in bladder cancer. We aimed to investigate the mechanism of TGF-β1 regulation of stromal fibroblast-mediated EMT in bladder cancer cells. METHODS: Primary CAFs with high expression of fibroblast activation protein (FAP) were isolated from bladder cancer tissue samples. Subsequently, different conditioned media were used to stimulate the bladder cancer cell line T24 in a co-culture system. Gene set enrichment analysis, a human cytokine antibody array, and cytological assays were performed to investigate the mechanism of TGF-β1 regulation of stromal fibroblast-mediated EMT in bladder cancer cells. RESULTS: Among the TGF-β family, TGF-β1 was the most highly expressed factor in bladder cancer tissue and primary stromal fibroblast supernatant. In the tumor microenvironment, TGF-β1 was mainly derived from stromal fibroblasts, especially CAFs. In stimulated bladder cells, stromal fibroblast-derived TGF-β1 promoted bladder cancer cell migration, invasion, and EMT. Furthermore, TGF-β1 promoted the activation of stromal fibroblasts, inducing CAF-like features, by upregulating FAP in primary normal fibroblasts and a normal fibroblast cell line. Stromal fibroblast-mediated EMT was induced in bladder cancer cells by TGF-β1/FAP. Versican (VCAN), a downstream molecule of FAP, plays an essential role in TGF-β1/FAP axis-induced EMT in bladder cancer cells. VCAN may also function through the PI3K/AKT1 signaling pathway. CONCLUSIONS: TGF-β1 is a critical mediator of crosstalk between stromal fibroblasts and bladder cancer cells. We revealed a new mechanism whereby TGF-β1 dominated stromal fibroblast-mediated EMT of bladder cancer cells via the FAP/VCAN axis and identified potential biomarkers (FAP, VCAN, N-cadherin, and Vimentin) of bladder cancer. These results enhance our understanding of bladder cancer invasion and metastasis and provide potential strategies for diagnosis, treatment, and prognosis.
18Targeting TGF-β signal transduction for fibrosis and cancer therapy.PubMed
Dandan Peng, Minyang Fu, Manni Wang, et al.
Mol Cancer. 2022 Apr 23;21(1):104. doi: 10.1186/s12943-022-01569-x.
Transforming growth factor β (TGF-β) has long been identified with its intensive involvement in early embryonic development and organogenesis, immune supervision, tissue repair, and adult homeostasis. The role of TGF-β in fibrosis and cancer is complex and sometimes even contradictory, exhibiting either inhibitory or promoting effects depending on the stage of the disease. Under pathological conditions, overexpressed TGF-β causes epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) deposition, cancer-associated fibroblast (CAF) formation, which leads to fibrotic disease, and cancer. Given the critical role of TGF-β and its downstream molecules in the progression of fibrosis and cancers, therapeutics targeting TGF-β signaling appears to be a promising strategy. However, due to potential systemic cytotoxicity, the development of TGF-β therapeutics has lagged. In this review, we summarized the biological process of TGF-β, with its dual role in fibrosis and tumorigenesis, and the clinical application of TGF-β-targeting therapies.
19Alternative splicing in EMT and TGF-β signaling during cancer progression.PubMed
Ying E Zhang, Christina H Stuelten
Semin Cancer Biol. 2024 Jun;101:1-11. doi: 10.1016/j.semcancer.2024.04.001. Epub 2024 Apr 15.
Epithelial to mesenchymal transition (EMT) is a physiological process during development where epithelial cells transform to acquire mesenchymal characteristics, which allows them to migrate and colonize secondary tissues. Many cellular signaling pathways and master transcriptional factors exert a myriad of controls to fine tune this vital process to meet various developmental and physiological needs. Adding to the complexity of this network are post-transcriptional and post-translational regulations. Among them, alternative splicing has been shown to play important roles to drive EMT-associated phenotypic changes, including actin cytoskeleton remodeling, cell-cell junction changes, cell motility and invasiveness. In advanced cancers, transforming growth factor-β (TGF-β) is a major inducer of EMT and is associated with tumor cell metastasis, cancer stem cell self-renewal, and drug resistance. This review aims to provide an overview of recent discoveries regarding alternative splicing events and the involvement of splicing factors in the EMT and TGF-β signaling. It will emphasize the importance of various splicing factors involved in EMT and explore their regulatory mechanisms.
20Developing Topics.PubMed
Chanikarn Sonpee, Chanida Ruchisrisarod, Watayuth Luechaipanit, et al.
Alzheimers Dement. 2025 Dec;21 Suppl 7:e108283. doi: 10.1002/alz70861_108283.
BACKGROUND: Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and behavioral impairment. A central hallmark of AD pathology is the abnormal accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles, accompanied by a sustained neuroinflammatory response. Emerging evidence suggests that inflammatory mediators, both central and peripheral, play a significant role in the pathogenesis and progression of AD, particularly neuroinflammatory cytokines, which influence Aβ production, aggregation, and clearance. METHODS: This study aimed to explore the association between systemic inflammatory cytokines and circulating Aβ levels in the peripheral blood of AD patients. Serum levels of pro-inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), were measured in AD patients and compared with age-matched healthy controls. Additionally, plasma Aβ₄₂ levels and the Aβ₄₂/Aβ₄₀ ratio were assessed to investigate amyloid metabolism in the periphery. Correlation analysis was performed to examine the relationship between cytokine levels and Aβ concentrations. RESULTS: AD patients exhibited significantly elevated serum levels of IL-1β, TNF-α, and IL-6, with IL-6 showing the most pronounced increase. Plasma Aβ₄₂ levels and the Aβ₄₂/Aβ₄₀ ratio were also significantly higher in AD patients, indicating altered amyloid metabolism in the peripheral circulation. A strong positive correlation was observed between IL-6 levels and plasma Aβ₄₂ concentrations (r = 0.72, p < 0.01), suggesting that systemic inflammation may contribute to amyloid dysregulation in AD. CONCLUSION: These findings support the potential use of blood-based biomarkers for the early detection and monitoring of AD. The study highlights the significance of targeting neuroinflammatory pathways as a potential therapeutic strategy to mitigate Aβ accumulation and slow disease progression. A deeper understanding of the molecular interactions between inflammatory cytokines and Aβ could open new therapeutic avenues for AD intervention.
21The relationship between circulating testosterone and inflammatory cytokines in men.PubMed
Nur-Vaizura Mohamad, Sok Kuan Wong, Wan Nuraini Wan Hasan, et al.
Aging Male. 2019 Jun;22(2):129-140. doi: 10.1080/13685538.2018.1482487. Epub 2018 Jun 21.
Testosterone is the predominant gonadal androgen in men. Low testosterone levels are found to be associated with an increased in metabolic risk and systematic inflammation. Since adipose tissue is a source of inflammatory cytokines, testosterone may regulate inflammation by acting on adipose tissue. This review aimed to explore the role of testosterone in inflammation and its mechanism of action. Both animal studies and human studies showed that (1) testosterone deficiency was associated with an increase in pro-inflammatory cytokines; (2) testosterone substitution reduced pro-inflammatory cytokines. The suppression of inflammation by testosterone were observed in patients with coronary artery disease, prostate cancer and diabetes mellitus through the increase in anti-inflammatory cytokines (IL-10) and the decrease in pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α). Despite these, some studies also reported a non-significant relationship. In conclusion, testosterone may possess anti-inflammatory properties but its magnitude is debatable. More evidence is needed to validate the use of testosterone as a marker and in the management of chronic inflammatory diseases.
22NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis.PubMed
Alena Grebe, Florian Hoss, Eicke Latz
Circ Res. 2018 Jun 8;122(12):1722-1740. doi: 10.1161/CIRCRESAHA.118.311362.
Inflammation is an important driver of atherosclerosis, the underlying pathology of cardiovascular diseases. Therefore, therapeutic targeting of inflammatory pathways is suggested to improve cardiovascular outcomes in patients with cardiovascular diseases. This concept was recently proven by CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study), which demonstrated the therapeutic potential of the monoclonal IL (interleukin)-1β-neutralizing antibody canakinumab. IL-1β and other IL-1 family cytokines are important vascular and systemic inflammatory mediators, which contribute to atherogenesis. The NLRP3 (NOD [nucleotide oligomerization domain]-, LRR [leucine-rich repeat]-, and PYD [pyrin domain]-containing protein 3) inflammasome, an innate immune signaling complex, is the key mediator of IL-1 family cytokine production in atherosclerosis. NLRP3 is activated by various endogenous danger signals abundantly present in atherosclerotic lesions, such as oxidized low-density lipoprotein and cholesterol crystals. Consequently, NLRP3 inflammasome activation contributes to the vascular inflammatory response driving atherosclerosis development and progression. Here, we review the mechanisms of NLRP3 inflammasome activation and proinflammatory IL-1 family cytokine production in the context of atherosclerosis and discuss treatment possibilities in light of the positive outcomes of the CANTOS trial.
23Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial.PubMed
Paul M Ridker, Jean G MacFadyen, Tom Thuren, et al.
Lancet. 2017 Oct 21;390(10105):1833-1842. doi: 10.1016/S0140-6736(17)32247-X. Epub 2017 Aug 27.
BACKGROUND: Inflammation in the tumour microenvironment mediated by interleukin 1β is hypothesised to have a major role in cancer invasiveness, progression, and metastases. We did an additional analysis in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), a randomised trial of the role of interleukin-1β inhibition in atherosclerosis, with the aim of establishing whether inhibition of a major product of the Nod-like receptor protein 3 (NLRP3) inflammasome with canakinumab might alter cancer incidence. METHODS: We did a randomised, double-blind, placebo-controlled trial of canakinumab in 10 061 patients with atherosclerosis who had had a myocardial infarction, were free of previously diagnosed cancer, and had concentrations of high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater. To assess dose-response effects, patients were randomly assigned by computer-generated codes to three canakinumab doses (50 mg, 150 mg, and 300 mg, subcutaneously every 3 months) or placebo. Participants were followed up for incident cancer diagnoses, which were adjudicated by an oncology endpoint committee masked to drug or dose allocation. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, NCT01327846. The trial is closed (the last patient visit was in June, 2017). FINDINGS: Baseline concentrations of hsCRP (median 6·0 mg/L vs 4·2 mg/L; p<0·0001) and interleukin 6 (3·2 vs 2·6 ng/L; p<0·0001) were significantly higher among participants subsequently diagnosed with lung cancer than among those not diagnosed with cancer. During median follow-up of 3·7 years, compared with placebo, canakinumab was associated with dose-dependent reductions in concentrations of hsCRP of 26-41% and of interleukin 6 of 25-43% (p<0·0001 for all comparisons). Total cancer mortality (n=196) was significantly lower in the pooled canakinumab group than in the placebo group (p=0·0007 for trend across groups), but was significantly lower than placebo only in the 300 mg group individually (hazard ratio [HR] 0·49 [95% CI 0·31-0·75]; p=0·0009). Incident lung cancer (n=129) was significantly less frequent in the 150 mg (HR 0·61 [95% CI 0·39-0·97]; p=0·034) and 300 mg groups (HR 0·33 [95% CI 0·18-0·59]; p<0·0001; p<0·0001 for trend across groups). Lung cancer mortality was significantly less common in the canakinumab 300 mg group than in the placebo group (HR 0·23 [95% CI 0·10-0·54]; p=0·0002) and in the pooled canakinumab population than in the placebo group (p=0·0002 for trend across groups). Fatal infections or sepsis were significantly more common in the canakinumab groups than in the placebo group. All-cause mortality did not differ significantly between the canakinumab and placebo groups (HR 0·94 [95% CI 0·83-1·06]; p=0·31). INTERPRETATION: Our hypothesis-generating data suggest the possibility that anti-inflammatory therapy with canakinumab targeting the interleukin-1β innate immunity pathway could significantly reduce incident lung cancer and lung cancer mortality. Replication of these data in formal settings of cancer screening and treatment is required. FUNDING: Novartis Pharmaceuticals.
24The interleukin-8 pathway in cancer.PubMed
David J J Waugh, Catherine Wilson
Clin Cancer Res. 2008 Nov 1;14(21):6735-41. doi: 10.1158/1078-0432.CCR-07-4843.
Interleukin-8 (IL-8) is a proinflammatory CXC chemokine associated with the promotion of neutrophil chemotaxis and degranulation. This chemokine activates multiple intracellular signaling pathways downstream of two cell-surface, G protein-coupled receptors (CXCR1 and CXCR2). Increased expression of IL-8 and/or its receptors has been characterized in cancer cells, endothelial cells, infiltrating neutrophils, and tumor-associated macrophages, suggesting that IL-8 may function as a significant regulatory factor within the tumor microenvironment. The induction of IL-8 signaling activates multiple upstream signaling pathways that (a) impinge on gene expression via regulation of numerous transcription factor activities, (b) modulate the cellular proteome at the level of translation, and/or (c) effect the organization of the cell cytoskeleton through posttranslational regulation of regulatory proteins. As a consequence of the diversity of effectors and downstream targets, IL-8 signaling promotes angiogenic responses in endothelial cells, increases proliferation and survival of endothelial and cancer cells, and potentiates the migration of cancer cells, endothelial cells, and infiltrating neutrophils at the tumor site. Accordingly, IL-8 expression correlates with the angiogenesis, tumorigenicity, and metastasis of tumors in numerous xenograft and orthotopic in vivo models. Recently, IL-8 signaling has been implicated in regulating the transcriptional activity of the androgen receptor, underpinning the transition to an androgen-independent proliferation of prostate cancer cells. In addition, stress and drug-induced IL-8 signaling has been shown to confer chemotherapeutic resistance in cancer cells. Therefore, inhibiting the effects of IL-8 signaling may be a significant therapeutic intervention in targeting the tumor microenvironment.
25Platelets promote primary hepatocellular carcinoma metastasis through TGF-β1-mediated cancer cell autophagy.PubMed
Meng Lu, Xue Gong, Yu-Min Zhang, et al.
Cancer Lett. 2024 Sep 28;600:217161. doi: 10.1016/j.canlet.2024.217161. Epub 2024 Aug 6.
Previous research has revealed that platelets promote tumor metastasis by binding to circulating tumor cells (CTCs). However, the role of platelets in epithelial-mesenchymal transition (EMT) of cancer cells at the primary tumor site, the crucial initial step of tumor metastasis, remains to be elucidated. Here, we found that platelet releasate enhanced EMT and motility of hepatocellular carcinoma (HCC) cells via AMPK/mTOR-induced autophagy. RNA-seq indicated that platelet releasate altered TGF-β signaling pathway of cancer cells. Inhibiting TGFBR or deleting platelet TGF-β1 suppressed AMPK/mTOR pathway activation and autophagy induced by platelet releasate. Compared with Pf4cre; Tgfb1 mice, HCC orthotopic models established on Pf4cre; Tgfb1 mice showed reduced TGF-β1 in primary tumors, which corresponded with decreased cancer cell EMT, autophagy, migration ability and tumor metastasis. Inhibition of autophagy via Atg5 knockdown in cancer cells negated EMT and metastasis induced by platelet-released TGF-β1. Clinically, higher platelet count correlated with increased TGF-β1, LC3 and N-cad expression in primary tumors of HCC patients, suggesting a link between platelets and HCC progression. Our study indicates that platelets promote cancer cell EMT in the primary tumor and HCC metastasis through TGF-β1-induced HCC cell autophagy via the AMPK/mTOR pathway. These findings offer novel insights into the role of platelets in HCC metastasis and the potential therapeutic targets for HCC metastasis.
26HBV induced carcinogenesis.PubMed
Delphine Cougot, Christine Neuveut, Marie Annick Buendia
J Clin Virol. 2005 Dec;34 Suppl 1:S75-8. doi: 10.1016/s1386-6532(05)80014-9.
Hepatocellular carcinoma (HCC) is one of the rare human neoplasms associated with viral infections. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most important etiological factors of HCC, accounting for more than 70% of cases worldwide. The risk of HCC development is greatly increased in chronic viral carriers exposed to other recognized risk factors, including exposure to aflatoxin B1, alcoholic cirrhosis and diabetes. The importance of HBV genotypes and precore or core promoter mutants remains incompletely understood. The role of HBV in tumour formation appears to be complex and may involve both direct and indirect mechanisms. Integration of HBV DNA into the host genome occurs at early steps of clonal tumour expansion, and it has been shown to induce direct insertional mutagenesis of diverse cancer-related genes in a number of cases. Chronic liver inflammation and hepatic regeneration induced by cellular immune responses may favour the accumulation of genetic alterations in infected hepatocytes. Prolonged expression of the viral regulatory protein HBx and the large envelope protein LHBs may contribute in deregulating the cellular transcription program and proliferation control, and sensitize liver cells to carcinogenic factors. Recent genetic studies have provided insight into the mechanisms underlying viral-associated hepatocarcinogenesis. It has been shown that the rate of chromosomal alterations is significantly increased in HBV-related tumours compared with tumours associated with other risk factors. HBV might therefore play a role in enhancing genomic instability. Inactivation of p53 by mutations and regional allelic deletions is found more frequently in tumours associated with HBV infection. By contrast, HBV related tumours harbour a low rate of beta-catenin mutations. Together, these data strongly support the notion that chronic HBV infection might trigger specific oncogenic pathways, thus playing a role beyond stimulation of host immune responses and chronic necro-inflammatory liver disease.
27Natural history of hepatitis C.PubMed
Rachel H Westbrook, Geoffrey Dusheiko
J Hepatol. 2014 Nov;61(1 Suppl):S58-68. doi: 10.1016/j.jhep.2014.07.012. Epub 2014 Nov 3.
There has long been evidence that hepatitis C can lead to persistent infection in a high proportion of infected individuals, and can progress to chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC). The transition from acute to chronic hepatitis C is usually sub-clinical. Accurate studies of the time course for clearance of acute hepatitis C are difficult to carry out because of the silent onset of the acute disease. The likelihood of spontaneous HCV resolution is associated with several genetic factors, including IL28B inheritance and the DQB1*0301 allele of the major histocompatibility complex class II. Most data suggest that resolution in the acute phase without progression to chronic disease is not accompanied by significant disease, but minor histological lesions have been observed in anti-HCV positive, HCV RNA negative individuals. The risk of reinfection remains a possibility after clearance of acute hepatitis C. High rates of sexually-transmitted infection are being reported in HIV positive men who have sex with men (MSM). Chronic infection with HCV is the leading cause of end-stage liver disease, hepatocellular carcinoma (HCC) and liver related death in the Western world. The natural history of the chronic disease remains incompletely defined. It is generally a slowly progressive disease characterized by persistent hepatic inflammation, leading to the development of cirrhosis in approximately 10-20% of patients over 20-30 years of HCV infection. However, the published data indicate varying progression rates to cirrhosis. Overall, once cirrhosis has developed there is a 1-5% annual risk of HCC and a 3-6% annual risk of hepatic decompensation. Following an episode of decompensation the risk of death in the following year is between 15% and 20%. The high number of chronically infected individuals, the burden of disease, and the absence of a vaccine indicates that treatment will form part of the disease control but the impact, effectiveness and outcomes of treatment in various groups remain uncertain. Several studies and meta-analysis have concluded that eradication of HCV with antiviral therapy reduces the risk of HCC in patients with chronic hepatitis C, independent of fibrosis stage, but the risk is not eliminated.
28Mechanisms of HBV-induced hepatocellular carcinoma.PubMed
Massimo Levrero, Jessica Zucman-Rossi
J Hepatol. 2016 Apr;64(1 Suppl):S84-S101. doi: 10.1016/j.jhep.2016.02.021.
Hepatitis B virus (HBV) contributes to hepatocellular carcinoma (HCC) development through direct and indirect mechanisms. HBV DNA integration into the host genome occurs at early steps of clonal tumor expansion and induces both genomic instability and direct insertional mutagenesis of diverse cancer-related genes. Prolonged expression of the viral regulatory protein HBx and/or altered versions of the preS/S envelope proteins dysregulates cell transcription and proliferation control and sensitizes liver cells to carcinogenic factors. Accumulation of preS1 large envelope proteins and/or preS2/S mutant proteins activates the unfold proteins response, that can contribute to hepatocyte transformation. Epigenetic changes targeting the expression of tumor suppressor genes occur early in the development of HCC. A major role is played by the HBV protein, HBx, which is recruited on cellular chromatin and modulates chromatin dynamics at specific gene loci. Compared with tumors associated with other risk factors, HBV-related tumors have a higher rate of chromosomal alterations, p53 inactivation by mutations and overexpression of fetal liver/hepatic progenitor cells genes. The WNT/β-catenin pathway is also often activated but HBV-related tumors display a low rate of activating β-catenin mutations. HBV-related HCCs may arise on non-cirrhotic livers, further supporting the notion that HBV plays a direct role in liver transformation by triggering both common and etiology specific oncogenic pathways in addition to stimulating the host immune response and driving liver chronic necro-inflammation.
29Molecular mechanisms of HBV-associated hepatocarcinogenesis.PubMed
Francesca Guerrieri, Laura Belloni, Natalia Pediconi, et al.
Semin Liver Dis. 2013 May;33(2):147-56. doi: 10.1055/s-0033-1345721. Epub 2013 Jun 8.
Hepatitis B virus (HBV) contributes to hepatocellular carcinoma (HCC) development through direct and indirect mechanisms. HBV-DNA integration into the host genome occurs at early steps of clonal tumor expansion and induces both genomic instability and direct insertional mutagenesis of diverse cancer-related genes. Prolonged expression of the viral regulatory protein HBx and the large envelope protein deregulate the cellular transcription program and proliferation control and sensitize liver cells to carcinogenic factors. Epigenetic changes targeting the expression of tumor suppressor genes occur early in the development of HCC. A major role is played by HBx that is recruited on cellular chromatin and modulates chromatin dynamics at specific gene loci. Compared with tumors associated with other risk factors, HBV-related tumors have a higher rate of chromosomal alterations and p53 inactivation by mutations, overexpress fetal liver/hepatic progenitor cells genes, and show a specific activation of the AKT pathway. The wnt/β-catenin pathway is also often activated, but HBV-related tumors display a low rate of activating β-catenin mutations. All available evidence strongly supports the notion that chronic HBV infection triggers both common and etiology-specific oncogenic pathways, thus playing a direct role beyond stimulation of host immune responses and chronic necroinflammatory liver disease.
30Multi-parametric analysis of human livers reveals variation in intrahepatic inflammation across phases of chronic hepatitis B infection.PubMed
Noe Rico Montanari, Ricardo Ramírez, Abhishek Aggarwal, et al.
J Hepatol. 2022 Aug;77(2):332-343. doi: 10.1016/j.jhep.2022.02.016. Epub 2022 Feb 24.
BACKGROUND & AIMS: Chronic HBV is clinically categorized into 4 phases by a combination of serum HBV DNA levels, HBeAg status and alanine aminotransferase (ALT): immunotolerant (IT), immune-active (IA), inactive carrier (IC) and HBeAg-negative hepatitis (ENEG). Immune and virological measurements in the blood have proven useful but are insufficient to explain the interrelation between the immune system and the virus since immune dynamics differ in the blood and liver. Furthermore, the inflammatory response in the liver and parenchymal cells cannot be fully captured in blood. METHODS: Immunological composition and transcriptional profiles of core needle liver-biopsies in chronic HBV phases were compared to those of healthy controls by multiplex immunofluorescence and RNA-sequencing (n = 37 and 78, respectively) analyses. RESULTS: Irrespective of the phase-specific serological profiles, increased immune-gene expression and frequency was observed in chronic HBV compared to healthy livers. Greater transcriptomic deregulation was seen in IA and ENEG (172 vs. 243 DEGs) than in IT and IC (13 vs. 35 DEGs) livers. Interferon-stimulated genes, immune-activation and exhaustion genes (ICOS, CTLA4, PDCD1) together with chemokine genes (CXCL10, CXCL9) were significantly induced in IA and ENEG livers. Moreover, distinct immune profiles associated with ALT elevation and a more accentuated immune-exhaustion profile (CTLA4, TOX, SLAMF6, FOXP3) were observed in ENEG, which set it apart from the IA phase (LGALS9, PDCD1). Interestingly, all HBV phases showed downregulation of metabolic pathways vs. healthy livers (fatty and bile acid metabolism). Finally, increased leukocyte infiltrate correlated with serum ALT, but not with HBV DNA or viral proteins. CONCLUSION: Our comprehensive multi-parametric analysis of human livers revealed distinct inflammatory profiles and pronounced differences in intrahepatic gene profiles across all chronic HBV phases in comparison to healthy liver. LAY SUMMARY: Immunological studies on chronic HBV remain largely restricted to assessment of peripheral responses due to the limited access to the site of infection, the liver. In this study, we comprehensively analyzed livers from a well-defined cohort of patients with chronic HBV and uninfected controls with state-of-the-art techniques, and evaluated the differences in gene expression profiles and inflammation characteristics across distinct disease phases in patients with chronic HBV.
31SEMA6B induces macrophage-mediated inflammation and hepatocyte apoptosis in hepatitis B virus-related acute-on-chronic liver failure.PubMed
Hui Yang, Qun Cai, Jiaojiao Xin, et al.
Theranostics. 2024 Aug 19;14(13):5200-5218. doi: 10.7150/thno.97007. eCollection 2024.
Patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) have a high short-term mortality rate. Semaphorin-6B (SEMA6B) plays a crucial role in the pathogenesis of HBV-ACLF, but its molecular basis remains unclear. This study aimed to elucidate the mechanisms of SEMA6B in HBV-ACLF progression. A total of 321 subjects with HBV-ACLF, liver cirrhosis (LC), chronic hepatitis B (CHB), and normal controls (NC) from a prospective multicenter cohort were studied. 84 subjects (HBV-ACLF, n = 50; LC, n = 10; CHB, n = 10; NC, n = 14) among them underwent mRNA sequencing using peripheral blood mononuclear cells (PBMCs) to clarify the mechanisms of SEMA6B in HBV-ACLF. These mechanisms were validated through in vitro studies with hepatocytes and macrophages, as well as in vivo using SEMA6B knockout mice and mice treated with synthetic SEMA6B siRNA. Transcriptome analysis of PBMCs showed that SEMA6B was among the most differentially expressed genes when comparing patients with HBV-ACLF to those with LC, CHB, or NC. ROC analysis demonstrated the reliable diagnostic value of SEMA6B for HBV-ACLF in both the sequencing cohort and an external validation cohort (AUROC = 0.9788 and 0.9026, respectively). SEMA6B levels were significantly higher in the HBV-ACLF patients, especially in non-survivors, with high expression mainly observed in macrophages and hepatocytes in liver tissue. Genes significantly associated with highly expressed SEMA6B were enriched in inflammation and apoptosis pathways in HBV-ACLF non-survivors. Overexpression of SEMA6B in macrophages activated systemic inflammatory responses, while its overexpression in hepatocytes inhibited proliferation through G0/G1 cell cycle arrest and induced apoptosis. Knocking out SEMA6B rescued mice with liver failure by improving liver functions, reducing inflammatory responses, and decreasing hepatocyte apoptosis. Transcriptome analysis of liver tissue showed that SEMA6B knockout significantly ameliorated the liver failure signature, significantly downregulating inflammation-related pathways. Importantly, therapeutic delivery of synthetic SEMA6B siRNA also improved liver function, and reduced both inflammation and hepatocyte apoptosis in mice with liver failure. SEMA6B, a potential diagnostic biomarker for HBV-ACLF, exacerbates liver failure through macrophage-mediated systemic inflammation and hepatocyte apoptosis. These findings highlight SEMA6B as a promising early treatment target for HBV-ACLF patients.
32Overcoming CD8+ T-Cell Exhaustion in Viral Hepatitis: Lessons from the Mouse Model and Clinical Perspectives.PubMed
Dominik Wieland, Maike Hofmann, Robert Thimme
Dig Dis. 2017;35(4):334-338. doi: 10.1159/000456584. Epub 2017 May 3.
About 500 million people all over the world are chronically infected with hepatitis B virus (HBV) or hepatitis C virus (HCV) and are thus at high risk of developing liver fibrosis, cirrhosis or hepatocellular carcinoma. While in adults about 90% of acutely HBV-infected patients clear the virus, only 30% of acute HCV infections clear spontaneously. Several mechanisms contribute to the failure in viral clearance. The main factors responsible for the chronification of HBV and HCV infection are, on the one hand, viral escape mutations leading to lack of recognition by antiviral immune cells and, on the other hand, loss of antiviral effector functions of virus-specific CD8+ T cells, called T-cell exhaustion. This review focuses on the latter highlighting current knowledge about the heterogeneity of exhausted CD8+ T cells and the potential for re-invigoration of exhausted T-cell populations during chronic viral hepatitis. Although direct-acting antivirals successfully clear chronic HCV infection, there is still the need for a prophylactic vaccine to prevent primary infection. Moreover, a therapeutic strategy eliminating HBV infection still does not exist. A better understanding of T-cell exhaustion and the potential for functional recovery will help to develop new immunotherapeutic approaches for chronic viral hepatitis.
33Targeting virus-specific CD8+ T cells for treatment of chronic viral hepatitis: from bench to bedside.PubMed
Julia Lang-Meli, Christoph Neumann-Haefelin, Robert Thimme
Expert Opin Biol Ther. 2024 Jan-Feb;24(1-2):77-89. doi: 10.1080/14712598.2024.2313112. Epub 2024 Feb 7.
INTRODUCTION: More than 350 million people worldwide live with chronic viral hepatitis and are thus at risk for severe complications like liver cirrhosis and hepatocellular carcinoma (HCC). To meet the goals of the World Health Organization (WHO) global hepatitis strategy, there is an urgent need for new immunotherapeutic approaches. These are particularly required for chronic hepatitis B virus infection and - B/D coinfection. AREAS COVERED: This review summarizes data on mechanisms of CD8+ T cells failure in chronic hepatitis B, D, C and E virus infection. The relative contribution of the different concepts (viral escape, CD8+ T cell exhaustion, defective priming) will be discussed. On this basis, examples for future therapeutic approaches targeting virus-specific CD8+ T cells for the individual hepatitis viruses will be discussed. EXPERT OPINION: Immunotherapeutic approaches targeting virus-specific CD8+ T cells have the potential to change clinical practice, especially in chronic hepatitis B virus infection. Further clinical development, however, requires a more detailed understanding of T cell immunology in chronic viral hepatitis. Some important conceptual questions remain to be addressed, e.g. regarding heterogeneity of exhausted virus-specific CD8+ T cells.
34Plasma levels of soluble PD-1, TIM-3, LAG-3 and galectin-3 and the degree of liver fibrosis in CHC and the impact of successful antiviral treatment on their levels.PubMed
Sylwia Osuch, Aleksandra Kumorek, Paweł Kozłowski, et al.
Sci Rep. 2025 May 2;15(1):15436. doi: 10.1038/s41598-025-99096-4.
Chronic hepatitis C (CHC), caused by the hepatitis C virus, commonly leads to liver fibrosis. CHC is also related to T-cell exhaustion, phenotypically manifesting as overexpression of inhibitory receptors (iRs), e.g., programmed death receptor-1 (PD-1), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) and lymphocyte activation gene 3 (LAG-3), which have corresponding plasma-soluble analogs. Galectin-3 (Gal-3) is a pro-fibrotic and pro-inflammatory molecule, but its role in CHC is controversial. The study aimed to assess the relationship between plasma levels of soluble PD-1 (sPD-1), sTIM-3, sLAG-3 and Gal-3 and the degree of fibrosis in CHC and successful CHC treatment effect on these markers. The study comprised 98 CHC patients, qualified for treatment with direct-acting antivirals. Plasma samples were collected prior to and six months post-treatment. iRs were determined by ELISA. sPD-1 levels were significantly higher in more advanced fibrosis (F2 + F3 vs. F0/1). Regardless of the degree of fibrosis, sPD-1 and sLAG-3 levels significantly decreased after therapy. sTIM-3 levels also decreased, however, mostly in patients with no or mild (i.e., F0/1) fibrosis. Furthermore, Gal-3 increased in patients with more advanced fibrosis (F2 + F3). sPD-1 is associated with liver disease stage in CHC and effective treatment is related to the iRs levels reduction.
35CD4 T cells license Kupffer cells to reverse CD8 T cell dysfunction induced by hepatocellular priming.PubMed
Valentina Venzin, Cristian G Beccaria, Chiara Perucchini, et al.
Nat Immunol. 2025 Aug;26(8):1352-1366. doi: 10.1038/s41590-025-02199-3. Epub 2025 Jun 30.
Chronic hepatitis B virus (HBV) infection is marked by dysfunctional HBV-specific CD8 T cells, and restoring their effector activity is a major therapeutic goal. Here, we generated HBV-specific CD4 T cell receptor transgenic mice to show that CD4 effector T cells can prevent and reverse the CD8⁺ T cell dysfunction induced by hepatocellular priming. This rescue enhances antiviral CD8 T cell function and suppresses viral replication. CD4 T cell help occurs directly within the liver, independent of secondary lymphoid organs, and requires local antigen recognition. Kupffer cells, rather than dendritic cells, are the critical antigen-presenting platform. CD4 T cells license Kupffer cells via CD40-CD40L interactions, triggering interleukin (IL)-12 and IL-27 production. IL-12 expands the CD4 T cell pool, while IL-27 is essential for CD8 T cell rescue. Exogenous IL-27 similarly restores HBV-specific CD8 T cell function in mice and in T cells isolated from chronically infected patients. These findings identify IL-27 as a tractable immunotherapeutic target in chronic HBV infection.
36Hepatitis C virus-induced up-regulation of microRNA-155 promotes hepatocarcinogenesis by activating Wnt signaling.PubMed
Yiliang Zhang, Wei Wei, Na Cheng, et al.
Hepatology. 2012 Nov;56(5):1631-40. doi: 10.1002/hep.25849. Epub 2012 Oct 9.
UNLABELLED: Hepatitis C virus (HCV) infection usually induces chronic hepatic inflammation, which favors the initiation and progression of hepatocellular carcinoma (HCC). Moreover, microRNA-155 (miR-155) plays an important role in regulating both inflammation and tumorigenesis. However, little is known about whether and how miR-155 provides the link between inflammation and cancer. In this study we found that miR-155 levels were markedly increased in patients infected with HCV. MiR-155 transcription was regulated by nuclear factor kappa B (NF-κB), and p300 increased NF-κB-dependent miR-155 expression. The overexpression of miR-155 significantly inhibited hepatocyte apoptosis and promoted cell proliferation, whereas miR-155 inhibition induced G(0) /G(1) arrest. Up-regulated miR-155 resulted in nuclear accumulation of β-catenin and a concomitant increase in cyclin D1, c-myc, and survivin. Gain-of-function and loss-of-function studies demonstrated that miR-155 promoted hepatocyte proliferation and tumorigenesis by increasing Wnt signaling in vitro and in vivo, and DKK1 (Wnt pathway inhibitor) overexpression inhibited the biological role of miR-155 in hepatocytes. Finally, adenomatous polyposis coli (APC), which negatively regulates Wnt signaling, was identified as the direct and functional target of miR-155. CONCLUSION: HCV-induced miR-155 expression promotes hepatocyte proliferation and tumorigenesis by activating Wnt signaling. The present study provides a better understanding of the relationship between inflammation and tumorigenesis, and thus may be helpful in the development of effective diagnosis and treatment strategies against HCV-HCC.
37Hepatitis C Virus-Associated Cancers.PubMed
Zhigang Yi, Zhenghong Yuan
Adv Exp Med Biol. 2017;1018:129-146. doi: 10.1007/978-981-10-5765-6_8.
Most hepatitis C virus (HCV) infection results in persistent infection. Significant portion of chronic HCV-infected patients develop hepatocellular carcinoma (HCC). Chronic hepatitis C is also associated with extrahepatic manifestations, including cryoglobulinemia, lymphoma, insulin resistance, type 2 diabetes, and neurological disorders. The molecular mechanisms of how HCV infection causes liver cancer are largely unknown. HCV replication or viral proteins may perturb cellular hemostasis and induce the generation of reactive oxygen species (ROS); viral components or viral replication products act as agonist to trigger innate immune response and cause chronic inflammation. Within the liver, non-hepatocytes such as hepatic stellate cell (HSC) are activated upon HCV infection to provide the major source of extracellular proteins and play important roles in fibrogenesis. With the great achievements of HCV treatment, especially the direct-acting antivirals (DAAs) against HCV, HCV eradication is possible. However, until now there are only very limited data on the effect of DAA-based anti-HCV treatment on HCC patients.
38How do persistent infections with hepatitis C virus cause liver cancer?PubMed
Jonathan K Mitchell, Stanley M Lemon, David R McGivern
Curr Opin Virol. 2015 Oct;14:101-8. doi: 10.1016/j.coviro.2015.09.003. Epub 2015 Sep 29.
Persistent infection with hepatitis C virus (HCV) is associated with an increased risk of hepatocellular carcinoma (HCC). Cancer typically develops in a setting of chronic hepatic inflammation and advanced fibrosis or cirrhosis, and such tissue represents a pre-neoplastic 'cancer field'. However, not all persistent infections progress to HCC and a combination of viral and host immune factors likely contributes to carcinogenesis. HCV may disrupt cellular pathways involved in detecting and responding to DNA damage, potentially adding to the risk of cancer. Efforts to unravel how HCV promotes HCC are hindered by lack of a robust small animal model, but a better understanding of molecular mechanisms could identify novel biomarkers for early detection and allow for development of improved therapies.
39Cytokines and HCV-related autoimmune disorders.PubMed
Alessandro Antonelli, Silvia Martina Ferrari, Ilaria Ruffilli, et al.
Immunol Res. 2014 Dec;60(2-3):311-9. doi: 10.1007/s12026-014-8569-1.
Cytokines are intercellular mediators involved in viral control and liver damage being induced by infection with hepatitis C virus (HCV). The complex cytokine network operating during initial infection allows a coordinated, effective development of both innate and adaptive immune responses. However, HCV interferes with cytokines at various levels and escapes immune response by inducing a T-helper (Th)2/T cytotoxic 2 cytokine profile. Inability to control infection leads to the recruitment of inflammatory infiltrates into the liver parenchyma by interferon (IFN)-γ-inducible CXC chemokine ligand (CXCL)9, -10, and -11 chemokines, which results in sustained liver damage and eventually in liver cirrhosis. The most important systemic HCV-related extrahepatic diseases-mixed cryoglobulinemia, lymphoproliferative disorders, thyroid autoimmune disorders, and type 2 diabetes-are associated with a complex dysregulation of the cytokine/chemokine network, involving proinflammatory and Th1 chemokines. The therapeutical administration of cytokines such as IFN-α may result in viral clearance during persistent infection and revert this process. Theoretically agents that selectively neutralize CXCL10 could increase patient responsiveness to traditional IFN-based HCV therapy. Several studies have reported IL-28B polymorphisms and circulating CXCL10 may be a prognostic markers for HCV treatment efficacy in HCV genotype 1 infection.
40Beta-catenin mutations are frequent in human hepatocellular carcinomas associated with hepatitis C virus infection.PubMed
H Huang, H Fujii, A Sankila, et al.
Am J Pathol. 1999 Dec;155(6):1795-801. doi: 10.1016/s0002-9440(10)65496-x.
Hepatocellular carcinoma (HCC) is one of the most common fatal cancers worldwide. Hepatitis B virus and hepatitis C virus infections, exposure to aflatoxin, and excessive intake of alcohol have been identified as major risk factors. However, the molecular mechanisms underlying their development are still poorly understood. Recently, beta-catenin, one of the key components of the Wnt signaling pathway, has been found to be mutated in about 20% of HCCs, suggesting a role of the Wnt pathway in their development. In this study, we examined beta-catenin and APC mutations in 22 HCCs associated with HCV infection, using single-strand conformation polymorphism (SSCP) followed by direct DNA sequencing. beta-Catenin mutations were found in nine (41%) cases, but no APC mutations were found. beta-Catenin immunohistochemistry revealed nuclear accumulation of beta-catenin protein in all nine tumors with a beta-catenin mutation and two additional tumors without a mutation. These results suggest that activation of the Wnt signaling pathway by beta-catenin mutation contributes significantly to the hepatocellular carcinogenesis associated with HCV infection.
41Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma.PubMed
Simmone D'souza, Keith Ck Lau, Carla S Coffin, et al.
World J Gastroenterol. 2020 Oct 14;26(38):5759-5783. doi: 10.3748/wjg.v26.i38.5759.
Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis, cancer, and liver failure. Liver cancer is the third leading cause of cancer-associated mortality, of which hepatocellular carcinoma (HCC) represents 90% of all primary liver cancers. Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management. Chronic infection with hepatitis B virus (HBV), hepatitis delta virus (HDV), and hepatitis C virus (HCV) are the greatest etiological risk factors for HCC. Due to the significant role of chronic viral infection in HCC development, it is important to investigate direct (viral associated) and indirect (immune-associated) mechanisms involved in the pathogenesis of HCC. Common mechanisms used by HBV, HCV, and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response, immune and viral protein-mediated oxidative stress, and deregulation of cellular signaling pathways by viral proteins. DNA integration to promote genome instability is a feature of HBV infection, and metabolic reprogramming leading to steatosis is driven by HCV infection. The current review aims to provide a brief overview of HBV, HCV and HDV molecular biology, and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC, and current as well as emerging treatments for HCC.
42Oxidative Stress-Induced Liver Damage and Remodeling of the Liver Vasculature.PubMed
Priyanka Banerjee, Niyanshi Gaddam, Vanessa Chandler, et al.
Am J Pathol. 2023 Oct;193(10):1400-1414. doi: 10.1016/j.ajpath.2023.06.002. Epub 2023 Jun 23.
As an organ critically important for targeting and clearing viruses, bacteria, and other foreign material, the liver operates via immune-tolerant, anti-inflammatory mechanisms indispensable to the immune response. Stress and stress-induced factors disrupt the homeostatic balance in the liver, inflicting tissue damage, injury, and remodeling. These factors include oxidative stress (OS) induced by viral infections, environmental toxins, drugs, alcohol, and diet. A recurrent theme seen among stressors common to multiple liver diseases is the induction of mitochondrial dysfunction, increased reactive oxygen species expression, and depletion of ATP. Inflammatory signaling additionally exacerbates the condition, generating a proinflammatory, immunosuppressive microenvironment and activation of apoptotic and necrotic mechanisms that disrupt the integrity of liver morphology. These pathways initiate signaling pathways that significantly contribute to the development of liver steatosis, inflammation, fibrosis, cirrhosis, and liver cancers. In addition, hypoxia and OS directly enhance angiogenesis and lymphangiogenesis in chronic liver diseases. Late-stage consequences of these conditions often narrow the outcomes for liver transplantation or result in death. This review provides a detailed perspective on various stress-induced factors and the specific focus on role of OS in different liver diseases with special emphasis on different molecular mechanisms. It also highlights how resultant changes in the liver vasculature correlate with pathogenesis.
43Epigenetics in hepatocellular carcinoma.PubMed
Ganji Purnachandra Nagaraju, Begum Dariya, Prameswari Kasa, et al.
Semin Cancer Biol. 2022 Nov;86(Pt 3):622-632. doi: 10.1016/j.semcancer.2021.07.017. Epub 2021 Jul 26.
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and has a high fatality rate. Genetic and epigenetic aberrations are commonly observed in HCC. The epigenetic processes include chromatin remodelling, histone alterations, DNA methylation, and noncoding RNA (ncRNA) expression and are connected with the progression and metastasis of HCC. Due to their potential reversibility, these epigenetic alterations are widely targeted for the development of biomarkers. In-depth understanding of the epigenetics of HCC is critical for developing rational clinical strategies that can provide a meaningful improvement in overall survival and prediction of therapeutic outcomes. In this article, we have summarised the epigenetic modifications involved in HCC progression and highlighted the potential biomarkers for diagnosis and drug development.
44WTAP facilitates progression of hepatocellular carcinoma via m6A-HuR-dependent epigenetic silencing of ETS1.PubMed
Yunhao Chen, Chuanhui Peng, Junru Chen, et al.
Mol Cancer. 2019 Aug 22;18(1):127. doi: 10.1186/s12943-019-1053-8.
BACKGROUND: N6-methyladenosine (m6A) methylation, a well-known modification with new epigenetic functions, has been reported to participate in the tumorigenesis of hepatocellular carcinoma (HCC), providing novel insights into the molecular pathogenesis of this disease. However, as the key component of m6A methylation, Wilms tumor 1-associated protein (WTAP) has not been well studied in HCC. Here we investigated the biological role and underlying mechanism of WTAP in liver cancer. METHODS: We determined the expression of WTAP and its correlation with clinicopathological features using tissue microarrays and the Cancer Genome Atlas (TCGA) dataset. And we clarified the effects of WTAP on HCC cells using cell proliferation assay, colony formation, Edu assay and subcutaneous xenograft experiments. We then applied RNA sequencing combined with gene expression omnibus (GEO) data to screen candidate targets of WTAP. Finally, we investigated the regulatory mechanism of WTAP in HCC by m6A dot blot assay, methylated RNA immunoprecipitation (MeRIP) assay, dual luciferase reporter assay, RNA immunoprecipitation (RIP) assay and Chromatin immunoprecipitation (ChIP) assay. RESULTS: We demonstrated that WTAP was highly expressed in HCC which indicated the poor prognosis, and that WTAP expression served as an independent predictor of HCC survival. Functionally, WTAP promoted the proliferation capability and tumor growth of HCC cells in vitro and in vivo. Furthermore, ETS proto-oncogene 1 (ETS1) was identified as the downstream effector of WTAP. The m6A modification regulated by WTAP led to post-transcriptional suppression of ETS1, with the implication of Hu-Antigen R (HuR) as an RNA stabilizer. Then ETS1 was found to inhibit the progression of HCC and could rescue the phenotype induced by WTAP deficiency. Moreover, WTAP modulated the G2/M phase of HCC cells through a p21/p27-dependent pattern mediated by ETS1. CONCLUSION: We have identified that WTAP is significantly up-regulated in HCC and promotes liver cancer development. WTAP-guided m6A modification contributes to the progression of HCC via the HuR-ETS1-p21/p27 axis. Our study is the first to report that WTAP-mediated m6A methylation has a crucial role in HCC oncogenesis, and highlights WTAP as a potential therapeutic target of HCC treatment.
45Metabolic reprogramming and its clinical implication for liver cancer.PubMed
Flora Yang, Leena Hilakivi-Clarke, Aurpita Shaha, et al.
Hepatology. 2023 Nov 1;78(5):1602-1624. doi: 10.1097/HEP.0000000000000005. Epub 2023 Jan 3.
Cancer cells often encounter hypoxic and hypo-nutrient conditions, which force them to make adaptive changes to meet their high demands for energy and various biomaterials for biomass synthesis. As a result, enhanced catabolism (breakdown of macromolecules for energy production) and anabolism (macromolecule synthesis from bio-precursors) are induced in cancer. This phenomenon is called "metabolic reprogramming," a cancer hallmark contributing to cancer development, metastasis, and drug resistance. HCC and cholangiocarcinoma (CCA) are 2 different liver cancers with high intertumoral heterogeneity in terms of etiologies, mutational landscapes, transcriptomes, and histological representations. In agreement, metabolism in HCC or CCA is remarkably heterogeneous, although changes in the glycolytic pathways and an increase in the generation of lactate (the Warburg effect) have been frequently detected in those tumors. For example, HCC tumors with activated β-catenin are addicted to fatty acid catabolism, whereas HCC tumors derived from fatty liver avoid using fatty acids. In this review, we describe common metabolic alterations in HCC and CCA as well as metabolic features unique for their subsets. We discuss metabolism of NAFLD as well, because NAFLD will likely become a leading etiology of liver cancer in the coming years due to the obesity epidemic in the Western world. Furthermore, we outline the clinical implication of liver cancer metabolism and highlight the computation and systems biology approaches, such as genome-wide metabolic models, as a valuable tool allowing us to identify therapeutic targets and develop personalized treatments for liver cancer patients.
46Metabolic reprogramming in the tumor microenvironment of liver cancer.PubMed
Jian Lin, Dongning Rao, Mao Zhang, et al.
J Hematol Oncol. 2024 Jan 31;17(1):6. doi: 10.1186/s13045-024-01527-8.
The liver is essential for metabolic homeostasis. The onset of liver cancer is often accompanied by dysregulated liver function, leading to metabolic rearrangements. Overwhelming evidence has illustrated that dysregulated cellular metabolism can, in turn, promote anabolic growth and tumor propagation in a hostile microenvironment. In addition to supporting continuous tumor growth and survival, disrupted metabolic process also creates obstacles for the anticancer immune response and restrains durable clinical remission following immunotherapy. In this review, we elucidate the metabolic communication between liver cancer cells and their surrounding immune cells and discuss how metabolic reprogramming of liver cancer impacts the immune microenvironment and the efficacy of anticancer immunotherapy. We also describe the crucial role of the gut-liver axis in remodeling the metabolic crosstalk of immune surveillance and escape, highlighting novel therapeutic opportunities.
47ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways.PubMed
Zongli Zhang, Yue Yuan, Lin Hu, et al.
J Adv Res. 2023 May;47:41-56. doi: 10.1016/j.jare.2022.08.006. Epub 2022 Aug 27.
INTRODUCTION: High calorie intake is known to induce nonalcoholic fatty liver disease (NAFLD) by promoting chronic inflammation. However, the mechanisms are poorly understood. OBJECTIVES: This study examined the roles of ANGPTL8 in the regulation of NAFLD-associated liver fibrosis progression induced by high fat diet (HFD)-mediated inflammation. METHODS: The ANGPTL8 concentration was measured in serum samples from liver cancer and liver cirrhosis patients. ANGPTL8 knockout(KO) mice were used to induce disease models (HFD, HFHC and CCL4) followed by pathological staining, western blot and immunohistochemistry. Hydrodynamic injection of an adeno-associated virus 8 (AAV8) was used to establish a model for restoring ANGPTL8 expression specifically in ANGPTL8 KO mice livers. RNA-sequencing, protein array, Co-IP, etc. were used to study ANGPTL8's mechanisms in regulating liver fibrosis progression, and drug screening was used to identify an effective inhibitor of ANGPTL8 expression. RESULTS: ANGPTL8 level is associated with liver fibrogenesis in both cirrhosis and hepatocellular carcinoma patients. Mouse studies demonstrated that ANGPTL8 deficiency suppresses HFD-stimulated inflammatory activity, hepatic steatosis and liver fibrosis. The AAV-mediated restoration of liver ANGPTL8 expression indicated that liver-derived ANGPTL8 accelerates HFD-induced liver fibrosis. Liver-derived ANGPTL8, as a proinflammatory factor, activates HSCs (hepatic stellate cells) by interacting with the LILRB2 receptor to induce ERK signaling and increase the expression of genes that promote liver fibrosis. The FDA-approved anti-diabetic drug metformin, an ANGPTL8 inhibitor, inhibited HFD-induced liver fibrosis in vivo. CONCLUSIONS: Our data support that ANGPTL8 is a proinflammatory factor that accelerates NAFLD-associated liver fibrosis induced by HFD. The serum ANGPTL8 level may be a potential and specific diagnostic marker for liver fibrosis, and targeting ANGPTL8 holds great promise for developing innovative therapies to treat NAFLD-associated liver fibrosis.
48Hypoxia, Metabolic Reprogramming, and Drug Resistance in Liver Cancer.PubMed
Macus Hao-Ran Bao, Carmen Chak-Lui Wong
Cells. 2021 Jul 6;10(7):1715. doi: 10.3390/cells10071715.
Hypoxia, low oxygen (O) level, is a hallmark of solid cancers, especially hepatocellular carcinoma (HCC), one of the most common and fatal cancers worldwide. Hypoxia contributes to drug resistance in cancer through various molecular mechanisms. In this review, we particularly focus on the roles of hypoxia-inducible factor (HIF)-mediated metabolic reprogramming in drug resistance in HCC. Combination therapies targeting hypoxia-induced metabolic enzymes to overcome drug resistance will also be summarized. Acquisition of drug resistance is the major cause of unsatisfactory clinical outcomes of existing HCC treatments. Extra efforts to identify novel mechanisms to combat refractory hypoxic HCC are warranted for the development of more effective treatment regimens for HCC patients.
49Targeting p300/CBP Attenuates Hepatocellular Carcinoma Progression through Epigenetic Regulation of Metabolism.PubMed
Ling-Yan Cai, Shi-Jie Chen, Sen-Hao Xiao, et al.
Cancer Res. 2021 Feb 15;81(4):860-872. doi: 10.1158/0008-5472.CAN-20-1323. Epub 2020 Dec 23.
Targeting epigenetics in cancer has emerged as a promising anticancer strategy. p300/CBP is a central regulator of epigenetics and plays an important role in hepatocellular carcinoma (HCC) progression. Tumor-associated metabolic alterations contribute to the establishment and maintenance of the tumorigenic state. In this study, we used a novel p300 inhibitor, B029-2, to investigate the effect of targeting p300/CBP in HCC and tumor metabolism. p300/CBP-mediated acetylation of H3K18 and H3K27 increased in HCC tissues compared with surrounding noncancerous tissues. Conversely, treatment with B029-2 specifically decreased H3K18Ac and H3K27Ac and displayed significant antitumor effects in HCC cells and . Importantly, ATAC-seq and RNA-seq integrated analysis revealed that B029-2 disturbed metabolic reprogramming in HCC cells. Moreover, B029-2 decreased glycolytic function and nucleotide synthesis in Huh7 cells by reducing H3K18Ac and H3K27Ac levels at the promoter regions of amino acid metabolism and nucleotide synthesis enzyme genes, including and . Overexpression of PSPH and DTYMK partially reversed the inhibitory effect of B029-2 on HCC cells. These findings suggested that p300/CBP epigenetically regulates the expression of glycolysis-related metabolic enzymes through modulation of histone acetylation in HCC and highlights the value of targeting the histone acetyltransferase activity of p300/CBP for HCC therapy. SIGNIFICANCE: This study demonstrates p300/CBP as a critical epigenetic regulator of glycolysis-related metabolic enzymes in HCC and identifies the p300/CBP inhibitor B029-2 as a potential therapeutic strategy in this disease.
50Lactylation-Driven IGF2BP3-Mediated Serine Metabolism Reprogramming and RNA m6A-Modification Promotes Lenvatinib Resistance in HCC.PubMed
Yuanxiang Lu, Jinghan Zhu, Yuxin Zhang, et al.
Adv Sci (Weinh). 2024 Dec;11(46):e2401399. doi: 10.1002/advs.202401399. Epub 2024 Oct 25.
Acquired resistance remains a bottleneck for molecular-targeted therapy in advanced hepatocellular carcinoma (HCC). Metabolic adaptation and epigenetic remodeling are recognized as hallmarks of cancer that may contribute to acquired resistance. In various lenvatinib-resistant models, increased glycolysis leads to lactate accumulation and lysine lactylation of IGF2BP3. This lactylation is crucial for capturing PCK2 and NRF2 mRNAs, thereby enhancing their expression. This process reprograms serine metabolism and strengthens the antioxidant defense system. Additionally, altered serine metabolism increases the availability of methylated substrates, such as S-adenosylmethionine (SAM), for N6-methyladenosine (m6A) methylation of PCK2 and NRF2 mRNAs. The lactylated IGF2BP3-PCK2-SAM-m6A loop maintains elevated PCK2 and NRF2 levels, enhancing the antioxidant system and promoting lenvatinib resistance in HCC. Treatment with liposomes carrying siRNAs targeting IGF2BP3 or the glycolysis inhibitor 2-DG restored lenvatinib sensitivity in vivo. These findings highlight the connection between metabolic reprogramming and epigenetic regulation and suggest that targeting metabolic pathways may offer new strategies to overcome lenvatinib resistance in HCC.
51Arginine reprograms metabolism in liver cancer via RBM39.PubMed
Dirk Mossmann, Christoph Müller, Sujin Park, et al.
Cell. 2023 Nov 9;186(23):5068-5083.e23. doi: 10.1016/j.cell.2023.09.011. Epub 2023 Oct 6.
Metabolic reprogramming is a hallmark of cancer. However, mechanisms underlying metabolic reprogramming and how altered metabolism in turn enhances tumorigenicity are poorly understood. Here, we report that arginine levels are elevated in murine and patient hepatocellular carcinoma (HCC), despite reduced expression of arginine synthesis genes. Tumor cells accumulate high levels of arginine due to increased uptake and reduced arginine-to-polyamine conversion. Importantly, the high levels of arginine promote tumor formation via further metabolic reprogramming, including changes in glucose, amino acid, nucleotide, and fatty acid metabolism. Mechanistically, arginine binds RNA-binding motif protein 39 (RBM39) to control expression of metabolic genes. RBM39-mediated upregulation of asparagine synthesis leads to enhanced arginine uptake, creating a positive feedback loop to sustain high arginine levels and oncogenic metabolism. Thus, arginine is a second messenger-like molecule that reprograms metabolism to promote tumor growth.
52Hepatitis B virus promotes liver cancer by modulating the immune response to environmental carcinogens.PubMed
Mei Huang, Dongyao Wang, Jiao Huang, et al.
Nat Commun. 2025 Jun 27;16(1):5360. doi: 10.1038/s41467-025-60894-z.
Hepatitis B virus (HBV) infection is associated with hepatitis and hepatocellular carcinoma (HCC). Considering that most HBV-infected individuals remain asymptomatic, the mechanism linking HBV to hepatitis and HCC remains uncertain. Herein, we demonstrate that HBV alone does not cause liver inflammation or cancer. Instead, HBV alters the chronic inflammation induced by chemical carcinogens to promote liver carcinogenesis. Long-term HBV genome expression in mouse liver increases liver inflammation and cancer propensity caused by a carcinogen, diethylnitrosamine (DEN). HBV plus DEN-activated interleukin-33 (IL-33)/regulatory T cell axis is required for liver carcinogenesis. Pitavastatin, an IL-33 inhibitor, suppresses HBV plus DEN-induced liver cancer. IL-33 is markedly elevated in HBV hepatitis patients, and pitavastatin use significantly correlates with reduced risk of hepatitis and its associated HCC in patients. Collectively, our findings reveal that environmental carcinogens are the link between HBV and HCC risk, creating a window of opportunity for cancer prevention in HBV carriers.
53From Sidney to OLGA: an overview of atrophic gastritis.PubMed
Pellegrino Crafa, Michele Russo, Chiara Miraglia, et al.
Acta Biomed. 2018 Dec 17;89(8-S):93-99. doi: 10.23750/abm.v89i8-S.7946.
Chronic gastritis is a long-lasting disease that can lead to a loss of appropriate gastric glands. Gastritis, as term, apply to an inflammation of the stomach, histologically proven, sometimes with structural mucosal changes. Worldwide Helicobacter pylori's infection play a pivotal role as the main etiological effector of chronic active gastritis. H. p. is a bacterium with a selective tropism for the gastric mucosa, able to survive in a hostile environment for colonization of organisms other than itself, able to develop strategies for survival and for avoidance of the defence mechanisms, causing inflammatory changes, that vary from asymptomatic mild gastritis to more severe injury such as peptic ulcer as well as premalignant lesions and malignant tumours. The pattern and distribution of gastritis strongly correlate with these sequelae and chronic atrophic gastritis with intestinal metaplasia is now assessed as a precancerous lesion with definite risk of evolution towards intraepithelial lesions of both low and high grade, as expected in the model of the Correa's cascade. In fact, the leading complication of chronic gastritis remains its close correlation with gastric cancer being biologically linked to H. pylori infection, nowadays known as a class I carcinogen. Gastric carcinogenesis is due to environmental factors, as well as to bacterial strain, host responses and gastric mucosal microbiome dysbiosis. Since, individual patients show different gastric cancer risk, it is mandatory to identify patients at risk of developing gastric cancer to offer a targeted search for lesions with a more rapid development of neoplasm liable, in an early phase, to a less destructive treatment. OLGA staging system is the most reliable and powerful system that allow the recognition of patient with a higher risk of developing gastric cancer.
54Decoding the Ability of Helicobacter pylori to Evade Immune Recognition and Cause Disease.PubMed
Isabella S Sirit, Richard M Peek
Cell Mol Gastroenterol Hepatol. 2025;19(5):101470. doi: 10.1016/j.jcmgh.2025.101470. Epub 2025 Jan 30.
Helicobacter pylori (H pylori) successfully and chronically colonizes the gastric mucosa of approximately 43% of the world's population. Infection with this organism is the strongest known risk factor for the development of gastric cancer, and disease development is dependent on several interactive components. One H pylori determinant that augments cancer risk is the strain-specific cag type IV secretion system, which not only translocates a pro-inflammatory and oncogenic protein, CagA, into host cells but also DNA, peptidoglycan, and a lipopolysaccharide intermediate, heptose-1,7-bisphosphate. However, cognate interactions between certain microbial and host constituents can also attenuate pro-inflammatory responses, and H pylori harbors multiple effectors that function differently than the respective counterparts in other mucosal pathogens. In this review, we discuss current data related to mechanisms utilized by H pylori to evade the immune response, sustain its longevity in the host, and further disease progression, as well as implications for developing targeted, immune-based eradication strategies.
55Helicobacter pylori: A Paradigm Pathogen for Subverting Host Cell Signal Transmission.PubMed
Michael Naumann, Olga Sokolova, Nicole Tegtmeyer, et al.
Trends Microbiol. 2017 Apr;25(4):316-328. doi: 10.1016/j.tim.2016.12.004. Epub 2017 Jan 3.
Helicobacter pylori colonizes the gastric mucosa in the human stomach and represents a major risk factor for peptic ulcer disease and gastric cancer. Here, we summarize our current knowledge of the complex impact of H. pylori on manipulating host signalling networks, that is, by the cag pathogenicity island (cagPAI)-encoded type IV secretion system (T4SS). We show that H. pylori infections reflect a paradigm for interspecies contact-dependent molecular communication, which includes the disruption of cell-cell junctions and cytoskeletal rearrangements, as well as proinflammatory, cell cycle-related, proliferative, antiapoptotic, and DNA damage responses. The contribution of these altered signalling cascades to disease outcome is discussed.
56Subversion of host kinases: a key network in cellular signaling hijacked by Helicobacter pylori CagA.PubMed
Nicole Tegtmeyer, Matthias Neddermann, Carmen Isabell Asche, et al.
Mol Microbiol. 2017 Aug;105(3):358-372. doi: 10.1111/mmi.13707. Epub 2017 May 30.
Helicobacter pylori is a paradigm of persistent pathogens and major risk factor for developing severe diseases including adenocarcinoma in the human stomach. An important bacterial factor linked to gastric disease progression is the cag pathogenicity island-encoded type-IV secretion system (T4SS) effector protein CagA. Translocated CagA undergoes tyrosine phosphorylation at EPIYA-motifs and then activates or inactivates multiple host signaling proteins in a phosphorylation-dependent and phosphorylation-independent fashion. In this way, intracellular CagA acts as a 'masterkey' or 'picklock', which evolved during evolution to hijack key host cell signal transduction functions. Crucial targets of CagA represent a variety of serine/threonine and tyrosine kinases, which control major checkpoints of eukaryotic signaling. Here we review the signal transmission by translocated CagA on multiple receptor kinases (c-Met and EGFR) and non-receptor kinases (Src, Abl, Csk, aPKC, Par1, PI3K, Akt, FAK, GSK-3, JAK, PAK1, PAK2 and MAP kinases), manipulating a selection of fundamental processes in the human gastric epithelium such as cell adhesion, polarity, proliferation, motility, receptor endocytosis, cytoskeletal rearrangements, apoptosis, inflammation and cell cycle progression. This enormous complexity generates a highly remarkable and puzzling scenario during H. pylori infection. The contribution of these signaling pathways to bacterial survival, persistence and gastric pathogenesis is discussed.
57alphaPix interacts with Helicobacter pylori CagA to induce IL-8 expression in gastric epithelial cells.PubMed
Joo Weon Lim, Kyung Hwan Kim, Hyeyoung Kim
Scand J Gastroenterol. 2009;44(10):1166-72. doi: 10.1080/00365520903144398.
OBJECTIVE: Helicobacter pylori CagA, translocated into gastric epithelial cells, induces IL-8 expression through the signalling pathways, including extracellular signal-regulated kinase (ERK) and nuclear factor-kappaB (NF-kappaB). We previously demonstrated that CagA interacts with host alphaPix. The present study was purposed to determine the role of the interaction of alphaPix with CagA on the signalling pathways for IL-8 expression in H. pylori-infected gastric epithelial cells. MATERIAL AND METHODS: H. pylori HP99 strain (CagA+, VacA+) was infected to gastric epithelial AGS cells transfected with non-targeting (NT) or alphaPix- targeting siRNA. Activation of signalling molecules including p21-activated kinase (PAK), ERK and NF-kappaB, and expression of IL-8 in the cells were assessed. RESULTS: H. pylori CagA was delivered into AGS cells and then interacted with alphaPix at 4 h following H. pylori infection. PAK1, ERK and NF-kappaB were activated in the cells containing NT and alphaPix siRNA at 1-2 h following H. pylori infection. However, after 4 h, the time when CagA was delivered into the cells, the activations of PAK1, ERK and NF-kappaB were inhibited by down-regulation of alphaPix using siRNA but not by NT siRNA. The results indicate that alphaPix is required for H. pylori-mediated signalling of PAK1, ERK and NF-kappaB. Additionally, alphaPix siRNA suppressed IL-8 induction after translocation of CagA into the cells, indicating that interaction of CagA with alphaPix is critical for CagA-mediating signalling for IL-8 expression. CONCLUSIONS: The interaction of alphaPix with CagA activates PAK1, ERK and NF-kappaB, which induces IL-8 expression in H. pylori-infected gastric epithelial cells.
58Differential effects of multiplicity of infection on Helicobacter pylori-induced signaling pathways and interleukin-8 gene transcription.PubMed
Birgit Ritter, Petra Kilian, Marc Rene Reboll, et al.
J Clin Immunol. 2011 Feb;31(1):60-8. doi: 10.1007/s10875-010-9467-5. Epub 2010 Oct 1.
Interleukin-8 (IL-8) plays a central role in the pathogenesis of Helicobacter pylori infection. We used four different H. pylori strains isolated from patients with gastritis or duodenal ulcer disease to examine their differential effects on signaling pathways and IL-8 gene response in gastric epithelial cells. IL-8 mRNA level is elevated in response to high (100) multiplicity of infection (MOI) independent of cagA, vacA, and dupA gene characteristics. By lower MOIs (1 or 10), only cagA ( + ) strains significantly induce IL-8 gene expression. This is based on differential regulation of IL-8 promoter activity. Analysis of intracellular signaling pathways indicates that H. pylori clinical isolates induce IL-8 gene transcription through NF-κB p65, but by a MOI-dependent differential activation of MAPK pathways. Thus, the major virulence factors of H. pylori CagA, VacA, and DupA might play a minor role in the level of IL-8 gene response to a high bacterial load.
59H. Pylori-Facilitated TERT/Wnt/β-Catenin Triggers Spasmolytic Polypeptide-Expressing Metaplasia and Oxyntic Atrophy.PubMed
Lijiao He, Xiao Zhang, Shengwei Zhang, et al.
Adv Sci (Weinh). 2025 Jan;12(3):e2401227. doi: 10.1002/advs.202401227. Epub 2024 Nov 25.
Persistent H. pylori infection triggers the repair program of the mucosa, such as spasmolytic polypeptide-expressing metaplasia (SPEM). However, the mechanism underlying the initiation of SPEM in gastric tissues by H. pylori remains unclear. Here, an increase in telomerase reverse transcriptase (TERT) protein expression is observed in chief cells upon infection with cagA-positive H. pylori. Tert knockout significantly ameliorated H. pylori-induced SPEM and single-cell RNA sequencing demonstrated that the Wnt/β-Catenin pathway is suppressed in gastric cells with Tert knockout. Mechanism study revealed that CagA elevated TERT abundance by disrupting the interaction between TERT and its novel E3 ligase, SYVN1. Interestingly, Nitazoxanide effectively relieved SPEM via inhibition of the Wnt/β-Catenin signaling in vivo. This results clarified the mechanism underlying which CagA activated the TERT/Wnt/β-Catenin pathway, thus promoting the dedifferentiation of chief cells and the occurrence of SPEM in gastric mucosa. This highlights a molecular basis for targeting CagA-activated Wnt signaling in chief cells for the treatment of gastric precancerous lesions.
60Activation of activator protein 1 and stress response kinases in epithelial cells colonized by Helicobacter pylori encoding the cag pathogenicity island.PubMed
M Naumann, S Wessler, C Bartsch, et al.
J Biol Chem. 1999 Oct 29;274(44):31655-62. doi: 10.1074/jbc.274.44.31655.
Helicobacter pylori interacts with the apical membrane of the gastric epithelium and induces a number of proinflammatory cytokines/chemokines. The subsequent infiltration of macrophages and granulocytes into the mucosa leads to gastric inflammation accompanied by epithelial degeneration. Gastric diseases, e.g. peptic ulcer or gastric adenocarcinoma, are more common among people infected with H. pylori strains producing VacA (vacuolating cytotoxin A) and possessing a cag (cytotoxin-associated antigen A) pathogenicity island. For the induction of the cytokine/chemokine genes in response to H. pylori, we studied the signaling leading to the nuclear activation of the early response transcription factor activator protein 1 (AP-1). We found that H. pylori strains carrying the pathogenicity island induce activation of AP-1 and nuclear factor kappaB. In contrast to the wild type or an isogenic strain without the vacA gene, isogenic H. pylori strains with mutations in certain cag genes revealed only weak AP-1 and nuclear factor kappaB activation. In respect to the molecular components that direct AP-1 activity, our results indicate a cascade of the cellular stress response kinases c-Jun N-terminal kinase, MAP kinase kinase 4, and p21-activated kinase, and small Rho-GTPases including Rac1 and Cdc42, which contributes to the activation of proinflammatory cytokines/chemokines induced by H. pylori encoding the cag pathogenicity island.
61Helicobacter pylori in a Korean isolate activates mitogen-activated protein kinases, AP-1, and NF-kappaB and induces chemokine expression in gastric epithelial AGS cells.PubMed
Ji Hye Seo, Joo Weon Lim, Hyeyoung Kim, et al.
Lab Invest. 2004 Jan;84(1):49-62. doi: 10.1038/sj.labinvest.3700010.
Oxidant-sensitive transcription factors, nuclear factor-kappaB (NF-kappaB), and activator protein-1 (AP-1) have been considered as the regulators of inducible genes such as chemokines. Since oxygen radicals are considered as an important regulator in the pathogenesis of Helicobacter pylori (H. pylori)-induced gastric ulceration and carcinogenesis, chemokines such as interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) may be regulated by NF-kappaB and/or AP-1. Ras, the upstream activator for mitogen-activated protein kinase (MAPK) and MAPK cascade regulate AP-1 activation. The present study aims to investigate whether H. pylori in a Korean isolate (HP99) induces the expression of chemokines (IL-8, MCP-1), which is regulated by Ras, MAPK, AP-1, and NF-kappaB in gastric epithelial AGS cells, and whether these transcriptional regulations of chemokines are inhibited by transfection with mutant genes for Ras (ras N-17), c-Jun (TAM-67), and IkappaBalpha (MAD-3) or treatment with MAPK inhibitors (U0126 for extracellular signal-regulated kinase or SB203580 for p38 kinase). In addition, virulence factors of HP99 were characterized by PCR analysis for the isolated DNA. As a result, HP99 is identified as cagA+, vacA s1b, m2, iceA1 H. pylori strain. HP99 induced a time-dependent expression of mRNA and protein for IL-8 and MCP-1 via mediation of MAPK, AP-1, and NF-kappaB. Transfection with mutant genes for Ras, c-Jun, and IkappaBalpha and treatment with MAPK inhibitors suppressed H. pylori-induced activation of transcription factors (NF-kappaB, AP-1) and expression of chemokines (IL-8, MCP-1) in AGS cells. In conclusion, Ras and MAPK cascade may act as the upstream signaling for the activation of AP-1 and NF-kappaB, which induce chemokine expression in H. pylori-infected AGS cells. Specific targeting of the activation of NF-kappaB and AP-1 may be effective for the prevention or treatment of gastric inflammation associated with H. pylori infection.
62Research on drug treatment and the novel signaling pathway of chronic atrophic gastritis.PubMed
Jinhao Jia, Huijie Zhao, Fangfei Li, et al.
Biomed Pharmacother. 2024 Jul;176:116912. doi: 10.1016/j.biopha.2024.116912. Epub 2024 Jun 7.
BACKGROUND: Chronic atrophic gastritis (CAG) is a global digestive system disease and one of the important causes of gastric cancer. The incidence of CAG has been increasing yearly worldwide. PURPOSE: This article reviews the latest research on the common causes and future therapeutic targets of CAG as well as the pharmacological effects of corresponding clinical drugs. We provide a detailed theoretical basis for further research on possible methods for the treatment of CAG and reversal of the CAG process. RESULTS: CAG often develops from chronic gastritis, and its main pathological manifestation is atrophy of the gastric mucosa, which can develop into gastric cancer. The drug treatment of CAG can be divided into agents that regulate gastric acid secretion, eradicate Helicobacter. pylori (H. pylori), protect gastric mucous membrane, or inhibit inflammatory factors according to their mechanism of action. Although there are limited specific drugs for the treatment of CAG, progress is being made in defining the pathogenesis and therapeutic targets of the disease. Growing evidence shows that NF-κB, PI3K/AKT, Wnt/ β-catenin, MAPK, Toll-like receptors (TLRs), Hedgehog, and VEGF signaling pathways play an important role in the development of CAG.
63Gastritis, Gastric Polyps and Gastric Cancer.PubMed
Helge Waldum, Reidar Fossmark
Int J Mol Sci. 2021 Jun 18;22(12):6548. doi: 10.3390/ijms22126548.
Gastric cancer is still an important disease causing many deaths worldwide, although there has been a marked reduction in prevalence during the last few decades. The decline in gastric cancer prevalence is due to a reduction in infection which has occurred for at least 50 years. The most probable mechanism for the carcinogenic effect of is hypergastrinemia since infected individuals do not have increased risk of gastric cancer before the development of oxyntic atrophy. When atrophy has developed, the carcinogenic process continues independent of . Autoimmune gastritis also induces oxyntic atrophy leading to marked hypergastrinemia and development of ECL cell neoplasia as well as adenocarcinoma. Similarly, long-term treatment with efficient inhibitors of acid secretion like the proton pump inhibitors (PPIs) predisposes to ECL cell neoplasia of a different degree of malignancy. Contrasting the colon where most cancers develop from polyps, most polyps in the stomach have a low malignant potential. Nevertheless, gastric polyps may also give rise to cancer and have some risk factors and mechanisms in common with gastric cancer. In this overview the most common gastric polyps, i.e., hyperplastic polyps, adenomatous polyps and fundic gland polyps will be discussed with respect to etiology and particularly use of PPIs and relation to gastric carcinogenesis.
64Stress and the gut: pathophysiology, clinical consequences, diagnostic approach and treatment options.PubMed
Peter C Konturek, T Brzozowski, S J Konturek
J Physiol Pharmacol. 2011 Dec;62(6):591-9.
Stress, which is defined as an acute threat to homeostasis, shows both short- and long-term effects on the functions of the gastrointestinal tract. Exposure to stress results in alterations of the brain-gut interactions ("brain-gut axis") ultimately leading to the development of a broad array of gastrointestinal disorders including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and other functional gastrointestinal diseases, food antigen-related adverse responses, peptic ulcer and gastroesophageal reflux disease (GERD). The major effects of stress on gut physiology include: 1) alterations in gastrointestinal motility; 2) increase in visceral perception; 3) changes in gastrointestinal secretion; 4) increase in intestinal permeability; 5) negative effects on regenerative capacity of gastrointestinal mucosa and mucosal blood flow; and 6) negative effects on intestinal microbiota. Mast cells (MC) are important effectors of brain-gut axis that translate the stress signals into the release of a wide range of neurotransmitters and proinflammatory cytokines, which may profoundly affect the gastrointestinal physiology. IBS represents the most important gastrointestinal disorder in humans, and is characterized by chronic or recurrent pain associated with altered bowel motility. The diagnostic testing for IBS patients include routine blood tests, stool tests, celiac disease serology, abdominal sonography, breath testing to rule out carbohydrate (lactose, fructose, etc.) intolerance and small intestinal bacterial overgrowth. Colonoscopy is recommended if alarming symptoms are present or to obtain colonic biopsies especially in patients with diarrhoea predominant IBS. The management of IBS is based on a multifactorial approach and includes pharmacotherapy targeted against the predominant symptom, behavioural and psychological treatment, dietary alterations, education, reassurance and effective patient-physician relationship. When evaluating for the stress-induced condition in the upper GI tract, the diagnostic testing includes mainly blood tests and gastroscopy to rule out GERD and peptic ulcer disease. The therapy for these conditions is mainly based on the inhibition of gastric acid by proton pump inhibitors and eradication of Helicobacter pylori-infection. Additionally, melatonin an important mediator of brain gut axis has been shown to exhibit important protective effects against stress-induced lesions in the gastrointestinal tract. Finally, probiotics may profoundly affect the brain-gut interactions ("microbiome-gut-brain axis") and attenuate the development of stress-induced disorders in both the upper and lower gastrointestinal tract. Further studies on the brain-gut axis are needed to open new therapeutic avenues in the future.
65Mucosal microbiome dysbiosis in gastric carcinogenesis.PubMed
Olabisi Oluwabukola Coker, Zhenwei Dai, Yongzhan Nie, et al.
Gut. 2018 Jun;67(6):1024-1032. doi: 10.1136/gutjnl-2017-314281. Epub 2017 Aug 1.
OBJECTIVES: We aimed to characterise the microbial changes associated with histological stages of gastric tumourigenesis. DESIGN: We performed 16S rRNA gene analysis of gastric mucosal samples from 81 cases including superficial gastritis (SG), atrophic gastritis (AG), intestinal metaplasia (IM) and gastric cancer (GC) from Xi'an, China, to determine mucosal microbiome dysbiosis across stages of GC. We validated the results in mucosal samples of 126 cases from Inner Mongolia, China. RESULTS: We observed significant mucosa microbial dysbiosis in IM and GC subjects, with significant enrichment of 21 and depletion of 10 bacterial taxa in GC compared with SG (q<0.05). Microbial network analysis showed increasing correlation strengths among them with disease progression (p<0.001). Five GC-enriched bacterial taxa whose species identifications correspond to , , , and had significant centralities in the GC ecological network (p<0.05) and classified GC from SG with an area under the receiver-operating curve (AUC) of 0.82. Moreover, stronger interactions among gastric microbes were observed in -negative samples compared with -positive samples in SG and IM. The fold changes of selected bacteria, and strengths of their interactions were successfully validated in the Inner Mongolian cohort, in which the five bacterial markers distinguished GC from SG with an AUC of 0.81. CONCLUSIONS: In addition to microbial compositional changes, we identified differences in bacterial interactions across stages of gastric carcinogenesis. The significant enrichments and network centralities suggest potentially important roles of , , , and in GC progression.
66Gastric microbiome profile throughout gastric carcinogenesis: beyond helicobacter.PubMed
Pedro Pimentel-Nunes, António Barros, Inês Pita, et al.
Scand J Gastroenterol. 2021 Jun;56(6):708-716. doi: 10.1080/00365521.2021.1902560. Epub 2021 Apr 29.
BACKGROUND: Gastric dysbiosis has been hinted as a potential cause of gastric cancer. However, changes in microbiome throughout the major stages of gastric carcinogenesis remain mostly unknown. OBJECTIVE: To describe gastric microbiome at different stages, analysing for the first time dysbiosis specifically in patients with early gastric cancer (EGC). METHODS: Cross-sectional study including patients ( = 77) with endoscopically and histologically confirmed normal stomachs (controls; = 25), advanced atrophic gastritis with intestinal metaplasia (IM; = 18) and EGC ( = 34). Endoscopic biopsies from antrum and corpus ( = 154) were analyzed. Next-generation sequencing was performed characterizing microbial communities down to the species level based on full-length 16SrRNA gene profiling. RESULTS: Significant differences were found in the microbiome profile between the groups. Firmicutes were more frequent ( = .012) and Proteobacteria were less frequent ( = .04) both in the IM and EGC when comparing to controls. Relative frequency of , when present, was much higher in the controls (83%) when comparing to the other groups (IM 1%, EGC 27%; = .006), being the dominant bacteria only in the controls. Dysbiosis was present already and more significantly at the IM stage, with two bacteria progressively increasing from controls to IM then to cancer: from 1.48 to 3.9% ( = .014); and from 19.3 to 33.7% ( = .04), being the EGC dominant bacteria. CONCLUSIONS: Our results confirm dominancy in non-atrophic stomachs and progressive dysbiosis throughout gastric carcinogenesis. but particularly is significantly increased in patients with EGC. Specific modulation of these bacteria may change gastric cancer risk.
67Effect of on gastrointestinal microbiota: a population-based study in Linqu, a high-risk area of gastric cancer.PubMed
Yang Guo, Yang Zhang, Markus Gerhard, et al.
Gut. 2020 Sep;69(9):1598-1607. doi: 10.1136/gutjnl-2019-319696. Epub 2019 Dec 19.
OBJECTIVE: Gastrointestinal microbiota may be involved in associated gastric cancer development. The aim of this study was to explore the possible microbial mechanisms in gastric carcinogenesis and potential dysbiosis arising from infection. DESIGN: Deep sequencing of the microbial 16S ribosomal RNA gene was used to investigate alterations in paired gastric biopsies and stool samples in 58 subjects with successful and 57 subjects with failed anti- treatment, relative to 49 negative subjects. RESULTS: In positive subjects, richness and Shannon indexes increased significantly (both p<0.001) after successful eradication and showed no difference to those of negative subjects (p=0.493 for richness and p=0.420 for Shannon index). Differential taxa analysis identified 18 significantly altered gastric genera after eradication. The combination of these genera into a Microbial Dysbiosis Index revealed that the dysbiotic microbiota in positive mucosa was associated with advanced gastric lesions (chronic atrophic gastritis and intestinal metaplasia/dysplasia) and could be reversed by eradication. Strong coexcluding interactions between and , , , , were found only in advanced gastric lesion patients, and were absent in normal/superficial gastritis group. Changes in faecal microbiota included increased after successful eradication and more upregulated drug-resistant functional orthologs after failed treatment. CONCLUSION: infection contributes significantly to gastric microbial dysbiosis that may be involved in carcinogenesis. Successful eradication potentially restores gastric microbiota to a similar status as found in uninfected individuals, and shows beneficial effects on gut microbiota.
68Spatiotemporal genomic profiling of intestinal metaplasia reveals clonal dynamics of gastric cancer progression.PubMed
Kie Kyon Huang, Haoran Ma, Roxanne Hui Heng Chong, et al.
Cancer Cell. 2023 Dec 11;41(12):2019-2037.e8. doi: 10.1016/j.ccell.2023.10.004. Epub 2023 Oct 26.
Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. Analyzing 1,256 gastric samples (1,152 IMs) across 692 subjects from a prospective 10-year study, we identify 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9). Single-cell and spatial profiles highlight changes in tissue ecology and IM lineage heterogeneity, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling reveals expression-based molecular subtypes of IM associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only models in predicting IMs likely to transform to GC. By highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression, our results raise opportunities for GC precision prevention and interception.
69The road to a world-unified approach to the management of patients with gastric intestinal metaplasia: a review of current guidelines.PubMed
Mario Dinis-Ribeiro, Shailja Shah, Hashem El-Serag, et al.
Gut. 2024 Sep 9;73(10):1607-1617. doi: 10.1136/gutjnl-2024-333029.
OBJECTIVE: During the last decade, the management of gastric intestinal metaplasia (GIM) has been addressed by several distinct international evidence-based guidelines. In this review, we aimed to synthesise these guidelines and provide clinicians with a global perspective of the current recommendations for managing patients with GIM, as well as highlight evidence gaps that need to be addressed with future research. DESIGN: We conducted a systematic review of the literature for guidelines and consensus statements published between January 2010 and February 2023 that address the diagnosis and management of GIM. RESULTS: From 426 manuscripts identified, 16 guidelines were assessed. There was consistency across guidelines regarding the purpose of endoscopic surveillance of GIM, which is to identify prevalent neoplastic lesions and stage gastric preneoplastic conditions. The guidelines also agreed that only patients with high-risk GIM phenotypes (eg, corpus-extended GIM, OLGIM stages III/IV, incomplete GIM subtype), persistent refractory infection or first-degree family history of gastric cancer should undergo regular-interval endoscopic surveillance. In contrast, low-risk phenotypes, which comprise most patients with GIM, do not require surveillance. Not all guidelines are aligned on histological staging systems. If surveillance is indicated, most guidelines recommend a 3-year interval, but there is some variability. All guidelines recommend eradication as the only non-endoscopic intervention for gastric cancer prevention, while some offer additional recommendations regarding lifestyle modifications. While most guidelines allude to the importance of high-quality endoscopy for endoscopic surveillance, few detail important metrics apart from stating that a systematic gastric biopsy protocol should be followed. Notably, most guidelines comment on the role of endoscopy for gastric cancer screening and detection of gastric precancerous conditions, but with high heterogeneity, limited guidance regarding implementation, and lack of robust evidence. CONCLUSION: Despite heterogeneous populations and practices, international guidelines are generally aligned on the importance of GIM as a precancerous condition and the need for a risk-stratified approach to endoscopic surveillance, as well as eradication when present. There is room for harmonisation of guidelines regarding (1) which populations merit index endoscopic screening for gastric cancer and GIM detection/staging; (2) objective metrics for high-quality endoscopy; (3) consensus on the need for histological staging and (4) non-endoscopic interventions for gastric cancer prevention apart from eradication alone. Robust studies, ideally in the form of randomised trials, are needed to bridge the ample evidence gaps that exist.
70Gastric Cancer in the Era of Epigenetics.PubMed
Grigorios Christodoulidis, Konstantinos-Eleftherios Koumarelas, Marina-Nektaria Kouliou, et al.
Int J Mol Sci. 2024 Mar 16;25(6):3381. doi: 10.3390/ijms25063381.
Gastric cancer (GC) remains a significant contributor to cancer-related mortality. Novel high-throughput techniques have enlightened the epigenetic mechanisms governing gene-expression regulation. Epigenetic characteristics contribute to molecular taxonomy and give rise to cancer-specific epigenetic patterns. (Hp) infection has an impact on aberrant DNA methylation either through its pathogenic CagA protein or by inducing chronic inflammation. The hypomethylation of specific repetitive elements generates an epigenetic field effect early in tumorigenesis. Epstein-Barr virus (EBV) infection triggers DNA methylation by dysregulating DNA methyltransferases (DNMT) enzyme activity, while persistent Hp-EBV co-infection leads to aggressive tumor behavior. Distinct histone modifications are also responsible for oncogene upregulation and tumor-suppressor gene silencing in gastric carcinomas. While histone methylation and acetylation processes have been extensively studied, other less prevalent alterations contribute to the development and migration of gastric cancer via a complex network of interactions. Enzymes, such as Nicotinamide N-methyltransferase (NNMT), which is involved in tumor's metabolic reprogramming, interact with methyltransferases and modify gene expression. Non-coding RNA molecules, including long non-coding RNAs, circular RNAs, and miRNAs serve as epigenetic regulators contributing to GC development, metastasis, poor outcomes and therapy resistance. Serum RNA molecules hold the potential to serve as non-invasive biomarkers for diagnostic, prognostic or therapeutic applications. Gastric fluids represent a valuable source to identify potential biomarkers with diagnostic use in terms of liquid biopsy. Ongoing clinical trials are currently evaluating the efficacy of next-generation epigenetic drugs, displaying promising outcomes. Various approaches including multiple miRNA inhibitors or targeted nanoparticles carrying epigenetic drugs are being designed to enhance existing treatment efficacy and overcome treatment resistance.
71Helicobacter pylori as an oncogenic pathogen, revisited.PubMed
Muhammad Miftahussurur, Yoshio Yamaoka, David Y Graham
Expert Rev Mol Med. 2017 Mar 21;19:e4. doi: 10.1017/erm.2017.4.
Gastric cancer is an inflammation-associated malignancy aetiologically related to infection with the bacterium, Helicobacter pylori, which is considered a necessary but insufficient cause. Unless treated, H. pylori causes life-long acute and chronic gastric inflammation resulting in progressive gastric mucosal damage that may result in gastric cancer. The rate of progression from superficial gastritis, to an atrophic metaplastic mucosa, and ultimately to cancer relates to the virulence of the infecting H. pylori as well as host and environmental factors. H. pylori virulence is a reflection of its propensity to cause severe gastric inflammation. Both mucosal inflammation and H. pylori can cause host genomic instability, including dysregulation of DNA mismatch repair, stimulation of expression of activation-induced cytidine deaminase, abnormal DNA methylation and dysregulation of micro RNAs, which may result in an accumulation of mutations and loss of normal regulation of cell growth. The difference in cancer risk between the most and least virulent H. pylori strain is only approximately 2-fold. Overall, none of the putative virulence factors identified to date have proved to be disease-specific. The presence, severity, extent and duration of inflammation appear to be the most important factors and current evidence suggests that any host, environmental or bacterial factor that reliably enhances the inflammatory response to the H. pylori infection increases the risk of gastric cancer.
72Inflammation and cancer.PubMed
Mariko Murata
Environ Health Prev Med. 2018 Oct 20;23(1):50. doi: 10.1186/s12199-018-0740-1.
Infection and inflammation account for approximately 25% of cancer-causing factors. Inflammation-related cancers are characterized by mutagenic DNA lesions, such as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-nitroguanine. Our previous studies demonstrated the formation of 8-oxodG and 8-nitroguanine in the tissues of cancer and precancerous lesions due to infection (e.g., Opisthorchis viverrini-related cholangiocarcinoma, Schistosoma haematobium-associated bladder cancer, Helicobacter pylori-infected gastric cancer, human papillomavirus-related cervical cancer, Epstein-Barr virus-infected nasopharyngeal carcinoma) and pro-inflammatory factors (e.g., asbestos, nanomaterials, and inflammatory diseases such as Barrett's esophagus and oral leukoplakia). Interestingly, several of our studies suggested that inflammation-associated DNA damage in cancer stem-like cells leads to cancer development with aggressive clinical features. Reactive oxygen/nitrogen species from inflammation damage not only DNA but also other biomacromolecules, such as proteins and lipids, resulting in their dysfunction. We identified oxidatively damaged proteins in cancer tissues by 2D Oxyblot followed by MALDI-TOF/TOF. As an example, oxidatively damaged transferrin released iron ion, which may mediate Fenton reactions and generate additional reactive oxygen species. Dysfunction of anti-oxidative proteins due to this damage might increase oxidative stress. Such damage in biomacromolecules may form a vicious cycle of oxidative stress, leading to cancer development. Epigenetic alterations such as DNA methylation and microRNA dysregulation play vital roles in carcinogenesis, especially in inflammation-related cancers. We examined epigenetic alterations, DNA methylation and microRNA dysregulation, in Epstein-Barr virus-related nasopharyngeal carcinoma in the endemic area of Southern China and found several differentially methylated tumor suppressor gene candidates by using a next-generation sequencer. Among these candidates, we revealed higher methylation rates of RAS-like estrogen-regulated growth inhibitor (RERG) in biopsy specimens of nasopharyngeal carcinoma more conveniently by using restriction enzyme-based real-time PCR. This result may help to improve cancer screening strategies. We profiled microRNAs of nasopharyngeal carcinoma tissues using microarrays. Quantitative RT-PCR analysis confirmed the concordant downregulation of miR-497 in cancer tissues and plasma, suggesting that plasma miR-497 could be used as a diagnostic biomarker for nasopharyngeal carcinoma. Chronic inflammation promotes genetic and epigenetic aberrations, with various pathogeneses. These changes may be useful biomarkers in liquid biopsy for early detection and prevention of cancer.
73DNA methylation in gastric cancer, related to Helicobacter pylori and Epstein-Barr virus.PubMed
Keisuke Matsusaka, Sayaka Funata, Masashi Fukayama, et al.
World J Gastroenterol. 2014 Apr 14;20(14):3916-26. doi: 10.3748/wjg.v20.i14.3916.
Gastric cancer is a leading cause of cancer death worldwide, and significant effort has been focused on clarifying the pathology of gastric cancer. In particular, the development of genome-wide analysis tools has enabled the detection of genetic and epigenetic alterations in gastric cancer; for example, aberrant DNA methylation in gene promoter regions is thought to play a crucial role in gastric carcinogenesis. The etiological viewpoint is also essential for the study of gastric cancers, and two distinct pathogens, Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV), are known to participate in gastric carcinogenesis. Chronic inflammation of the gastric epithelium due to H. pylori infection induces aberrant polyclonal methylation that may lead to an increased risk of gastric cancer. In addition, EBV infection is known to cause extensive methylation, and EBV-positive gastric cancers display a high methylation epigenotype, in which aberrant methylation extends to not only Polycomb repressive complex (PRC)-target genes in embryonic stem cells but also non-PRC-target genes. Here, we review aberrant DNA methylation in gastric cancer and the association between methylation and infection with H. pylori and EBV.
74-induced DNA Methylation as an Epigenetic Modulator of Gastric Cancer: Recent Outcomes and Future Direction.PubMed
Jibran Sualeh Muhammad, Mohamed Ahmed Eladl, Ghalia Khoder
Pathogens. 2019 Feb 13;8(1):23. doi: 10.3390/pathogens8010023.
Gastric cancer is ranked fifth in cancer list and has the third highest mortality rate. is a class I carcinogen and a predominant etiological factor of gastric cancer. infection may induce carcinogenesis via epigenetic alterations in the promoter region of various genes. is known to induce hypermethylation-silencing of several tumor suppressor genes in -infected cancerous and -infected non-cancerous gastric mucosae. This article presents a review of the published literature mainly from the last year 15 years. The topic focuses on -induced DNA methylation linked to gastric cancer development. The authors have used MeSH terms "" with "epigenetic," "DNA methylation," in combination with "gastric inflammation", gastritis" and "gastric cancer" to search SCOPUS, PubMed, Ovid, and Web of Science databases. The success of epigenetic drugs such as de-methylating agents in the treatment of certain cancers has led towards new prospects that similar approaches could also be applied against gastric cancer. However, it is very important to understand the role of all the genes that have already been linked to -induced DNA methylation in order to in order to evaluate the potential benefits of epigenetic drugs.
75Epigenetic changes in gastric cancer induction by Helicobacter pylori.PubMed
Bahman Yousefi, Maryam Mohammadlou, Maryam Abdollahi, et al.
J Cell Physiol. 2019 Dec;234(12):21770-21784. doi: 10.1002/jcp.28925. Epub 2019 Jun 6.
Epigenetic disorder mechanisms are one of the causes of cancer. The most important of these changes is the DNA methylation, which leads to the spread of Helicobacter pylori and inflammatory processes followed by induction of DNA methylation disorder. Mutations and epigenetic changes are the two main agents of neoplasia. Epithelial cells infection by H. pylori associated with activating several intracellular pathways including: MAPK, NF-κB, Wnt/β-catenin, and PI3K are affects a variety of cells and caused to an increase in the production of inflammatory cytokines, changes in apoptosis, proliferation, differentiation, and ultimately leads to the transformation of epithelial cells into oncogenic. The arose of free radicals impose the DNA cytosine methylation, and NO can increase the activity of DNA methyltransferase. H. pylori infection causes an environment that mediates inflammation and signaling pathways that probably caused to stomach tumorigenicity. The main processes that change by decreasing or increasing the expression of various microRNAs expressions include immune responses, apoptosis, cell cycle, and autophagy. In this review will be describe a probably H. pylori roles in infection and mechanisms that have contribution in epigenetic changes in the promoter of genes.
76Helicobacter pylori-induced inflammation and epigenetic changes during gastric carcinogenesis.PubMed
Manuel A Valenzuela, Jimena Canales, Alejandro H Corvalán, et al.
World J Gastroenterol. 2015 Dec 7;21(45):12742-56. doi: 10.3748/wjg.v21.i45.12742.
The sequence of events associated with the development of gastric cancer has been described as "the gastric precancerous cascade". This cascade is a dynamic process that includes lesions, such as atrophic gastritis, intestinal metaplasia and dysplasia. According to this model, Helicobacter pylori (H. pylori) infection targets the normal gastric mucosa causing non-atrophic gastritis, an initiating lesion that can be cured by clearing H. pylori with antibiotics or that may then linger in the case of chronic infection and progress to atrophic gastritis. The presence of virulence factors in the infecting H. pylori drives the carcinogenesis process. Independent epidemiological and animal studies have confirmed the sequential progression of these precancerous lesions. Particularly long-term follow-up studies estimated a risk of 0.1% for atrophic gastritis/intestinal metaplasia and 6% in case of dysplasia for the long-term development of gastric cancer. With this in mind, a better understanding of the genetic and epigenetic changes associated with progression of the cascade is critical in determining the risk of gastric cancer associated with H. pylori infection. In this review, we will summarize some of the most relevant mechanisms and focus predominantly but not exclusively on the discussion of gene promoter methylation and miRNAs in this context.
77Association between RUNX3 promoter methylation and gastric cancer: a meta-analysis.PubMed
Xiao-yuan Fan, Xin-lei Hu, Tie-mei Han, et al.
BMC Gastroenterol. 2011 Aug 25;11:92. doi: 10.1186/1471-230X-11-92.
BACKGROUND: Runt-related transcription factor 3 (RUNX3) is a member of the runt-domain family of transcription factors and has been reported to be a candidate tumor suppressor in gastric cancer. However, the association between RUNX3 promoter methylation and gastric cancer remains unclear. METHODS: We systematically reviewed studies of RUNX3 promoter methylation and gastric cancer published in English or Chinese from January 2000 to January 2011, and quantified the association between RUNX3 promoter methylation and gastric cancer using meta-analysis methods. RESULTS: A total of 1740 samples in 974 participants from seventeen studies were included in the meta-analysis. A significant association was observed between RUNX3 promoter methylation and gastric cancer, with an aggregated odds ratio (OR) of 5.63 (95%CI 3.15, 10.07). There was obvious heterogeneity among studies. Subgroup analyses (including by tissue origin, country and age), meta-regression were performed to determine the source of the heterogeneity. Meta-regression showed that the trend in ORs was inversely correlated with age. No publication bias was detected. The ORs for RUNX3 methylation in well-differentiated vs undifferentiated gastric cancers, and in intestinal-type vs diffuse-type carcinomas were 0.59 (95%CI: 0.30, 1.16) and 2.62 (95%CI: 1.33, 5.14), respectively. There were no significant differences in RUNX3 methylation in cancer tissues in relation to age, gender, TNM stage, invasion of tumors into blood vessel or lymphatic ducts, or tumor stage. CONCLUSIONS: This meta-analysis identified a strong association between methylation of the RUNX3 promoter and gastric cancer, confirming the role of RUNX3 as a tumor suppressor gene.
78Genomic Analyses Reveal the Evolving Characteristics of Intestinal Metaplasia and Gastric Cancer.PubMed
Xianfeng Xu, Caiwang Yan, Lijun Bian, et al.
Cancer Res. 2025 Aug 15;85(16):3123-3138. doi: 10.1158/0008-5472.CAN-24-4065.
UNLABELLED: Intestinal metaplasia (IM) represents a precancerous condition associated with an increased risk of gastric cancer. A better understanding of whether and how precancerous lesions progress to gastric cancer is crucial for patient stratification and personalized prevention. In this study, we reconstruct evolutionary trajectories of genomic alterations in 330 multiregion matched samples of IM and tumors from 93 patients with gastric cancer. Intestinal-type gastric cancer (IGC) exhibited a higher mutation burden than diffuse-type gastric cancer (DGC), notably in genomically stable patients. IM from genomically stable patients carried more mutations associated with alcohol consumption. The 20 significantly mutated genes identified were classified into three evolutionary patterns. "Maintained" genes (TP53, APC, and PIK3CA) were commonly altered in IM and matched gastric cancer samples in both IGC and DGC, whereas CDH1 mutations were specific to DGC. "Maintained" mutations in IM accelerated gastric cancer progression. Alterations in "IM-favored" genes (MUC6, CFTR, BMP6, and MTRR) were associated with IM development but were negatively selected in gastric cancer. Interestingly, MUC6 mutations were enriched in specific pit cells with upregulation of GKN1 and GKN2. The remaining genes were "gastric cancer-favored" and showed high heterogeneity in gastric cancer. These findings illuminate the genomic evolution from IM to IGC or DGC, providing insights that could guide precancerous lesion surveillance and early prevention strategies. SIGNIFICANCE: Comprehensive genomic characterization uncovers maintained and gained alterations during evolution from intestinal metaplasia to gastric cancer, which could serve as predictive biomarkers to identify individuals at high risk of developing cancer.
79Association of APC gene promoter methylation and the risk of gastric cancer: A meta-analysis and bioinformatics study.PubMed
Xueliang Zhou, Dechao Jiao, Mengmeng Dou, et al.
Medicine (Baltimore). 2020 Apr;99(16):e19828. doi: 10.1097/MD.0000000000019828.
BACKGROUND: The methylation status of the adenomatous polyposis coli (APC) promoter has been shown to be associated with the occurrence of gastric cancer, but this finding remains controversial. The aim of this study was to investigate the relationship between methylation of the APC gene promoter and gastric cancer. METHODS: We searched the Web of Science, EMBASE, Medline, and Cochrane Central Register of Controlled Trials (CENTRAL) databases from the date of creation until August 1, 2019. According to the inclusion criteria, the relationship between the methylation status of the APC gene promoter and gastric cancer was investigated. The incidence of APC promoter methylation in the tissues or blood of patients with and without gastric cancer was compared. The results are expressed as the odds ratio (OR) and 95% confidence interval (CI). The pooled OR of each study was estimated using a fixed effects model or a random effects model to generate forest plots. We further validated the results using the MethHC database. RESULTS: Eight studies (985 samples) were included. Our meta-analysis showed that the incidence of APC promoter methylation in patients with gastric cancer was higher than that of patients without gastric cancer (OR = 3.86, 95% CI 1.71-8.74, P = .001). Methylation of the APC promoter is associated with the incidence of gastric cancer, and it increases the risk of gastric cancer. CONCLUSION: This study provides a new strategic direction for research on gastric cancer. Methylation of the APC promoter may be a potential biomarker for the diagnosis of gastric cancer, but the results of this work require further confirmation.
80P16 gene promoter methylation is associated with oncogenesis and progression of gastric carcinomas: A systematic review and meta-analysis.PubMed
Luigi Wolkmer Spagnol, Jossimara Polettini, Daniela Augustin Silveira, et al.
Crit Rev Oncol Hematol. 2022 Dec;180:103843. doi: 10.1016/j.critrevonc.2022.103843. Epub 2022 Oct 19.
INTRODUCTION: Gastric cancer is the fourth leading cause of neoplastic morbidity worldwide, and its pathogenesis has been related to genetic and epigenetic alterations in cell cycle regulatory genes, such as p16. OBJECTIVES: This systematic review was developed to investigate the association of the p16 gene promoter methylation with oncogenesis and the progression of gastric carcinomas. METHODOLOGY: MEDLINE and Scopus databases were searched for relevant subsidiary studies, with the publication until July 2021 and without language restriction. The complete protocol was registered in the PROSPERO platform under the identification 308218. The Newcastle-Ottawa scale (NOS) was used to assess the methodological quality of the included manuscripts. The meta-analysis was conducted using RevMan 5.4 ® software. The random effects model was used, Odds Ratio (OR) was calculated with 95% confidence intervals (95% CI). Heterogeneity and inferential significance were measured. RESULTS: 48 articles were aggregated in the qualitative synthesis and 47 in the meta-analysis, totaling 6599 gastric specimens evaluated. Associations of p16 methylation with the following outcomes were observed: gastric oncogenesis (p < 0.00001); intestinal metaplasia (p = 0.002); poor histological differentiation (p = 0.03); local invasion (p = 0.001); lymph node dissemination (p = 0.03); more advanced TNM staging (p = 0.01); and Epstein Barr virus infection (p < 0.00001). In contrast, no association of p16 methylation was found with Lauren's histological classification (p = 0.62); distant metastasis (p = 0.71); or Helicobacter pylori infection (p = 0.79). CONCLUSIONS: the findings described provide empirical evidence for the categorization of p16 methylation as a substantial biomolecular step in gastric carcinogenesis, and reveal a crucial role of Epstein Barr virus in triggering this epigenetic alteration.
81miR-30a acts as a tumor suppressor by double-targeting COX-2 and BCL9 in H. pylori gastric cancer models.PubMed
Xuan Liu, Qing Ji, Chengcheng Zhang, et al.
Sci Rep. 2017 Aug 2;7(1):7113. doi: 10.1038/s41598-017-07193-w.
Helicobacter pylori (H. pylori) is one of the most important factors that affect the development of gastric cancer, and its mechanism remains un-elucidated. Our present study found that, miR-30a is crucial for regulating the growth and migration of H. pylori infected gastric cancer in vitro by targeting COX-2 and BCL9. In details, double-stranded miR-30a precursor produced two single-stranded and matured miRNAs including miR-30a-3p and miR-30a-5p, which played significant biological functions in two different manners. First, miR-30a-3p inhibited COX-2 expression and regulated nuclear translocation of β-catenin, and second, miR-30a-5p targeted BCL9 to regulate TCF/LEF promoter activity followed by affecting β-catenin downstream target gene expression. In vivo, miR-30a knockout mice were successfully achieved using CRISPR/Cas9 gene editing technology. Compared with H. pylori-infected wild-type mice, H. pylori-infected miR-30a knockout mice showed increased incidence of chronic gastritis, chronic atrophic gastritis, atypical hyperplasia, and other precancerous lesions or adenocarcinoma manifestations in the antral or gastric mucosa of mice, as well as regulation of genes closely associated with tumor development. Taken together, miR-30a acts as a tumor suppressor by double-targeting COX-2 and BCL9, and significantly affects the development of H. pylori-induced gastric cancer, shedding new light on the mechanisms underlying H. pylori-associated gastric cancer.
82Single-cell transcriptomic profiling uncovers cellular complexity and microenvironment in gastric tumorigenesis associated with Helicobacter pylori.PubMed
Nianshuang Li, Sihai Chen, Xinbo Xu, et al.
J Adv Res. 2025 Aug;74:471-491. doi: 10.1016/j.jare.2024.10.012. Epub 2024 Oct 15.
INTRODUCTION: Helicobacter pylori (H. pylori) infection is the main risk for gastric cancer (GC). However, the cellular heterogeneity and underlying molecular mechanisms in H. pylori-driven gastric tumorigenesis are poorly understood. OBJECTIVE: Here, we generated a single-cell atlas of gastric tumorigenesis comprising 18 specimens of gastritis, gastric intestinal metaplasia (IM) and GC with or without H. pylori infection. METHODS: Single-cell RNA sequencing (scRNA-seq) was performed. Immunofluorescence, immunohistochemistry and qRT-PCR analysis were applied in a second human gastric tissues cohort for validation. Bioinformatics analyses of public TCGA and GEO datasets were applied. RESULTS: Single-cell RNA profile highlights cellular heterogeneity and alterations in tissue ecology throughout the progression of gastric carcinoma. Various cell lineages exhibited unique cancer-associated expression profiles, such as tumor-like epithelial cell subset (EPC), inflammatory cancer-associated fibroblasts (iCAFs) and Tumor-associated macrophage (TAM). Notably, we revealed that the specific epithelial subset enterocytes from the precancerous lesion GIM, exhibited elevated expression of genes related to lipid metabolism, and HNF4G was predicted as its specific transcription factor. Furthermore, we identified differentially expressed genes in H. pylori-positive and negative epithelial cells, fibroblasts and myeloid cells were identified. Futhermore, H. pylori-positive specimens exhibited enriched cell-cell communication, characterized by significantly active TNF, SPP1, and THY1 signaling networks. CONCLUSIONS: Our study provides a comprehensive landscape of the gastric carcinogenesis ecosystem and novel insights into the molecular mechanisms of different cell types in H. pylori-induced GC.
83Glycogen synthase kinase-3β ablation limits pancreatitis-induced acinar-to-ductal metaplasia.PubMed
Li Ding, Geou-Yarh Liou, Daniel M Schmitt, et al.
J Pathol. 2017 Sep;243(1):65-77. doi: 10.1002/path.4928. Epub 2017 Jul 27.
Acinar-to-ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase-3beta (GSK-3β) in ADM development using in vitro 3D cultures and genetically engineered mouse models. We show that GSK-3β promotes TGF-α-induced ADM in 3D cultured primary acinar cells, whereas deletion of GSK-3β attenuates caerulein-induced ADM formation and PanIN progression in Kras transgenic mice. Furthermore, we demonstrate that GSK-3β ablation influences ADM formation and PanIN progression by suppressing oncogenic KRas-driven cell proliferation. Mechanistically, we show that GSK-3β regulates proliferation by increasing the activation of S6 kinase. Taken together, these results indicate that GSK-3β participates in early pancreatitis-induced ADM and thus could be a target for the treatment of chronic pancreatitis and the prevention of PDAC progression. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
84Induction of Pancreatic Inflammation Accelerates Pancreatic Tumorigenesis in Mice.PubMed
Lu Zhuang, Xianbao Zhan, Yan Bi, et al.
Methods Mol Biol. 2019;1882:287-297. doi: 10.1007/978-1-4939-8879-2_25.
Pancreatitis is a major risk factor for the development of pancreatic cancer. In genetically engineered mouse models, induction of pancreatic inflammation dramatically accelerates oncogenic KRas-induced fibrosis, precancerous PanIN formation, and tumorigenesis. Here we describe simple methods of secretagogue-induced experimental acute and chronic pancreatitis, the most commonly used pancreatitis models, and their applications in pancreatic cancer research. Additionally, the preparation of primary pancreatic acinar cells is introduced. Primary acinar cells can be used to study the early events of pancreatic inflammation and pancreatic acinar-to-ductal (ADM) metaplasia.
85Suppression of dystroglycan function accompanies pancreatic acinar-to-ductal metaplasia and favours dysplasia development.PubMed
Ge Huang, Luke Ternes, Christian Lanciault, et al.
J Pathol. 2024 Dec;264(4):411-422. doi: 10.1002/path.6356. Epub 2024 Oct 22.
The basement membrane (BM) is among the predominant microenvironmental factors of normal epithelia and of precancerous epithelial lesions. Evidence suggests that the BM functions not only as a barrier to tumour invasion but also as an active tumour-suppressing signalling substrate during premalignancy. However, the molecular foundations of such mechanisms have not been elucidated. Here we explore potential tumour-suppressing functions of the BM during precancer evolution, focusing on the expression and function of the extracellular matrix receptor dystroglycan in the pancreas and pancreatic disease. We show that the dystroglycan protein is highly expressed in the acinar compartment of the normal pancreas but lower in the ductal compartment. Moreover, there is a strong suppression of dystroglycan protein expression with acinar-to-ductal metaplasia in chronic pancreatitis and in all stages of pancreatic precancer and cancer evolution, from acinar-to-ductal metaplasia to dysplasia to adenocarcinoma. The conditional knockout of dystroglycan in the murine pancreas produced little evidence of developmental or functional deficiency. However, conditional deletion of dystroglycan expression in the context of oncogenic Kras expression led to a clear acceleration of pancreatic disease evolution, including accelerated dysplasia development and decreased survival. These data establish dystroglycan as a suppressor of pancreatic dysplasia development and one that is muted in chronic pancreatitis and at the earliest stages of oncogene-induced transformation. We conclude that dystroglycan is an important mediator of the tumour-suppressing functions of the BM during precancer evolution and that reduced dystroglycan function increases cancer risk, highlighting the dynamics of cell-BM interactions as important determinants of early cancer progression. © 2024 The Pathological Society of Great Britain and Ireland.
86Phosphatidylinositol 3-Kinase: A Link Between Inflammation and Pancreatic Cancer.PubMed
Chiara Birtolo, Vay Liang W Go, Andrzej Ptasznik, et al.
Pancreas. 2016 Jan;45(1):21-31. doi: 10.1097/MPA.0000000000000531.
Even though a strong association between inflammation and cancer has been widely accepted, the underlying precise molecular mechanisms are still largely unknown. A complex signaling network between tumor and stromal cells is responsible for the infiltration of inflammatory cells into the cancer microenvironment. Tumor stromal cells such as pancreatic stellate cells (PSCs) and immune cells create a microenvironment that protects cancer cells through a complex interaction, ultimately facilitating their local proliferation and their migration to different sites. Furthermore, PSCs have multiple functions related to local immunity, angiogenesis, inflammation, and fibrosis. Recently, many studies have shown that members of the phosphoinositol-3-phosphate kinase (PI3K) family are activated in tumor cells, PSCs, and tumor-infiltrating inflammatory cells to promote cancer growth. Proinflammatory cytokines and chemokines secreted by immune cells and fibroblasts within the tumor environment can activate the PI3K pathway both in cancer and inflammatory cells. In this review, we focus on the central role of the PI3K pathway in regulating the cross talk between immune/stromal cells and cancer cells. Understanding the role of the PI3K pathway in the development of chronic pancreatitis and cancer is crucial for the discovery of novel and efficacious treatment options.
87Regulation of p38 MAPK and glucocorticoid receptor activation by hydrocortisone in mono-and co-cultured pancreatic acinar and stellate cells.PubMed
Merja Bläuer, Juhani Sand, Johanna Laukkarinen
Pancreatology. 2021 Mar;21(2):384-389. doi: 10.1016/j.pan.2020.12.024. Epub 2021 Jan 6.
BACKGROUND/OBJECTIVES: Acute pancreatitis develops as an inflammatory response to pancreatic tissue injury. Postoperative pancreatitis has recently been associated with increased occurrence of complications. Activation of the mitogen-activated protein kinase p38 (p38 MAPK) pathway occurs early in acute pancreatitis and its inhibition has been suggested to alleviate pancreatic inflammation. Glucocorticoids are potent anti-inflammatory steroids whose use in the management of acute pancreatitis remains controversial. Our aim was to examine the effect of crosstalk between pancreatic acinar cells (PACs) and stellate cells (PSCs) on p38 MAPK and glucocorticoid receptor (GR) activation and to assess the impact of hydrocortisone on these events. METHODS: The long-term co-culture setting for mouse PACs and PSCs developed in our laboratory was used. Parallel 4d mono- and co-cultures with or without 10 nM hydrocortisone were performed followed by immunocytochemical analysis of nuclear GR and phospho-p38 MAPK (pp38 MAPK). RESULTS: Hydrocortisone inhibited pp38 MAPK up-regulation evoked by co-culture in PACs and PSCs and increased nuclear translocation of GR in PAC monocultures and in co-cultured PACs and PSCs. In PSC monocultures and co-cultured PACs, ligand-independent expression of nuclear GR was observed. In the former no change in nuclear GR but a significant decrease in total GR as analyzed by Western blot was caused by hydrocortisone. CONCLUSIONS: Cellular microenvironment plays a significant role on p38 MAPK and GR activation in PACs and PSCs. Hydrocortisone is an effective means to inhibit p38 MAPK activation in PACs and PSCs. Both ligand-dependent and -independent regulatory roles for GR are suggested in the exocrine pancreas.
88Slug inhibits pancreatic cancer initiation by blocking Kras-induced acinar-ductal metaplasia.PubMed
Kazumi Ebine, Christina R Chow, Brian T DeCant, et al.
Sci Rep. 2016 Jul 1;6:29133. doi: 10.1038/srep29133.
Cells in the pancreas that have undergone acinar-ductal metaplasia (ADM) can transform into premalignant cells that can eventually become cancerous. Although the epithelial-mesenchymal transition regulator Snail (Snai1) can cooperate with Kras in acinar cells to enhance ADM development, the contribution of Snail-related protein Slug (Snai2) to ADM development is not known. Thus, transgenic mice expressing Slug and Kras in acinar cells were generated. Surprisingly, Slug attenuated Kras-induced ADM development, ERK1/2 phosphorylation and proliferation. Co-expression of Slug with Kras also attenuated chronic pancreatitis-induced changes in ADM development and fibrosis. In addition, Slug attenuated TGF-α-induced acinar cell metaplasia to ductal structures and TGF-α-induced expression of ductal markers in ex vivo acinar explant cultures. Significantly, blocking the Rho-associated protein kinase ROCK1/2 in the ex vivo cultures induced expression of ductal markers and reversed the effects of Slug by inducing ductal structures. In addition, blocking ROCK1/2 activity in Slug-expressing Kras mice reversed the inhibitory effects of Slug on ADM, ERK1/2 phosphorylation, proliferation and fibrosis. Overall, these results increase our understanding of the role of Slug in ADM, an early event that can eventually lead to pancreatic cancer development.
89Akt1 signalling supports acinar proliferation and limits acinar-to-ductal metaplasia formation upon induction of acute pancreatitis.PubMed
Rong Chen, Ermanno Malagola, Maren Dietrich, et al.
J Pathol. 2020 Jan;250(1):42-54. doi: 10.1002/path.5348. Epub 2019 Nov 22.
Molecular signalling mediated by the phosphatidylinositol-3-kinase (PI3K)-Akt axis is a key regulator of cellular functions. Importantly, alteration of the PI3K-Akt signalling underlies the development of different human diseases, thus prompting the investigation of the pathway as a molecular target for pharmacologic intervention. In this regard, recent studies showed that small molecule inhibitors of PI3K, the upstream regulator of the pathway, reduced the development of inflammation during acute pancreatitis, a highly debilitating and potentially lethal disease. Here we investigated whether a specific reduction of Akt activity, by using either pharmacologic Akt inhibition, or genetic inactivation of the Akt1 isoform selectively in pancreatic acinar cells, is effective in ameliorating the onset and progression of the disease. We discovered that systemic reduction of Akt activity did not protect the pancreas from initial damage and only transiently delayed leukocyte recruitment. However, reduction of Akt activity decreased acinar proliferation and exacerbated acinar-to-ductal metaplasia (ADM) formation, two critical events in the progression of pancreatitis. These phenotypes were recapitulated upon conditional inactivation of Akt1 in acinar cells, which resulted in reduced expression of 4E-BP1, a multifunctional protein of key importance in cell proliferation and metaplasia formation. Collectively, our results highlight the critical role played by Akt1 during the development of acute pancreatitis in the control of acinar cell proliferation and ADM formation. In addition, these results harbour important translational implications as they raise the concern that inhibitors of PI3K-Akt signalling pathways may negatively affect the regeneration of the pancreas. Finally, this work provides the basis for further investigating the potential of Akt1 activators to boost pancreatic regeneration following inflammatory insults. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
90Hereditary chronic pancreatitis.PubMed
Jonas Rosendahl, Hans Bödeker, Joachim Mössner, et al.
Orphanet J Rare Dis. 2007 Jan 4;2:1. doi: 10.1186/1750-1172-2-1.
Hereditary chronic pancreatitis (HCP) is a very rare form of early onset chronic pancreatitis. With the exception of the young age at diagnosis and a slower progression, the clinical course, morphological features and laboratory findings of HCP do not differ from those of patients with alcoholic chronic pancreatitis. As well, diagnostic criteria and treatment of HCP resemble that of chronic pancreatitis of other causes. The clinical presentation is highly variable and includes chronic abdominal pain, impairment of endocrine and exocrine pancreatic function, nausea and vomiting, maldigestion, diabetes, pseudocysts, bile duct and duodenal obstruction, and rarely pancreatic cancer. Fortunately, most patients have a mild disease. Mutations in the PRSS1 gene, encoding cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin, and thus probably cause premature, intrapancreatic trypsinogen activation disturbing the intrapancreatic balance of proteases and their inhibitors. Other genes, such as the anionic trypsinogen (PRSS2), the serine protease inhibitor, Kazal type 1 (SPINK1) and the cystic fibrosis transmembrane conductance regulator (CFTR) have been found to be associated with chronic pancreatitis (idiopathic and hereditary) as well. Genetic testing should only be performed in carefully selected patients by direct DNA sequencing and antenatal diagnosis should not be encouraged. Treatment focuses on enzyme and nutritional supplementation, pain management, pancreatic diabetes, and local organ complications, such as pseudocysts, bile duct or duodenal obstruction. The disease course and prognosis of patients with HCP is unpredictable. Pancreatic cancer risk is elevated. Therefore, HCP patients should strongly avoid environmental risk factors for pancreatic cancer.
91Hereditary pancreatitis in children: surgical implications with special regard to genetic background.PubMed
Françoise Schmitt, Gaelle Le Henaff, Hugues Piloquet, et al.
J Pediatr Surg. 2009 Nov;44(11):2078-82. doi: 10.1016/j.jpedsurg.2009.05.023.
PURPOSE: Hereditary pancreatitis (HP) is the primary etiology of chronic pancreatitis during childhood, progressing through recurrent episodes of acute pancreatitis and finally leading to pancreatic insufficiencies. Hereditary pancreatitis is because of mutations of the cationic trypsinogen (PRSS1) gene. Some other genes, such as SPINK1 or CFTR, have been associated with familial idiopathic chronic pancreatitis. The aim of our study was to clearly define diagnostic and therapeutic strategies for HP patients, through an analysis of our study group and a review of the literature. METHODS: All children admitted from 1995 to 2007 with a final diagnosis of hereditary pancreatitis were restrospectively included in the study. We analyzed all medical records with special attention given to cases involving genetic screening (PRSS1, SPINK1, and CFTR genes). RESULTS: Ten children were included. Eight had HP with PRSS1 mutation, 2 of them without a familial history of chronic pancreatitis. The 2 others patients had SPINK1 mutations. Three HP patients were operated on for acute complications of pancreatitis and are well with a mean follow-up of 5.5 years. No patient had pancreatic insufficiencies or weight loss. CONCLUSIONS: Hereditary pancreatitis is associated with severe pancreatitis, with a greater risk of developing pancreatic cancer. It must therefore be diagnosed correctly and treated to prevent its considerable complications.
92PRSS1 intron mutations in patients with pancreatic cancer and chronic pancreatitis.PubMed
Feng Gao, Qi-Cai Liu, Sheng Zhang, et al.
Mol Med Rep. 2012 Feb;5(2):449-51. doi: 10.3892/mmr.2011.684. Epub 2011 Nov 21.
Genetic risk factors of chronic pancreatitis (CP) have been identified and a number of studies have found that CP can lead to pancreatic cancer. Therefore, the detection of pancreatitis-associated gene mutations can aid the pancreatic cancer diagnostic process. Mutations in three genes, the cationic trypsinogen (PRSS1) gene, the cystic fibrosis transmembrane conductance regulator (CFTR) gene and the pancreatic secretory trypsin inhibitor (SPINK1) gene, have been identified as risk factors for CP. The aim of this study was to describe specific novel mutations in the intron of the PRSS1 gene in patients with pancreatic cancer and CP. A total of 65 unrelated patients with pancreatic cancer and 29 with CP were reviewed. Mutations and polymorphisms of the PRSS1 gene were analyzed by direct sequencing. Information regarding clinical data and smoking exposure was collected by personal interviews using a structured questionnaire. IVS 3+36 A>G mutation in the PRSS1 gene was found in 2 cases with pancreatic cancer, and these 2 patients were classified as never-smokers. IVS 3+127 T>A and IVS 3+157 G>C double mutations were identified in one patient with CP. All patients were found to have serum trypsin levels lower than that of the normal controls. Therefore, the PRSS1 gene mutation may be a special common cause of pancreatic cancer and CP.
93CFTR, SPINK1, PRSS1, and CTRC mutations are not associated with pancreatic cancer in German patients.PubMed
Stephanie Schubert, Frank Traub, Kai Brakensiek, et al.
Pancreas. 2014 Oct;43(7):1078-82. doi: 10.1097/MPA.0000000000000166.
OBJECTIVE: Mutations in the cationic trypsinogen (PRSS1), cystic fibrosis transmembrane conductance regulator (CFTR), serine protease inhibitor Kazal type 1 (SPINK1), and chymotrypsin C (CTRC) genes are associated with an elevated risk for chronic pancreatitis, which is a known risk factor for pancreatic cancer (PC). Therefore, we analyzed whether PRSS1, CFTR, SPINK1, and/or CTRC mutations are associated with pancreatic adenocarcinoma. METHODS: The study cohort was composed of 121 PC patients, of whom 74 were classified as having chronic pancreatitis, 102 patients with idiopathic chronic pancreatitis, and 130 as healthy controls. Mutation analyses for the CFTR, SPINK1, PRSS1, and CTRC genes were performed for the presence of the most common mutations. RESULTS: The frequency of CFTR mutations in patients with PC was not significantly different in comparison with healthy controls and controls with pancreatitis. The SPINK1 mutation frequency was significantly decreased in patients with PC in comparison with patients with idiopathic pancreatitis but varied not significantly in comparison with healthy controls. None of the selected 121 PC samples showed a pancreatitis-predisposing mutation in the PRSS1 or CTRC gene. CONCLUSIONS: Mutations in the genes CFTR, SPINK1, PRSS1, and CTRC do not seem to significantly increase the risk for pancreatic adenocarcinoma.
94Clinical and morphological characteristics of sporadic genetically determined pancreatitis as compared to idiopathic pancreatitis: higher risk of pancreatic cancer in CFTR variants.PubMed
Coralie Hamoir, Xavier Pepermans, Hubert Piessevaux, et al.
Digestion. 2013;87(4):229-39. doi: 10.1159/000348439. Epub 2013 Jun 4.
BACKGROUND/AIMS: Idiopathic pancreatitis is considered to be a multigenic and multifactorial disease. Genetically determined pancreatitis is associated with mutations in the PRSS1,SPINK1 and CFTR genes. This study aimed at examining the clinical and morphological characteristics of patients diagnosed with genetically determined sporadic pancreatitis. METHODS: Inclusion criteria were the presence of PRSS1,CFTR or SPINK1 gene mutations in patients with idiopathic recurrent or chronic pancreatitis. Patients with hereditary pancreatitis were excluded. Age- and sex-matched patients with idiopathic pancreatitis and negative genetic testing served as controls (n = 68). RESULTS: Genetic testing was performed in 351 probands referred to our centre since 1999. Sixty-one patients (17.4%) carried at least 1 detected mutation in 1 of the 3 tested genes (34 CFTR, 10 PRSS1 and 13 SPINK1 mutations), and 4 patients showed a combination of mutations. Follow-up has been currently extended to a median of 5 years (range 1-40). Similar clinical features were noted in the case and matched groups except for an earlier age of onset of pancreatic symptoms and a higher incidence of pancreatic cancer in the case group and in patients with CFTR mutations compared to the control group (p < 0.05). The standardized incidence ratio, the ratio of observed to expected pancreatic cancers, averaged 26.5 (95% confidence interval 8.6-61.9). All pancreatic cancer patients were smokers. CONCLUSION: Clinical parameters of patients with sporadic idiopathic pancreatitis and gene mutations are similar to those of age- and sex-matched patients without gene mutations, except for the age of pancreatic disease onset. A significantly higher occurrence of pancreas cancer was observed in the case group, particularly in those patients carrying CFTR mutations. We therefore suggest to include patients with CFTR variants presenting with risk factors in a screening and surveillance programme and to strongly advise them to stop smoking.
95Gene-by-Environment Interactions in Pancreatic Cancer: Implications for Prevention.PubMed
Rick J Jansen, Xiang-Lin Tan, Gloria M Petersen
Yale J Biol Med. 2015 Jun 1;88(2):115-26. eCollection 2015 Jun.
Pancreatic cancer (PC) has been estimated to have higher incidence and correspondingly higher mortality rates in more developed regions worldwide. Overall, the age-adjusted incidence rate is 4.9/10(5) and age-adjusted mortality rate is at 4.8/10(5). We review here our current knowledge of modifiable risk factors (cigarette smoking, obesity, diet, and alcohol) for PC, genetic variants implicated by genome-wide association studies, possible genetic interactions with risk factors, and prevention strategies to provide future research directions that may further our understanding of this complex disease. Cigarette smoking is consistently associated with a two-fold increased PC risk. PC associations with dietary intake have been largely inconsistent, with the potential exception of certain unsaturated fatty acids decreasing risk and well-done red meat or meat mutagens increasing risk. There is strong evidence to support that obesity (and related measures) increase risk of PC. Only the heaviest alcohol drinkers seem to be at an increased risk of PC. Currently, key prevention strategies include avoiding tobacco and excessive alcohol consumption and adopting a healthy lifestyle. Screening technologies and PC chemoprevention are likely to become more sophisticated, but may only apply to those at high risk. Risk stratification may be improved by taking into account gene environment interactions. Research on these modifiable risk factors is key to reducing the incidence of PC and understanding who in the population can be considered high risk.
96Identification of a novel heterozygous GPD1 missense variant in a Chinese adult patient with recurrent HTG-AP consuming a high-fat diet and heavy smoking.PubMed
Xiao-Yao Li, Bei-Yuan Zhang, Xin-Ran Liang, et al.
BMC Med Genomics. 2025 Jan 23;18(1):17. doi: 10.1186/s12920-025-02088-6.
BACKGROUND: Glycerol-3-phosphate dehydrogenase 1 (GPD1) gene defect can cause hypertriglyceridemia (HTG), which usually occurs in infants. The gene defect has rarely been reported in adult HTG patients. In the present study, we described the clinical and functional analyses of a novel GPD1 missense variant in a Chinese adult patient with recurrent hypertriglyceridemia‑related acute pancreatitis (HTG-AP), consuming a high-fat diet and smoking heavily. METHODS: Exome sequencing was used to analyze the DNA of the adult patient's blood sample. It was found that there was a new variant of GPD1 gene-p.K327N, which was verified by gold standard-sanger sequencing method. In vitro, the corresponding plasmid was constructed and transfected into human renal HEK-293T cells, and GPD1 protein levels were detected. A biogenic analysis was performed to study the population frequency, conservation, and electric potential diagram of the new variant p.K327N. Finally, the previously reported GPD1 variants were sorted and their phenotypic relationships were compared. RESULTS: A novel heterozygous variant of GPD1, p.K327N (c.981G > C), was found in the proband. Furthermore, the patient's daughter carried this variant, whereas his wife did not carry the variant. The proband with obesity suffered eight episodes of HTG-AP from the age of 36 years, and each onset of AP was correlated to high-fat diet consumption and heavy smoking. In vitro, this variant exerted a relatively mild effect on GPD1 functions, which were associated with its effect upon secretion (~ 25% of secretion decreased compared with that of the wild-type); thus, eventually impairing protein synthesis. Additionally, 36 patients with GPD1 variants found in previous studies showed significant transient HTG in infancy. The proband carrying the GDP1 variant was the first reported adult with recurrent HTG-AP. CONCLUSION: We identified a novel GPD1 variant, p.K327N, in a Chinese adult male patient with recurrent HTG-AP. The variant probably exerted a mild effect on GPD1 functions. The heterozygosity of this GPD1 variant, in addition to high-fat diet consumption and heavy smoking, probably triggered HTG-AP in the patient.
97Detection of K-ras point mutation and telomerase activity during endoscopic retrograde cholangiopancreatography in diagnosis of pancreatic cancer.PubMed
Guo-Xiong Zhou, Jie-Fei Huang, Zhao-Shen Li, et al.
World J Gastroenterol. 2004 May 1;10(9):1337-40. doi: 10.3748/wjg.v10.i9.1337.
AIM: To study the value of monitoring K-ras point mutation at codon 12 and telomerase activity in exfoliated cells obtained from pancreatic duct brushings during endoscopic retrograde cholangiopancreatography (ERCP) in the diagnosis of pancreatic cancer. METHODS: Exfoliated cells obtained from pancreatic duct brushings during ERCP were examined in 27 patients: 23 with pancreatic cancers, 4 with chronic pancreatitis. K-ras point mutation was detected with the polymerase chain reaction and restriction fragment-length polymorphism (PCR-RFLP). Telomerase activity was detected by PCR and telomeric repeat amplification protocol assay (PCR-TRAP-ELISA). RESULTS: The telomerase activities in 27 patients were measured in 21 exfoliated cell samples obtained from pancreatic duct brushings. D450 value of telomerase activities in pancreatic cancer and chronic pancreatitis were 0.446+/-0.27 and 0.041+/-0.0111, respectively. Seventy-seven point eight percent (14/18) of patients with pancreatic cancer and none of the patients with chronic pancreatitis showed telomerase activity in cells collected from pancreatic duct brushings when cutoff value of telomerase activity was set at 2.0. The K-ras gene mutation rate (72.2%) in pancreatic cancer was higher than that in chronic pancreatitis (33.3%) (P<0.05). In considering of both telomerase activities and K-ras point mutation, the total positive rate was 83.3%(15/18), and the specificity was 100%. CONCLUSION: Changes of telomerase activities and K-ras point mutation at codon 12 may be an early event of malignant progression in pancreatic cancer. Detection of telomerase activity and K-ras point mutation at codon 12 may be complementary to each other, and is useful in diagnosis of pancreatic cancer.
98Pancreatic intraepithelial neoplasia in heterotopic pancreas: evidence for the progression model of pancreatic ductal adenocarcinoma.PubMed
Lizhi Zhang, Schuyler O Sanderson, Ricardo V Lloyd, et al.
Am J Surg Pathol. 2007 Aug;31(8):1191-5. doi: 10.1097/PAS.0b013e31806841e1.
Morphologic, clinical, and genetic evidence suggests that pancreatic intraepithelial neoplasia (PanIN) is a precursor to ductal adenocarcinoma. But understanding precursor lesions in a pancreas with existing tumor is hampered by the fact that chronic pancreatitis often accompanies carcinoma, and the possible interactions between tumor, chronic pancreatitis, and PanIN are complex. Furthermore, cancerization of ducts can mimic high-grade PanIN. Heterotopic pancreas has a genetic make-up, physiologic function, and local environmental exposure similar to that of the pancreas. It offers an opportunity to study putative precursor lesions in a setting with fewer confounding factors. We identified 6 pancreatic cancer patients who had heterotopic pancreas removed at the time of surgery. All 6 cases were immunostained for p53, cyclin D1, and p16. Molecular analysis of K-ras mutation was also done. All 6 cancer-associated heterotopias had PanIN-1A or 1B; 5 had PanIN-2 and 1 had PanIN-3. Three of 6 cases harbored the same K-ras codon 12 mutation as the PanINs in orthotopic pancreas, and a similar pattern of p53, cyclin D1, and p16 expression was observed between heterotopic and orthotopic pancreas in all 6 cases. There was no chronic pancreatitis in the cancer-associated heterotopias, but chronic pancreatitis was seen adjacent to carcinoma in 5 of 6 cases. The presence of PanIN in heterotopic pancreas from patients with ductal adenocarcinoma supports the progression model.
99From pancreatic intraepithelial neoplasia to cancer: a dramatic progression with K-ras status analysis.PubMed
Carla Fernandez, Bruno Chetaille, Anne-Marie Tasei, et al.
Gastroenterol Clin Biol. 2005 Apr;29(4):465-8. doi: 10.1016/s0399-8320(05)80818-8.
Pancreatic ductal carcinomas are thought to arise from precursor ductal lesions called pancreatic intra-epithelial neoplasias or PanINs. We report the case of a woman suffering from idiopathic chronic pancreatitis associated with PanINs lesions who developed six years later an invasive ductal carcinoma. Immunohistochemistry for p53, HER-2/neu and genetic analysis of K-ras oncogene were performed at different stages of disease and revealed that the PanINs and the carcinoma did not express p53 and HER-2/neu gene products whereas a K-ras mutation was present at the carcinoma stage. The relationship between cancer and chronic pancreatitis and the main difficulties concerning the early diagnostic of pancreatic cancer are discussed.
100A gene-environment-induced epigenetic program initiates tumorigenesis.PubMed
Direna Alonso-Curbelo, Yu-Jui Ho, Cassandra Burdziak, et al.
Nature. 2021 Feb;590(7847):642-648. doi: 10.1038/s41586-020-03147-x. Epub 2021 Feb 3.
Tissue damage increases the risk of cancer through poorly understood mechanisms. In mouse models of pancreatic cancer, pancreatitis associated with tissue injury collaborates with activating mutations in the Kras oncogene to markedly accelerate the formation of early neoplastic lesions and, ultimately, adenocarcinoma. Here, by integrating genomics, single-cell chromatin assays and spatiotemporally controlled functional perturbations in autochthonous mouse models, we show that the combination of Kras mutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution. This cancer-associated epigenetic state emerges within 48 hours of pancreatic injury, and involves an 'acinar-to-neoplasia' chromatin switch that contributes to the early dysregulation of genes that define human pancreatic cancer. Among the factors that are most rapidly activated after tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine interleukin 33, which recapitulates the effects of injury in cooperating with mutant Kras to unleash the epigenetic remodelling program of early neoplasia and neoplastic transformation. Collectively, our study demonstrates how gene-environment interactions can rapidly produce gene-regulatory programs that dictate early neoplastic commitment, and provides a molecular framework for understanding the interplay between genetic and environmental cues in the initiation of cancer.
101HMG Box-containing Protein 1 (HBP1) Protects Against Pancreatic Injury in Acute Pancreatitis but Promotes Neoplastic Progression.PubMed
Seung-Won Lee, Taelor Ekstrom, Elise C Manalo, et al.
Cell Mol Gastroenterol Hepatol. 2025;19(9):101536. doi: 10.1016/j.jcmgh.2025.101536. Epub 2025 May 20.
BACKGROUND & AIMS: Pancreatitis is an inflammatory disease of the exocrine pancreas and a known risk factor for pancreatic ductal adenocarcinoma (PDAC). Previously, we identified HMG-box transcription factor 1 (HBP1) as a potential master transcription factor (TF) in the early progression of PDAC, with its expression associated with poor patient survival, underscoring its significance in pancreatic disease. However, the functional role of HBP1 in the onset and progression of acute pancreatitis (AP) remains unknown. METHODS: We examined HBP1 expression in human pancreatitis samples and a cerulein-induced AP mouse model. Pancreatic-specific conditional HBP1 knockout mice, with or without an oncogenic Kras mutation, were generated and compared with their littermate controls. Spatial transcriptomics and multiplexed protein assays, histologic analysis, and immunostaining were utilized to characterize pathologic changes. Findings from mouse models were validated using inducible HBP1-overexpressing human pancreatic ductal epithelial cells. RESULTS: HBP1 was upregulated in pancreatic exocrine cells in human chronic pancreatitis and mouse acute pancreatitis, with its expression in human chronic pancreatitis correlating with cancer presence. Pancreatic HBP1 ablation disrupted acinar homeostasis by impairing autophagic flux and exacerbating inflammation following injury. In the presence of oncogenic KRAS, HBP1 ablation delayed the formation of pancreatic intraepithelial neoplasia (PanIN), the precursor to PDAC, and slowed its progression to higher-grade lesions. CONCLUSIONS: HBP1 upregulation in pancreatitis mitigates pancreatic inflammatory injury; however, in the presence of oncogenic KRAS, it facilitates PanIN progression. Thus, HBP1 serves as a critical regulator in both pancreatitis and early pancreatic neoplasia, representing a potential therapeutic target for intervening pancreatitis and PanIN progression.
102NF-κB, inflammation, immunity and cancer: coming of age.PubMed
Koji Taniguchi, Michael Karin
Nat Rev Immunol. 2018 May;18(5):309-324. doi: 10.1038/nri.2017.142. Epub 2018 Jan 22.
Fourteen years have passed since nuclear factor-κB (NF-κB) was first shown to serve as a molecular lynchpin that links persistent infections and chronic inflammation to increased cancer risk. The young field of inflammation and cancer has now come of age, and inflammation has been recognized by the broad cancer research community as a hallmark and cause of cancer. Here, we discuss how the initial discovery of a role for NF-κB in linking inflammation and cancer led to an improved understanding of tumour-elicited inflammation and its effects on anticancer immunity.
103Chronic Inflammation's Transformation to Cancer: A Nanotherapeutic Paradigm.PubMed
Sayed Sartaj Sohrab, Riya Raj, Amka Nagar, et al.
Molecules. 2023 May 29;28(11):4413. doi: 10.3390/molecules28114413.
The body's normal immune response against any invading pathogen that causes infection in the body results in inflammation. The sudden transformation in inflammation leads to the rise of inflammatory diseases such as chronic inflammatory bowel disease, autoimmune disorders, and colorectal cancer (different types of cancer develop at the site of chronic infection and inflammation). Inflammation results in two ways: short-term inflammation i.e., non-specific, involves the action of various immune cells; the other results in long-term reactions lasting for months or years. It is specific and causes angiogenesis, fibrosis, tissue destruction, and cancer progression at the site of inflammation. Cancer progression relies on the interaction between the host microenvironment and tumor cells along with the inflammatory responses, fibroblast, and vascular cells. The two pathways that have been identified connecting inflammation and cancer are the extrinsic and intrinsic pathways. Both have their own specific role in linking inflammation to cancer, involving various transcription factors such as Nuclear factor kappa B, Activator of transcription, Single transducer, and Hypoxia-inducible factor, which in turn regulates the inflammatory responses via Soluble mediators cytokines (such as Interleukin-6, Hematopoietin-1/Erythropoietin, and tumor necrosis factor), chemokines (such as Cyclooxygenase-2, C-X-C Motif chemokines ligand-8, and IL-8), inflammatory cells, cellular components (such as suppressor cells derived from myeloid, tumor-associated macrophage, and acidophils), and promotes tumorigenesis. The treatment of these chronic inflammatory diseases is challenging and needs early detection and diagnosis. Nanotechnology is a booming field nowadays for its rapid action and easy penetration inside the infected destined cells. Nanoparticles are widely classified into different categories based on their different factors and properties such as size, shape, cytotoxicity, and others. Nanoparticles emerged as excellent with highly progressive medical inventions to cure diseases such as cancer, inflammatory diseases, and others. Nanoparticles have shown higher binding capacity with the biomolecules in inflammation reduction and lowers the oxidative stress inside tissue/cells. In this review, we have overall discussed inflammatory pathways that link inflammation to cancer, major inflammatory diseases, and the potent action of nanoparticles in chronic inflammation-related diseases.
104Knockdown of trem2 promotes proinflammatory microglia and inhibits glioma progression via the JAK2/STAT3 and NF-κB pathways.PubMed
Yunji Yan, Shengwei Bai, Hongxi Han, et al.
Cell Commun Signal. 2024 May 15;22(1):272. doi: 10.1186/s12964-024-01642-6.
BACKGROUND: In the tumor immune microenvironment (TIME), triggering receptor expressed on myeloid cells 2 (trem2) is widely considered to be a crucial molecule on tumor-associated macrophages(TAMs). Multiple studies have shown that trem2 may function as an immune checkpoint in various malignant tumors, mediating tumor immune evasion. However, its specific molecular mechanisms, especially in glioma, remain elusive. METHODS: Lentivirus was transfected to establish cells with stable knockdown of trem2. A Transwell system was used for segregated coculture of glioma cells and microglia. Western blotting, quantitative real-time polymerase chain reaction (qRT‒PCR), and immunofluorescence (IF) were used to measure the expression levels of target proteins. The proliferation, invasion, and migration of cells were detected by colony formation, cell counting kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU) and transwell assays. The cell cycle, apoptosis rate and reactive oxygen species (ROS) level of cells were assessed using flow cytometry assays. The comet assay and tube formation assay were used to detect DNA damage in glioma cells and angiogenesis activity, respectively. Gl261 cell lines and C57BL/6 mice were used to construct the glioma orthotopic transplantation tumor model. RESULTS: Trem2 was highly overexpressed in glioma TAMs. Knocking down trem2 in microglia suppressed the growth and angiogenesis activity of glioma cells in vivo and in vitro. Mechanistically, knockdown of trem2 in microglia promoted proinflammatory microglia and inhibited anti-inflammatory microglia by activating jak2/stat1 and inhibiting the NF-κB p50 signaling pathway. The proinflammatory microglia produced high concentrations of nitric oxide (NO) and high levels of the proinflammatory cytokines TNF-α, IL-6, and IL-1β, and caused further DNA damage and promoted the apoptosis rate of tumor cells. CONCLUSIONS: Our findings revealed that trem2 in microglia plays a significant role in the TIME of gliomas. Knockdown of trem2 in microglia might help to improve the efficiency of inhibiting glioma growth and delaying tumor progression and provide new ideas for further treatment of glioma.
105Signal transducer and activator of transcription 3-mediated CD133 up-regulation contributes to promotion of hepatocellular carcinoma.PubMed
Cheolhee Won, Byung-Hak Kim, Eun Hee Yi, et al.
Hepatology. 2015 Oct;62(4):1160-73. doi: 10.1002/hep.27968. Epub 2015 Aug 28.
UNLABELLED: Enhanced expression of the cancer stem cell (CSC) marker, CD133, is closely associated with a higher rate of tumor formation and poor prognosis in hepatocellular carcinoma (HCC) patients. Despite its clinical significance, the molecular mechanism underlying the deregulation of CD133 during tumor progression remains to be clarified. Here, we report on a novel mechanism by which interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling up-regulates expression of CD133 and promotes HCC progression. STAT3 activated by IL-6 rapidly bound to CD133 promoter and increased protein levels of CD133 in HCC cells. Reversely, in hypoxic conditions, RNA interference silencing of STAT3 resulted in decrease of CD133 levels, even in the presence of IL-6, with a concomitant decrease of hypoxia-inducible factor 1 alpha (HIF-1α) expression. Active STAT3 interacted with nuclear factor kappa B (NF-κB) p65 subunit to positively regulate the transcription of HIF-1α providing a mechanistic explanation on how those three oncogenes work together to increase the activity of CD133 in a hypoxic liver microenvironment. Activation of STAT3 and its consequent induction of HIF-1α and CD133 expression were not observed in Toll-like receptor 4/IL-6 double-knockout mice. Long-term silencing of CD133 by a lentiviral-based approach inhibited cancer cell-cycle progression and suppressed in vivo tumorigenicity by down-regulating expression of cytokinesis-related genes, such as TACC1, ACF7, and CKAP5. We also found that sorafenib and STAT3 inhibitor nifuroxazide inhibit HCC xenograft formation by blocking activation of STAT3 and expression of CD133 and HIF-1α proteins. CONCLUSION: IL-6/STAT3 signaling induces expression of CD133 through functional cooperation with NF-κB and HIF-1α during liver carcinogenesis. Targeting STAT3-mediated CD133 up-regulation may represent a novel, effective treatment by eradicating the liver tumor microenvironment.
106Apolipoprotein E Promotes Immune Suppression in Pancreatic Cancer through NF-κB-Mediated Production of CXCL1.PubMed
Samantha B Kemp, Eileen S Carpenter, Nina G Steele, et al.
Cancer Res. 2021 Aug 15;81(16):4305-4318. doi: 10.1158/0008-5472.CAN-20-3929. Epub 2021 May 28.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with few effective therapeutic options. PDAC is characterized by an extensive fibroinflammatory stroma that includes abundant infiltrating immune cells. Tumor-associated macrophages (TAM) are prevalent within the stroma and are key drivers of immunosuppression. TAMs in human and murine PDAC are characterized by elevated expression of apolipoprotein E (ApoE), an apolipoprotein that mediates cholesterol metabolism and has known roles in cardiovascular and Alzheimer's disease but no known role in PDAC. We report here that ApoE is also elevated in peripheral blood monocytes in PDAC patients, and plasma ApoE protein levels stratify patient survival. Orthotopic implantation of mouse PDAC cells into syngeneic wild-type or in mice showed reduced tumor growth in mice. Histologic and mass cytometric (CyTOF) analysis of these tumors showed an increase in CD8 T cells in tumors in mice. Mechanistically, ApoE induced pancreatic tumor cell expression of and , known immunosuppressive factors, through LDL receptor and NF-κB signaling. Taken together, this study reveals a novel immunosuppressive role of ApoE in the PDAC microenvironment. SIGNIFICANCE: This study shows that elevated apolipoprotein E in PDAC mediates immune suppression and high serum apolipoprotein E levels correlate with poor patient survival..
107Intersection of retinoblastoma tumor suppressor function, stem cells, metabolism, and inflammation.PubMed
Shunsuke Kitajima, Chiaki Takahashi
Cancer Sci. 2017 Sep;108(9):1726-1731. doi: 10.1111/cas.13312. Epub 2017 Jul 29.
The Retinoblastoma (RB) tumor suppressor regulates G /S transition during cell cycle progression by modulating the activity of E2F transcription factors. The RB pathway plays a central role in the suppression of most cancers, and RB mutation was initially discovered by virtue of its role in tumor initiation. However, as cancer genome sequencing has evolved to profile more advanced and treatment-resistant cancers, it has become increasingly clear that, in the majority of cancers, somatic RB inactivation occurs during tumor progression. Furthermore, despite the presence of deregulation of cell cycle control due to an INK4A deletion, additional CCND amplification and/or other mutations in the RB pathway, mutation or deletion of the RB gene is often observed during cancer progression. Of note, RB inactivation during cancer progression not only facilitates G /S transition but also enhances some characteristics of malignancy, including altered drug sensitivity and a return to the undifferentiated state. Recently, we reported that RB inactivation enhances pro-inflammatory signaling through stimulation of the interleukin-6/STAT3 pathway, which directly promotes various malignant features of cancer cells. In this review, we highlight the consequences of RB inactivation during cancer progression, and discuss the biological and pathological significance of the interaction between RB and pro-inflammatory signaling.
108Effects and Mechanisms of Luteolin, a Plant-Based Flavonoid, in the Prevention of Cancers via Modulation of Inflammation and Cell Signaling Molecules.PubMed
Saleh A Almatroodi, Ahmad Almatroudi, Hajed Obaid A Alharbi, et al.
Molecules. 2024 Feb 29;29(5):1093. doi: 10.3390/molecules29051093.
Luteolin, a flavonoid, is mainly found in various vegetables and fruits, including carrots, cabbages, onions, parsley, apples, broccoli, and peppers. Extensive research in vivo and in vitro has been performed to explore its role in disease prevention and treatment. Moreover, this compound possesses the ability to combat cancer by modulating cell-signaling pathways across various types of cancer. The studies have confirmed that luteolin can inhibit cancer-cell survival and proliferation, angiogenesis, invasion, metastasis, mTOR/PI3K/Akt, STAT3, Wnt/β-catenin, and cell-cycle arrest, and induce apoptosis. Further, scientific evidence describes that this compound plays a vital role in the up/down-regulation of microRNAs (miRNAs) in cancer therapy. This review aims to outline the anti-cancer mechanisms of this compound and its molecular targets. However, a knowledge gap remains regarding the studies on its safety and efficacy and clinical trials. Therefore, it is essential to conduct more research based on safety, efficacy, and clinical trials to explore the beneficial role of this compound in disease management, including cancer.
109Interleukin-6 (IL-6) triggers the malignancy of hemangioma cells via activation of HIF-1α/VEGFA signals.PubMed
Xiaoyang Fu, Shuiting Zhai, Ji Yuan
Eur J Pharmacol. 2018 Dec 15;841:82-89. doi: 10.1016/j.ejphar.2018.10.022. Epub 2018 Oct 19.
Hemangioma (HA) is tumor formed by hyper-proliferation of vascular endothelial cells. The roles of interleukins on the progression of HA are not well illustrated. Our present study revealed that the expression of interleukin -6 (IL-6) and IL-8 in HA cells were significantly increased as compared with that in the human umbilical vein endothelial cell (HUVEC) cells. Targeted inhibition of IL-6, while not IL-8, can significantly suppress the proliferation and migration of HA cells. IL-6 treatment can increase the expression of vascular endothelial growth factor A (VEGFA), while had no significant effect on the expression of basic fibroblast growth factor (bFGF), in HA cells. Deletion of VEGFA can abolish IL-6 induced progression of HA, suggesting the essential role of VEGFA in IL-6 induced HA development. The specific inhibitor of hypoxia-inducible factor (HIF)-1α, while not Sp1, NF-κB, or AP1, abolished IL-6 induced VEGFA expression. Over expression of HIF-1α can attenuate anti-IL-6 suppressed expression of VEGFA in HA cells. Furthermore, IL-6 triggered the expression, nuclear translocation, and transcription activities of HIF-1α in HA cells via increasing its binding with the signal transducer and activator of transcription-3 (STAT3). STAT3 inhibitor CPA7 or si-STAT3 can abolish IL-6 induced upregulation of HIF-1α in HDEC cells. Collectively, our study revealed that IL-6 can trigger the malignancy of HA cells via induction of proliferation and migration. The activation of STAT3/HIF-1α/VEGFA signal was essential for this process. It suggested that IL-6/STAT3/HIF-1α/VEGFA signal may represent a novel therapeutic target for human HA treatment.
110Modified Biejia Jianwan decoction restrains PD-L1-mediated immune evasion through the HIF-1α/STAT3/NF-κB signaling pathway.PubMed
Xinchen Tian, Fen Liu, Zijian Wang, et al.
J Ethnopharmacol. 2024 Mar 25;322:117577. doi: 10.1016/j.jep.2023.117577. Epub 2023 Dec 15.
ETHNOPHARMACOLOGICAL RELEVANCE: Modified Biejia Jianwan (M-BJJW), a Traditional Chinese Medicine (TCM) decoction, has exhibited great potential in treating hepatocellular carcinoma (HCC). However, its underlying functional mechanism still remains unknown. AIM OF THE STUDY: The study aimed to explore the anti-hepatocarcinogenic effects of M-BJJW, specifically its influence on PD-L1-mediated immune evasion in hypoxic conditions, and elucidate the related molecular mechanisms in HCC. MATERIALS AND METHODS: To investigate the therapeutic efficacy and mechanisms underlying M-BJJW's effects on HCC, we employed a diethylnitrosamine (DEN)-induced rat model maintained for 120 days. Following model establishment, flow cytometry was utilized to assess the distribution of immune cell populations in peripheral blood, spleens, and tumor tissues after M-BJJW administration. Simultaneously, enzyme-linked immunosorbent assays (ELISA) were conducted to analyze cytokine profiles in serum samples. Immunohistochemistry was employed to determine the expression levels of crucial proteins within tumor tissues. Furthermore, HCC cells exposed to CoCl underwent Western blot analysis to validate the expression levels of HIF-1α, PD-L1, STAT3, and nuclear factor kappa B (NF-κB) p65. The modulatory effects of STAT3 and NF-κB p65 were investigated using specific inhibitors and activators in wild-type cell lines. High-performance liquid chromatography coupled with mass spectrometry (HPLC/MS) was utilized to identify the chemical constituents present in M-BJJW-medicated serum. The immunomodulatory properties and the anti-tumor activities of M-BJJW were evaluated by co-culturing with peripheral blood mononuclear cells (PBMC) and the CCK-8 assay. Additionally, we assessed M-BJJW's impact on hypoxia-induced alterations in HCC cell lines using immunofluorescence and Western blot assessments. RESULTS: M-BJJW exhibited substantial therapeutic advantages by effectively alleviating pathological deterioration within the HCC microenvironment. In the DEN-induced rat model, M-BJJW administration notably reduced tumor growth. Flow cytometry analyses revealed an increased proportion of Cytotoxic T lymphocytes (CTLs) accompanied by a simultaneous decrease in regulatory T cells (Tregs). ELISA data supported a marked decrease in pro-inflammatory cytokines, including interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor α (TNF-α). Immunohistochemistry confirmed the suppressive effect of M-BJJW on the expression of HIF-1α and PD-L1. Notably, western blotting unveiled the role of HIF-1α in regulating PD-L1 expression via the STAT3 and NF-κB signaling pathways in HCC cell lines, which was validated using activators and inhibitors of STAT3 and NF-κB. The CCK-8 assay and co-culture techniques demonstrated the anti-tumor activity of M-BJJW. Immunofluorescence and western blotting further confirmed that M-BJJW-containing serum dose-dependently inhibited HIF-1α, PD-L1, p-STAT3, and p-p65 in hypoxic HCC cell lines. CONCLUSIONS: M-BJJW demonstrates significant therapeutic potential against HCC by influencing the hypoxic microenvironment, thereby regulating the immunosuppressive milieu. Specifically, M-BJJW modulates the HIF-1α/STAT3/NF-κB signaling pathway, leading to reduced PD-L1 expression and an elevated ratio of cytotoxic T lymphocytes (CTLs), while concurrently decreasing T regulatory cells (Tregs) and immunosuppressive factors. These synergistic effects aid in countering PD-L1-mediated immune evasion, presenting compelling pharmacological evidence supporting the clinical application of M-BJJW as a therapeutic approach for HCC.
111Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation.PubMed
Tao Zhang, Daichao Xu, Jianping Liu, et al.
Nat Cell Biol. 2023 Jul;25(7):950-962. doi: 10.1038/s41556-023-01170-4. Epub 2023 Jul 3.
The prolyl hydroxylation of hypoxia-inducible factor 1α (HIF-1α) mediated by the EGLN-pVHL pathway represents a classic signalling mechanism that mediates cellular adaptation under hypoxia. Here we identify RIPK1, a known regulator of cell death mediated by tumour necrosis factor receptor 1 (TNFR1), as a target of EGLN1-pVHL. Prolyl hydroxylation of RIPK1 mediated by EGLN1 promotes the binding of RIPK1 with pVHL to suppress its activation under normoxic conditions. Prolonged hypoxia promotes the activation of RIPK1 kinase by modulating its proline hydroxylation, independent of the TNFα-TNFR1 pathway. As such, inhibiting proline hydroxylation of RIPK1 promotes RIPK1 activation to trigger cell death and inflammation. Hepatocyte-specific Vhl deficiency promoted RIPK1-dependent apoptosis to mediate liver pathology. Our findings illustrate a key role of the EGLN-pVHL pathway in suppressing RIPK1 activation under normoxic conditions to promote cell survival and a model by which hypoxia promotes RIPK1 activation through modulating its proline hydroxylation to mediate cell death and inflammation in human diseases, independent of TNFR1.
112Adrenomedullin and cancer.PubMed
E Zudaire, A Martínez, F Cuttitta
Regul Pept. 2003 Apr 15;112(1-3):175-83. doi: 10.1016/s0167-0115(03)00037-5.
Adrenomedullin (AM) is a pluripotent hormone with structural similarities to calcitonin gene-related peptide (CGRP), which is expressed by many tissues in the body and shows a remarkable range of effects mediated by paracrine/autocrine and possibly endocrine mechanisms. AM has been implicated as a mediator of several pathologies such as cardiovascular and renal disorders, sepsis, inflammation, diabetes and cancer, among others. AM is expressed in a variety of tumors where it aggravates several of the molecular and physiological features of malignant cells. AM has been shown to be a mitogenic factor stimulating growth in several cancer types and to encourage a more aggressive tumor phenotype. In addition, AM is an apoptosis survival factor for cancer cells and an indirect suppressor of the immune response through its binding protein, complement factor H, and regulation in expression of cytokines. AM plays an important role in environments subjected to low oxygen tensions, which is a typical feature in the proximity of solid tumors. Under these conditions, AM is upregulated through a hypoxia-inducible factor 1 (HIF-1)-dependent pathway and acts as a potent angiogenic factor promoting neovascularization. The collective findings brought together over the last years place AM as a major regulator of carcinogenesis-tumor progression and identifies its autocrine loop as a putative target for developing new strategies against human cancers.
113Chronic and Cycling Hypoxia: Drivers of Cancer Chronic Inflammation through HIF-1 and NF-κB Activation: A Review of the Molecular Mechanisms.PubMed
Jan Korbecki, Donata Simińska, Magdalena Gąssowska-Dobrowolska, et al.
Int J Mol Sci. 2021 Oct 2;22(19):10701. doi: 10.3390/ijms221910701.
Chronic (continuous, non-interrupted) hypoxia and cycling (intermittent, transient) hypoxia are two types of hypoxia occurring in malignant tumors. They are both associated with the activation of hypoxia-inducible factor-1 (HIF-1) and nuclear factor κB (NF-κB), which induce changes in gene expression. This paper discusses in detail the mechanisms of activation of these two transcription factors in chronic and cycling hypoxia and the crosstalk between both signaling pathways. In particular, it focuses on the importance of reactive oxygen species (ROS), reactive nitrogen species (RNS) together with nitric oxide synthase, acetylation of HIF-1, and the action of MAPK cascades. The paper also discusses the importance of hypoxia in the formation of chronic low-grade inflammation in cancerous tumors. Finally, we discuss the effects of cycling hypoxia on the tumor microenvironment, in particular on the expression of VEGF-A, CCL2/MCP-1, CXCL1/GRO-α, CXCL8/IL-8, and COX-2 together with PGE. These factors induce angiogenesis and recruit various cells into the tumor niche, including neutrophils and monocytes which, in the tumor, are transformed into tumor-associated neutrophils (TAN) and tumor-associated macrophages (TAM) that participate in tumorigenesis.
114Neutrophil HIF-1α stabilization is augmented by mitochondrial ROS produced via the glycerol 3-phosphate shuttle.PubMed
Joseph A Willson, Simone Arienti, Pranvera Sadiku, et al.
Blood. 2022 Jan 13;139(2):281-286. doi: 10.1182/blood.2021011010.
Neutrophils are predominantly glycolytic cells that derive little ATP from oxidative phosphorylation; however, they possess an extensive mitochondrial network and maintain a mitochondrial membrane potential. Although studies have shown neutrophils need their mitochondria to undergo apoptosis and regulate NETosis, the metabolic role of the respiratory chain in these highly glycolytic cells is still unclear. Recent studies have expanded on the role of reactive oxygen species (ROS) released from the mitochondria as intracellular signaling molecules. Our study shows that neutrophils can use their mitochondria to generate ROS and that mitochondrial ROS release is increased in hypoxic conditions. This is needed for the stabilization of a high level of the critical hypoxic response factor and pro-survival protein HIF-1α in hypoxia. Further, we demonstrate that neutrophils use the glycerol 3-phosphate pathway as a way of directly regulating mitochondrial function through glycolysis, specifically to maintain polarized mitochondria and produce ROS. This illustrates an additional pathway by which neutrophils can regulate HIF-1α stability and will therefore be an important consideration when looking for treatments of inflammatory conditions in which HIF-1α activation and neutrophil persistence at the site of inflammation are linked to disease severity.
115Modified Zuojin pill alleviates gastric precancerous lesions by inhibiting glycolysis through the HIF-1α pathway.PubMed
Shan Liu, Haijie Ji, Tai Zhang, et al.
Phytomedicine. 2025 Jan;136:156255. doi: 10.1016/j.phymed.2024.156255. Epub 2024 Nov 17.
BACKGROUND: Gastric precancerous lesions (GPL) typically originates from chronic gastritis (CG), and the changes in glycolysis mediated by the HIF-1α pathway during the progression from CG to GPL are unclear. Modified Zuojin pill (SQQT) is a traditional Chinese herbal formula used for treating GPL. However, the underlying mechanism has not been fully elucidated. PURPOSE: To investigate the changes in glycolysis mediated by the HIF-1α pathway during the progression from CG to GPL and whether SQQT can alleviate GPL by attenuating glycolysis through the HIF-1α pathway. METHODS: A rat model of GPL was established, and the changes of glycolysis mediated by the HIF-1α pathway during the progression from CG to GPL were detected in 12, 18, 24, and 30 weeks. The therapeutic efficacy of SQQT was evaluated through pathological changes. In vitro, the GPL cell model (MC cell) originated from GES-1 cells intervened by MNNG. The effects of SQQT on glycolysis and the HIF-1α pathway were detected in vivo and in vitro. In vitro, HIF-1α overexpression was used to confirmed that SQQT attenuated glycolysis by targeting the HIF-1α pathway. RESULTS: Our study revealed that glycolysis mediated by the HIF-1α pathway exhibited dynamic changes in the progression from CG to GPL, characterized by sequential activation, deactivation, and reactivation. SQQT ameliorated gastric mucosal pathology and inflammation in GPL rats. Mechanistic studies revealed that SQQT alleviated glycolysis by targeting the HIF-1α pathway, and improved abnormal cellular proliferation and apoptosis. Importantly, HIF-1α overexpression blocked the effect of SQQT on glycolysis. CONCLUSION: In the progression from CG to GPL, the HIF-1α pathway-mediated glycolysis was characterized by sequential activation, deactivation, and reactivation. SQQT attenuated glycolysis by targeting the HIF-1α pathway and improved abnormal cellular proliferation and apoptosis in the gastric mucosa, thereby exerting therapeutic effects on GPL.
116H1.0 modulates IL-6 expression and paclitaxel resistance via HDAC5 in ovarian cancer cells.PubMed
Shang-Lang Huang, Ting-Chang Chang, Nian-Kang Sun
Biochem Pharmacol. 2025 Jun;236:116876. doi: 10.1016/j.bcp.2025.116876. Epub 2025 Mar 18.
Chemoresistance is a significant challenge and major obstacle to achieving cancer remission during chemotherapy, primarily due to the risk of recurrence and metastasis. This study reveals that linker histone H1.0 plays a crucial role in paclitaxel resistance (TXR) in ovarian cancer cells by regulating Histone deacetylase 5 (HDAC5), which deacetylates core histones and represses gene transactivation. Transcriptomic profile analysis revealed that cytokine signaling networks are enriched pathways that correlate with H1.0 expression. Advanced clustering analysis identified interleukin 6 (IL-6) as a key molecule connecting these enriched H1.0-related pathways. Furthermore, gain- and loss-of-H1.0 expression experiments showed that H1.0 controls IL-6 mRNA and protein expression in ovarian cancer cells. Additionally, our findings indicate that HDAC5 expression is downregulated in SKOV3/Txr cells compared with parental cells. H1.0 silencing in TXR cells increases HDAC5 levels, suggesting an antagonistic effect between H1.0 and HDAC5. Cell viability assays showed that HDAC5 overexpression markedly inhibited cell survival. Furthermore, ectopic HDAC5 overexpression reduced IL-6 mRNA and protein expression, which was increased by H1.0. This effect was associated with reduced H3K9Ac core histone acetylation and decreased NF-κB binding on the IL-6 promoter, as demonstrated by chromatin immunoprecipitation assays. Further analysis revealed that HDAC5 is downregulated in several tumor types. Furthermore, high H1.0 and IL-6 expression, coupled with low HDAC5 levels, was exclusively observed in ovarian carcinoma. Together, our results demonstrate an interplay between H1.0, HDAC5, and IL-6 in modulating paclitaxel resistance in ovarian cancer cells, highlighting new therapeutic targets to overcome chemoresistance.
117Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6.PubMed
Qian Zhang, Kai Zhao, Qicong Shen, et al.
Nature. 2015 Sep 17;525(7569):389-393. doi: 10.1038/nature15252. Epub 2015 Aug 19.
Epigenetic modifiers have fundamental roles in defining unique cellular identity through the establishment and maintenance of lineage-specific chromatin and methylation status. Several DNA modifications such as 5-hydroxymethylcytosine (5hmC) are catalysed by the ten eleven translocation (Tet) methylcytosine dioxygenase family members, and the roles of Tet proteins in regulating chromatin architecture and gene transcription independently of DNA methylation have been gradually uncovered. However, the regulation of immunity and inflammation by Tet proteins independent of their role in modulating DNA methylation remains largely unknown. Here we show that Tet2 selectively mediates active repression of interleukin-6 (IL-6) transcription during inflammation resolution in innate myeloid cells, including dendritic cells and macrophages. Loss of Tet2 resulted in the upregulation of several inflammatory mediators, including IL-6, at late phase during the response to lipopolysaccharide challenge. Tet2-deficient mice were more susceptible to endotoxin shock and dextran-sulfate-sodium-induced colitis, displaying a more severe inflammatory phenotype and increased IL-6 production compared to wild-type mice. IκBζ, an IL-6-specific transcription factor, mediated specific targeting of Tet2 to the Il6 promoter, further indicating opposite regulatory roles of IκBζ at initial and resolution phases of inflammation. For the repression mechanism, independent of DNA methylation and hydroxymethylation, Tet2 recruited Hdac2 and repressed transcription of Il6 via histone deacetylation. We provide mechanistic evidence for the gene-specific transcription repression activity of Tet2 via histone deacetylation and for the prevention of constant transcription activation at the chromatin level for resolving inflammation.
118HDAC3 mediates smoking-induced pancreatic cancer.PubMed
Mouad Edderkaoui, Shiping Xu, Chintan Chheda, et al.
Oncotarget. 2016 Feb 16;7(7):7747-60. doi: 10.18632/oncotarget.6820.
Smoking is a major risk factor for developing pancreatic adenocarcinoma (PDAC); however, little is known about the mechanisms involved. Here we employed a genetic animal model of early stages of PDAC that overexpresses oncogenic Kras in the pancreas to investigate the mechanisms of smoking-induced promotion of the disease in vivo. We confirmed the regulation of the interactions between the tumor microenvironment cells using in vitro cellular systems. Aerial exposure to cigarette smoke stimulated development of pancreatic intraepithelial neaoplasia (PanIN) lesions associated with a tumor microenvironment-containing features of human PDAC including fibrosis, activated stellate cells, M2-macrophages and markers of epithelial-mesenchymal transition (EMT). The pro-cancer effects of smoking were prevented by Histone Deacetylase HDAC I/II inhibitor Saha. Smoking decreased histone acetylation associated with recruitment of and phenotypic changes in macrophages; which in turn, stimulated survival and induction of EMT of the pre-cancer and cancer cells. The interaction between the cancer cells and macrophages is mediated by IL-6 produced under the regulation of HDAC3 translocation to the nucleus in the cancer cells. Pharmacological and molecular inhibitions of HDAC3 decreased IL-6 levels in cancer cells. IL-6 stimulated the macrophage phenotype change through regulation of the IL-4 receptor level of the macrophage. This study demonstrates a novel pathway of interaction between cancer cells and tumor promoting macrophages involving HDAC3 and IL-6. It further demonstrates that targeting HDAC3 prevents progression of the disease and could provide a strategy for treating the disease considering that the HDAC inhibitor we used is FDA approved for a different disease.
119Enterotoxigenic Bacteroidesfragilis Promotes Intestinal Inflammation and Malignancy by Inhibiting Exosome-Packaged miR-149-3p.PubMed
Yingying Cao, Zhenhua Wang, Yuqing Yan, et al.
Gastroenterology. 2021 Nov;161(5):1552-1566.e12. doi: 10.1053/j.gastro.2021.08.003. Epub 2021 Aug 8.
BACKGROUND & AIMS: Enterotoxigenic Bacteroides fragilis (ETBF) is strongly associated with the occurrence of inflammatory bowel disease (IBD), colitis-associated colorectal cancer, and colorectal cancer (CRC). However, the mechanism of ETBF-induced intestinal inflammation and tumorigenesis remains unclear. METHODS: microRNA sequencing was used to detect the differentially expressed microRNAs in both ETBF-treated cells and exosomes derived from ETBF-inoculated cells. Cell Counting Kit 8 assays were used to evaluate the effect of ETBF and exosomes on CRC cell proliferation. The biological role and mechanism of ETBF-mediated miR-149-3p in colitis and colon carcinogenesis were determined both in vitro and in vivo. RESULTS: ETBF promoted CRC cell proliferation by down-regulating miR-149-3p both in vitro and in vivo. ETBF-down-regulated miR-149-3p depended on METTL14-mediated N6-methyladenosine methylation. As the target gene of miR-149-3p, PHF5A transactivated SOD2 through regulating KAT2A messenger RNA alternative splicing after ETBF treatment in CRC cells. miR-149-3p could be released in exosomes and mediated intercellular communication by modulating T-helper type 17 cell differentiation. The level of plasma exosomal miR-149-3p was gradually decreased from healthy control individuals to patients with IBD and CRC. miR-149-3p, existing in plasma exosomes, negatively correlated with the abundance of ETBF in patients with IBD and CRC. CONCLUSIONS: Exosomal miR-149-3p derived from ETBF-treated cells facilitated T-helper type 17 cell differentiation. ETBF-induced colorectal carcinogenesis depended on down-regulating miR-149-3p and further promoting PHF5A-mediated RNA alternative splicing of KAT2A in CRC cells. Targeting the ETBF/miR-149-3p pathway presents a promising approach to treat patients with intestinal inflammation and CRC with a high amount of ETBF.
120Cancer metabolism and tumor microenvironment: fostering each other?PubMed
Yiyuan Yuan, Huimin Li, Wang Pu, et al.
Sci China Life Sci. 2022 Feb;65(2):236-279. doi: 10.1007/s11427-021-1999-2. Epub 2021 Nov 26.
The changes associated with malignancy are not only in cancer cells but also in environment in which cancer cells live. Metabolic reprogramming supports tumor cell high demand of biogenesis for their rapid proliferation, and helps tumor cell to survive under certain genetic or environmental stresses. Emerging evidence suggests that metabolic alteration is ultimately and tightly associated with genetic changes, in particular the dysregulation of key oncogenic and tumor suppressive signaling pathways. Cancer cells activate HIF signaling even in the presence of oxygen and in the absence of growth factor stimulation. This cancer metabolic phenotype, described firstly by German physiologist Otto Warburg, insures enhanced glycolytic metabolism for the biosynthesis of macromolecules. The conception of metabolite signaling, i.e., metabolites are regulators of cell signaling, provides novel insights into how reactive oxygen species (ROS) and other metabolites deregulation may regulate redox homeostasis, epigenetics, and proliferation of cancer cells. Moreover, the unveiling of noncanonical functions of metabolic enzymes, such as the moonlighting functions of phosphoglycerate kinase 1 (PGK1), reassures the importance of metabolism in cancer development. The metabolic, microRNAs, and ncRNAs alterations in cancer cells can be sorted and delivered either to intercellular matrix or to cancer adjacent cells to shape cancer microenvironment via media such as exosome. Among them, cancer microenvironmental cells are immune cells which exert profound effects on cancer cells. Understanding of all these processes is a prerequisite for the development of a more effective strategy to contain cancers.
121Energy metabolism: a new target for gastric cancer treatment.PubMed
Jiangrong Liu, Xue Bai, Meilan Zhang, et al.
Clin Transl Oncol. 2024 Feb;26(2):338-351. doi: 10.1007/s12094-023-03278-3. Epub 2023 Jul 21.
Gastric cancer is the fifth most common malignancy worldwide having the fourth highest mortality rate. Energy metabolism is key and closely linked to tumour development. Most important in the reprogramming of cancer metabolism is the Warburg effect, which suggests that tumour cells will utilise glycolysis even with normal oxygen levels. Various molecules exert their effects by acting on enzymes in the glycolytic pathway, integral to glycolysis. Second, mitochondrial abnormalities in the reprogramming of energy metabolism, with consequences for glutamine metabolism, the tricarboxylic acid cycle and oxidative phosphorylation, abnormal fatty acid oxidation and plasma lipoprotein metabolism are important components of tumour metabolism. Third, inflammation-induced oxidative stress is a danger signal for cancer. Fourth, patterns of signalling pathways involve all aspects of metabolic transduction, and many clinical drugs exert their anticancer effects through energy metabolic signalling. This review summarises research on energy metabolism genes, enzymes and proteins and transduction pathways associated with gastric cancer, and discusses the mechanisms affecting their effects on postoperative treatment resistance and prognoses of gastric cancer. We believe that an in-depth understanding of energy metabolism reprogramming will aid the diagnosis and subsequent treatment of gastric cancer.
122Exploring the diverse role of pyruvate kinase M2 in cancer: Navigating beyond glycolysis and the Warburg effect.PubMed
Saurabh Upadhyay, Shumayila Khan, Md Imtaiyaz Hassan
Biochim Biophys Acta Rev Cancer. 2024 May;1879(3):189089. doi: 10.1016/j.bbcan.2024.189089. Epub 2024 Mar 6.
Pyruvate Kinase M2, a key enzyme in glycolysis, has garnered significant attention in cancer research due to its pivotal role in the metabolic reprogramming of cancer cells. Originally identified for its association with the Warburg effect, PKM2 has emerged as a multifaceted player in cancer biology. The functioning of PKM2 is intricately regulated at multiple levels, including controlling the gene expression via various transcription factors and non-coding RNAs, as well as adding post-translational modifications that confer distinct functions to the protein. Here, we explore the diverse functions of PKM2, encompassing newly emerging roles in non-glycolytic metabolic regulation, immunomodulation, inflammation, DNA repair and mRNA processing, beyond its canonical role in glycolysis. The ever-expanding list of its functions has recently grown to include roles in subcellular compartments such as the mitochondria and extracellular milieu as well, all of which make PKM2 an attractive drug target in the pursuit of therapeutics for cancer.
123Pharmacologic or Genetic Targeting of Glutamine Synthetase Skews Macrophages toward an M1-like Phenotype and Inhibits Tumor Metastasis.PubMed
Erika M Palmieri, Alessio Menga, Rosa Martín-Pérez, et al.
Cell Rep. 2017 Aug 15;20(7):1654-1666. doi: 10.1016/j.celrep.2017.07.054.
Glutamine-synthetase (GS), the glutamine-synthesizing enzyme from glutamate, controls important events, including the release of inflammatory mediators, mammalian target of rapamycin (mTOR) activation, and autophagy. However, its role in macrophages remains elusive. We report that pharmacologic inhibition of GS skews M2-polarized macrophages toward the M1-like phenotype, characterized by reduced intracellular glutamine and increased succinate with enhanced glucose flux through glycolysis, which could be partly related to HIF1α activation. As a result of these metabolic changes and HIF1α accumulation, GS-inhibited macrophages display an increased capacity to induce T cell recruitment, reduced T cell suppressive potential, and an impaired ability to foster endothelial cell branching or cancer cell motility. Genetic deletion of macrophagic GS in tumor-bearing mice promotes tumor vessel pruning, vascular normalization, accumulation of cytotoxic T cells, and metastasis inhibition. These data identify GS activity as mediator of the proangiogenic, immunosuppressive, and pro-metastatic function of M2-like macrophages and highlight the possibility of targeting this enzyme in the treatment of cancer metastasis.
124Cachexia Anorexia Syndrome and Associated Metabolic Dysfunction in Peritoneal Metastasis.PubMed
Rami Archid, Wiebke Solass, Clemens Tempfer, et al.
Int J Mol Sci. 2019 Oct 31;20(21):5444. doi: 10.3390/ijms20215444.
Patients with peritoneal metastasis (PM) of gastrointestinal and gynecological origin present with a nutritional deficit characterized by increased resting energy expenditure (REE), loss of muscle mass, and protein catabolism. Progression of peritoneal metastasis, as with other advanced malignancies, is associated with cancer cachexia anorexia syndrome (CAS), involving poor appetite (anorexia), involuntary weight loss, and chronic inflammation. Eventual causes of mortality include dysfunctional metabolism and energy store exhaustion. Etiology of CAS in PM patients is multifactorial including tumor growth, host response, cytokine release, systemic inflammation, proteolysis, lipolysis, malignant small bowel obstruction, ascites, and gastrointestinal side effects of drug therapy (chemotherapy, opioids). Metabolic changes of CAS in PM relate more to a systemic inflammatory response than an adaptation to starvation. Metabolic reprogramming is required for cancer cells shed into the peritoneal cavity to resist anoikis (i.e., programmed cell death). Profound changes in hexokinase metabolism are needed to compensate ineffective oxidative phosphorylation in mitochondria. During the development of PM, hypoxia inducible factor-1α (HIF-1α) plays a key role in activating both aerobic and anaerobic glycolysis, increasing the uptake of glucose, lipid, and glutamine into cancer cells. HIF-1α upregulates hexokinase II, phosphoglycerate kinase 1 (PGK1), pyruvate dehydrogenase kinase (PDK), pyruvate kinase muscle isoenzyme 2 (PKM2), lactate dehydrogenase (LDH) and glucose transporters (GLUT) and promotes cytoplasmic glycolysis. HIF-1α also stimulates the utilization of glutamine and fatty acids as alternative energy substrates. Cancer cells in the peritoneal cavity interact with cancer-associated fibroblasts and adipocytes to meet metabolic demands and incorporate autophagy products for growth. Therapy of CAS in PM is challenging. Optimal nutritional intake alone including total parenteral nutrition is unable to reverse CAS. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) stabilized nutritional status in a significant proportion of PM patients. Agents targeting the mechanisms of CAS are under development.
125EZH2 directly methylates PARP1 and regulates its activity in cancer.PubMed
Qingshu Meng, Jiangchuan Shen, Yanan Ren, et al.
Sci Adv. 2024 Nov 29;10(48):eadl2804. doi: 10.1126/sciadv.adl2804. Epub 2024 Nov 27.
DNA repair dysregulation is a key driver of cancer development. Understanding the molecular mechanisms underlying DNA repair dysregulation in cancer cells is crucial for cancer development and therapies. Here, we report that enhancer of zeste homolog 2 (EZH2) directly methylates poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1), an essential enzyme involved in DNA repair, and regulates its activity. Functionally, EZH2-catalyzed methylation represses PARP1 catalytic activity, down-regulates the recruitment of x-ray repair cross-complementing group-1 to DNA lesions and its associated DNA damage repair; on the other hand, it protects the cells from nicotinamide adenine dinucleotide overconsumption upon DNA damage formation. Meanwhile, EZH2-mediated methylation regulates PARP1 transcriptional and oncogenic activity, at least in part, through impairing PARP1-E2F1 interaction and E2F1 transcription factor activity. EZH2 and PARP1 inhibitors synergistically suppress prostate cancer growth. Collectively, our findings uncover an insight of EZH2 functions in fine-tuning PARP1 activity during DNA damage repair and cancer progression, which provides a rationale for combinational targeting EZH2 and PARP1 in cancer.
126Prevention of hepatitis B.PubMed
Mei-Hwei Chang, Ding-Shinn Chen
Cold Spring Harb Perspect Med. 2015 Mar 2;5(3):a021493. doi: 10.1101/cshperspect.a021493.
Hepatitis B virus (HBV) causes life-threatening liver disease. It is transmitted through a horizontal route or a mother-to-infant route, and the latter is the major route in endemic areas. Prevention of HBV infection by immunization is the best way to eliminate HBV-related diseases. The HBV vaccine is the first human vaccine using a viral antigen from infected persons, which is safe and effective. Either passive immunization by hepatitis B immunoglobulin (HBIG) or active immunization by HBV vaccine is effective, and a combination of both yields the best efficacy in preventing HBV infection. The impact of universal HBV immunization is huge, with 90%-95% effectiveness in preventing chronic HBV infection. It is the first cancer preventive vaccine with a protective efficacy against hepatocellular carcinoma (HCC) of ∼ 70%. Nevertheless, further effort is still needed to avoid vaccine failure and to increase the global coverage rate.
127Hepatitis B vaccination and prevention of hepatocellular carcinoma.PubMed
Jia-Horng Kao
Best Pract Res Clin Gastroenterol. 2015 Dec;29(6):907-17. doi: 10.1016/j.bpg.2015.09.011. Epub 2015 Sep 11.
Hepatitis B virus (HBV) infection is a global health threat; with 240 million people are chronic carriers of the virus. The infection can cause acute and chronic liver disease including liver cirrhosis and hepatocellular carcinoma (HCC). On the basis of disease burden and the availability of safe and effective vaccines, World Health Organization has recommended that hepatitis B vaccine be incorporated into routine infant and childhood immunization programs for all countries. The efficacy of universal immunization has been proven in many countries, with substantial reductions of the prevalence of HBV carriage in children, adolescents and young adults. Most important, hepatitis B vaccination can protect them from HCC, as has been demonstrated in Taiwan and other countries. Nevertheless, the implementation of worldwide vaccination against HBV indeed requires more effort to overcome the social and economic challenges. To have a global control of HBV infection, we have to continue the universal HBV vaccination, interrupt the possible transmission routes and treat eligible patients with antiviral agents. However, current treatments are still far from ideal as they cannot eradicate intrahepatic HBV cccDNA, and lifelong administration of these agents will pose a major economic burden, especially in the endemic Asia-Pacific region. Thus we need innovative treatment strategies and novel agents with difference modes of action to overcome the unmet medical need for an efficient HBV cure with subsequent global eradication of HBV infection, hopefully by the first half of 21st century.
128[Hepatitis B vaccine and liver cancer].PubMed
Fanny Lebossé, Fabien Zoulim
Bull Cancer. 2021 Jan;108(1):90-101. doi: 10.1016/j.bulcan.2020.10.014. Epub 2020 Dec 25.
Hepatitis B Virus (HBV) chronic infection contributes to a high risk of hepatocellular cancer (HCC) development. HBV is a strong cancer inducer, due to natural history of infection, virological characteristics and viral DNA integrations events in host genome. Prolonged infection and high viral loads, particularly frequent in patients infected in childhood, are risk factors of HCC development for patients with HBV chronic infection. A HBV vaccine, based on immunization against the surface protein HBs, showed a strong efficacy to prevent chronic HBV infection. The development of universal neonatal vaccination programmes contributed to the decrease of HBV chronic infection incidence in children of high endemic areas. Although HBs antibodies levels diminished years after vaccination, HBV neonatal vaccination programmes led to a lower incidence of chronic HBV infection among young adults. The decrease of HBV chronic infection incidence was associated to a reduction of HCC incidence in children and young adults from areas with a high prevalence of HBV infection.
129Helicobacter pylori infection.PubMed
Peter Malfertheiner, M Constanza Camargo, Emad El-Omar, et al.
Nat Rev Dis Primers. 2023 Apr 20;9(1):19. doi: 10.1038/s41572-023-00431-8.
Helicobacter pylori infection causes chronic gastritis, which can progress to severe gastroduodenal pathologies, including peptic ulcer, gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. H. pylori is usually transmitted in childhood and persists for life if untreated. The infection affects around half of the population in the world but prevalence varies according to location and sanitation standards. H. pylori has unique properties to colonize gastric epithelium in an acidic environment. The pathophysiology of H. pylori infection is dependent on complex bacterial virulence mechanisms and their interaction with the host immune system and environmental factors, resulting in distinct gastritis phenotypes that determine possible progression to different gastroduodenal pathologies. The causative role of H. pylori infection in gastric cancer development presents the opportunity for preventive screen-and-treat strategies. Invasive, endoscopy-based and non-invasive methods, including breath, stool and serological tests, are used in the diagnosis of H. pylori infection. Their use depends on the specific individual patient history and local availability. H. pylori treatment consists of a strong acid suppressant in various combinations with antibiotics and/or bismuth. The dramatic increase in resistance to key antibiotics used in H. pylori eradication demands antibiotic susceptibility testing, surveillance of resistance and antibiotic stewardship.
130Gastric cancer: a comprehensive review of current and future treatment strategies.PubMed
Rachel E Sexton, Mohammed Najeeb Al Hallak, Maria Diab, et al.
Cancer Metastasis Rev. 2020 Dec;39(4):1179-1203. doi: 10.1007/s10555-020-09925-3. Epub 2020 Sep 7.
Gastric cancer remains a major unmet clinical problem with over 1 million new cases worldwide. It is the fourth most commonly occurring cancer in men and the seventh most commonly occurring cancer in women. A major fraction of gastric cancer has been linked to variety of pathogenic infections including but not limited to Helicobacter pylori (H. pylori) or Epstein Barr virus (EBV). Strategies are being pursued to prevent gastric cancer development such as H. pylori eradication, which has helped to prevent significant proportion of gastric cancer. Today, treatments have helped to manage this disease and the 5-year survival for stage IA and IB tumors treated with surgery are between 60 and 80%. However, patients with stage III tumors undergoing surgery have a dismal 5-year survival rate between 18 and 50% depending on the dataset. These figures indicate the need for more effective molecularly driven treatment strategies. This review discusses the molecular profile of gastric tumors, the success, and challenges with available therapeutic targets along with newer biomarkers and emerging targets.
131Global burden of gastric cancer: epidemiological trends, risk factors, screening and prevention.PubMed
Aaron P Thrift, Theresa Nguyen Wenker, Hashem B El-Serag
Nat Rev Clin Oncol. 2023 May;20(5):338-349. doi: 10.1038/s41571-023-00747-0. Epub 2023 Mar 23.
Gastric cancer remains a major cause of cancer-related mortality worldwide. The temporal trends for this malignancy, however, are dynamic, and reports from the past decade indicate important declines in some regions and demographic groups, as well as a few notable exceptions in which gastric cancer rates are either stable or increasing. Two main anatomical subtypes of gastric cancer exist, non-cardia and cardia, with different temporal trends and risk factors (such as obesity and reflux for cardia gastric cancer and Helicobacter pylori infection for non-cardia gastric cancer). Shifts in the distribution of anatomical locations have been detected in several high-incidence regions. H. pylori is an important aetiological factor for gastric cancer; importantly, the anticipated long-term findings from studies examining the effect of H. pylori eradication on the risk of (re)developing gastric cancer have emerged in the past few years. In this Review, we highlight the latest trends in incidence and mortality using an evidence-based approach. We make the best possible inferences, including clinical and public health inference, on the basis of the quality of the evidence available, and highlight burning questions as well as gaps in knowledge and public health practice that need to be addressed to reduce gastric cancer burden worldwide.
132Helicobacter pylori.PubMed
David Y Graham
Curr Top Microbiol Immunol. 2024;445:127-154. doi: 10.1007/82_2021_235.
Helicobacter pylori (H. pylori) is an important human pathogen etiologically associated with peptic ulcers and gastric cancer. The infection is present in approximately one-half of the world's population. Population-based H. pylori eradiation has confirmed that cure or prevention of the infection produces a marked reduction in gastric cancer and peptic ulcer disease. Antimicrobial therapy has become increasingly ineffective, and complexity and costs of antimicrobial therapy for infected individuals residing in and, immigrating from, the developing world combined with the cost of treatment for cancer make vaccine development a cost-effective alternative. Challenge studies allowed making a "go-no go" decision regarding vaccine effectiveness. We provide detailed protocols regarding challenge strain selection and administration as well as guidance regarding the clinical and laboratory tests used to confirm and monitor experimental infection. Experience shows that reliance of noninvasive methods led to the erroneous conclusion that some subjects were not infected. The current data suggests that histologic assessment of gastric mucosal biopsies may be one of the most sensitive and specific means of assessment of the presence of experimental infection as well as of successful H. pylori eradication. We recommend detailed recommendations for acquiring, processing, embedding, sectioning, and examining the gastric biopsies.
133Screening for Helicobacter pylori to Prevent Gastric Cancer: A Pragmatic Randomized Clinical Trial.PubMed
Yi-Chia Lee, Tsung-Hsien Chiang, Han-Mo Chiu, et al.
JAMA. 2024 Nov 19;332(19):1642-1651. doi: 10.1001/jama.2024.14887.
IMPORTANCE: Effects of screening for Helicobacter pylori on gastric cancer incidence and mortality are unknown. OBJECTIVE: To evaluate the effects of an invitation to screen for H pylori on gastric cancer incidence and mortality. DESIGN, SETTING, AND PARTICIPANTS: A pragmatic randomized clinical trial of residents aged 50 to 69 years in Changhua County, Taiwan, eligible for biennial fecal immunochemical tests (FIT) for colon cancer screening. Participants were randomized to either an invitation for H pylori stool antigen (HPSA) + FIT assessment or FIT alone. The study was conducted between January 1, 2014, and September 27, 2018. Final follow-up occurred December 31, 2020. INTERVENTION: Invitation for testing for H pylori stool antigen. MAIN OUTCOMES AND MEASURES: The primary outcomes were gastric cancer incidence and gastric cancer mortality. All invited individuals were analyzed according to the groups to which they were randomized. RESULTS: Of 240 000 randomized adults (mean age, 58.1 years [SD, 5.6]; 46.8% female), 63 508 were invited for HPSA + FIT, and 88 995 were invited for FIT alone. Of the 240 000 randomized, 38 792 who were unreachable and 48 705 who did not receive an invitation were excluded. Of those invited, screening participation rates were 49.6% (31 497/63 508) for HPSA + FIT and 35.7% (31 777/88 995) for FIT alone. Among 12 142 participants (38.5%) with positive HPSA results, 8664 (71.4%) received antibiotic treatment, and eradication occurred in 91.9%. Gastric cancer incidence rates were 0.032% in the HPSA + FIT group and 0.037% in the FIT-alone group (mean difference, -0.005% [95% CI, -0.013% to 0.003%]; P = .23). Gastric cancer mortality rates were 0.015% in the HPSA + FIT group and 0.013% in the FIT-alone group (mean difference, 0.002% [95% CI, -0.004% to 0.007%]; P = .57). After adjusting for differences in screening participation, length of follow-up, and patient characteristics in post hoc analyses, an invitation for HPSA + FIT was associated with lower rates of gastric cancer (0.79 [95% CI, 0.63-0.98]) but not with gastric cancer mortality (1.02 [95% CI, 0.73-1.40]), compared with FIT alone. Among participants who received antibiotics, the most common adverse effects were abdominal pain or diarrhea (2.1%) and dyspepsia or poor appetite (0.8%). CONCLUSIONS AND RELEVANCE: Among residents of Taiwan, an invitation to test for HPSA combined with FIT did not reduce rates of gastric cancer or gastric cancer mortality, compared with an invitation for FIT alone. However, when differences in screening participation and length of follow-up were accounted for, gastric cancer incidence, but not gastric cancer mortality, was lower in the HSPA + FIT group, compared with FIT alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01741363.
134Gastric neuroendocrine neoplasms and proton pump inhibitors: fact or coincidence?PubMed
Federica Cavalcoli, Alessandra Zilli, Dario Conte, et al.
Scand J Gastroenterol. 2015;50(11):1397-403. doi: 10.3109/00365521.2015.1054426. Epub 2015 Jun 10.
OBJECTIVE: Reporting on three cases of gastric neuroendocrine tumors (g-NETs) in patients taking long-term proton pump inhibitors (PPIs). These tumors are not classifiable considering current criteria. g-NETs are currently grouped as: types 1 and 2, related to hypergastrinemia due to chronic atrophic gastritis and Zollinger-Ellison syndrome respectively, and type 3, normogastrinemic and more aggressive. Although the g-NETs onset in patients taking PPIs is biologically plausible, only a few cases have been reported so far. MATERIALS AND METHODS: From January 2005 to July 2014, 31 g-NETs were referred to our Unit: 24 (77%), one (3%) and three (10%) resulted types 1, 2 and 3, respectively. Three cases (10%) did not meet the current classification criteria. RESULTS: The three patients were administered long-term PPIs for gastro-esophageal reflux disease. Patient 1: a 78-year-old man, with a 4-mm well-differentiated g-NET (Ki-67<1%) and marked hypergastrinemia. Patient 2: a 58-year-old man affected by a 6-mm well-differentiated (Ki-67 = 4%) g-NET, with normal gastrin levels. Patients 3: a 67-year-old woman with an 18-mm well-differentiated g-NET (Ki-67 <2%), with mild hypergastrinemia. In the three patients, histology and pertinent blood tests excluded chronic atrophic gastritis, Helicobacter pylori infection or Zollinger-Ellison syndrome. The first two patients underwent endoscopic polypectomy; in the third case total gastrectomy was performed. Further clinical, endoscopic and imaging follow-up did not show any g-NET recurrence. CONCLUSIONS: The present data point to the existence and epidemiological relevance of g-NETs associated with PPIs intake. These neoplasms are not included in the current classification, thus their treatment and follow-up have not been established.
135Proton Pump Inhibitor Use, Hypergastrinemia, and Gastric Carcinoids-What Is the Relationship?PubMed
Denis M McCarthy
Int J Mol Sci. 2020 Jan 19;21(2):662. doi: 10.3390/ijms21020662.
Neuroendocrine tumors (NETs) throughout the body are the focus of much current interest. Most occur in the gastrointestinal tract and have shown a major increase in incidence over the past 30 years, roughly paralleling the world-wide increase in the use of proton pump inhibitor (PPI) drugs. The greatest rise has occurred in gastric carcinoids (g-NETs) arising from enterochromaffin-like (ECL) cells. These tumors are long known to occur in auto-immune chronic atrophic gastritis (CAG) and Zollinger-Ellison syndrome (ZES), with or without multiple endocrine neoplasia type-1 (MEN-1), but the incidences of these conditions do not appear to have increased over the same time period. Common to these disease states is persistent hypergastrinemia, generally accepted as causing g-NETs in CAG and ZES, and postulated as having similar tumorigenic effects in PPI users. In efforts to study the increase in their occurrence, g-NETs have been classified in a number of discussed ways into different grades that differ in their incidence and apparent pathogenesis. Based on a large amount of experimental data, tumorigenesis is mediated by gastrin's effects on the CCK2R-receptor on ECL-cells that in turn leads to hyperplasia, dysplasia, and finally neoplasia. However, in all three conditions, the extent of response of ECL-cells to gastrin is modified by a number of genetic influences and other underlying risk factors, and by the duration of exposure to the hormonal influence. Data relating to trophic effects of hypergastrinemia due to PPI use in humans are reviewed and, in an attached Appendix A, all 11 reports of g-NETs that occurred in long-term PPI users in the absence of CAG or ZES are summarized. Mention of additional suspected cases reported elsewhere are also listed. Furthermore, the risk in humans may be affected by the presence of underlying conditions or genetic factors, including their PPI-metabolizer phenotype, with slow metabolizers likely at increased risk. Other problems in estimating the true incidence of g-NETs are discussed, relating to non-reporting of small tumors and failure of the Surveillance, Epidemiology, and End Results Program (SEER) and other databases, to capture small tumors or those not accorded a T1 rating. Overall, it appears likely that the true incidence of g-NETs may be seriously underestimated: the possibility that hypergastrinemia also affects tumorigenesis in additional gastrointestinal sites or in tumors in other organ systems is briefly examined. Overall, the risk of developing a g-NET appears greatest in patients who are more than 10 years on drug and on higher doses: those affected by chronic gastritis and/or consequent gastric atrophy may also be at increased risk. While the overall risk of g-NETs induced by PPI therapy is undoubtedly low, it is real: this necessitates caution in using PPI therapy for long periods of time, particularly when initiated in young subjects.
136Association Between Long-Term Proton Pump Inhibitor Use and Low-Risk Gastric Neuroendocrine Tumors.PubMed
Taymeyah Al-Toubah, Eleonora Pelle, Mintallah Haider, et al.
Ann Surg Oncol. 2026 Jan;33(1):594-598. doi: 10.1245/s10434-025-18430-2. Epub 2025 Sep 30.
BACKGROUND: Gastric neuroendocrine tumors (NETs) account for approximately 2% of all gastric neoplasms and develop from enterochromaffin-like cells in the gastric mucosa. Types 1 and 2 develop because of hypergastrinemia; type 3 typically occurs sporadically, tends to be more aggressive, presents metastatically in over 50% of cases, and has normal fasting gastrin levels. Although the long-term use of proton pump inhibitors (PPIs) has been known to lead to chronic hypergastrinemia, only a small number of gastric NETs associated with PPI use have been reported, and the classification of these cases remains undefined. METHODS: This was a retrospective study of all gastric NETs seen at H. Lee Moffitt Cancer Center and Research Institute between January 2008 and August 2023. Patients with type 1 or type 2 gastric NETs and poorly differentiated neuroendocrine carcinomas were excluded. Data were collected from patients with "sporadic" gastric NETs, including PPI use, gastrin levels (both on and off PPI), pathologic features, and disease stage. RESULTS: A total of 90 patients met the eligibility criteria: 50% had long-term PPI use (≥5 years of consecutive treatment). All had well-differentiated tumors: 34 grade 1, 45 grade 2, 6 grade 3, and 5 with an unknown grade. Among 45 patients who received long-term PPI, none developed distant metastatic disease; among the remaining patients without long-term PPI use, 62% had metastatic disease (p < 0.0001). CONCLUSIONS: Gastric NETs diagnosed in patients with long-term PPI use tend to be less aggressive than those occurring sporadically in the absence of long-term PPI therapy. We propose that PPI-associated gastric NETs be considered a fourth category (type 4) with a prognosis more similar to type 1 than to type 3.
137Factors related to gastric neuroendocrine tumors.PubMed
R Soto-Solís, A F Romano-Munive, K Santana de Anda, et al.
Rev Gastroenterol Mex (Engl Ed). 2019 Jan-Mar;84(1):52-56. doi: 10.1016/j.rgmx.2018.03.002. Epub 2018 Apr 26.
INTRODUCTION AND AIMS: An association between long-term use of proton pump inhibitors and the development of gastric neuroendocrine tumors has been reported, but it is still a subject of debate. The aims of the present study were to determine the presence of this association in a Mexican population and to identify the risk factors for developing gastric neuroendocrine tumors. MATERIALS AND METHODS: A case-control study was conducted, in which the cases were patients with a histopathologic diagnosis of gastric neuroendocrine tumor and the controls were patients evaluated through upper endoscopy. The controls were paired by age, sex, and endoscopic examination indication. Proton pump inhibitor use was considered prolonged when consumption was longer than 5 years. RESULTS: Thirty-three patients with gastric neuroendocrine tumor and 66 controls were included in the study. Eighteen (54.5%) patients in the case group were women, as were 39 (59%) of the patients in the control group. The median age of the patients in the case group was 55 years (minimum-maximum range: 24-82) and it was 54 years (minimum-maximum range:18-85) in the control group. A greater number of patients in the gastric neuroendocrine tumor group presented with gastric atrophy (p<0.0001) and autoimmune atrophic gastritis (p=0.0002), compared with the control group. No association between gastric neuroendocrine tumor and prolonged proton pump inhibitor use, sex, smoking, gastroesophageal reflux disease, Helicobacter pylori infection, diabetes mellitus, or autoimmune diseases was found in the univariate analysis. CONCLUSIONS: The results of our study showed no association between proton pump inhibitor use for more than 5 years and the development of gastric neuroendocrine tumor. The presence of gastric atrophy and autoimmune atrophic gastritis was associated with gastric neuroendocrine tumor development.
138Environment, lifestyle, and cancer in women.PubMed
Sara Farina, Alessandra Sabatelli, Stefania Boccia, et al.
Int J Gynaecol Obstet. 2025 Sep;171 Suppl 1(Suppl 1):138-146. doi: 10.1002/ijgo.70156. Epub 2025 Apr 25.
Environmental and lifestyle factors significantly contribute to gynecological cancers. The risk of ovarian cancer, one the most lethal gynecological cancer, is associated with obesity, poor dietary habits, and environmental pollutants, exacerbating hormonal imbalances, inflammation, and oxidative stress. Protective factors, such as the Mediterranean diet and oral contraceptives, modulate risk by reducing ovulatory cycles, particularly in genetically predisposed women. Uterine cancer is associated with metabolic factors, with obesity driving hormonal disruptions and systemic inflammation. Physical inactivity and diets rich in animal fats increase the risk of endometrial cancer, along with air pollution and microbiome imbalances contribute to endometrial carcinogenesis. Cervical cancer is primarily driven by persistent high-risk HPV infection, with smoking enhancing viral persistence and oncogenesis. Nutritional deficiencies in antioxidants and folate weaken immune defenses, while vaginal and gut microbiome dysbiosis fosters neoplastic progression. Vulvar and vaginal cancers, though less common, share risk factors such as obesity, smoking, and occupational exposures, disrupting immune responses and epithelial integrity. Microbial imbalances exacerbate these malignancies, creating a pro-inflammatory microenvironment. The interplay between modifiable factors and genetic predisposition, including high-penetrance mutations and polygenic risk scores, highlights the complexity complexity of prevention of gynecological cancers. Epigenetic mechanisms, such as DNA methylation and histone modifications, further modulate susceptibility and tumor progression, influenced by environmental and lifestyle exposures. In addition, promoting and supporting healthy lifestyle changes, including smoking cessation, increased physical activity, and a balanced diet, are crucial for improving long-term outcomes and quality of life in gynecological cancer survivors. Addressing these factors through personalized prevention, leveraging predictive models incorporating genetics and modifiable risks, enables tailored lifestyle interventions and avoidance of environmental exposures. Combined with equitable public health initiatives, these strategies have the potential to reduce the burden of gynecological cancers and improve women's health globally.
139Epidemiology, pathophysiology and clinical aspects of Hepatocellular Carcinoma in MAFLD patients.PubMed
Maria Eva Argenziano, Mi Na Kim, Michele Montori, et al.
Hepatol Int. 2024 Oct;18(Suppl 2):922-940. doi: 10.1007/s12072-024-10692-4. Epub 2024 Jul 16.
Hepatocellular carcinoma (HCC) is undergoing a transformative shift, with metabolic-associated fatty liver disease (MAFLD) emerging as a dominant etiology. Diagnostic criteria for MAFLD involve hepatic steatosis and metabolic dysregulation. Globally, MAFLD prevalence stands at 38.77%, significantly linked to the escalating rates of obesity. Epidemiological data indicate a dynamic shift in the major etiologies of hepatocellular carcinoma (HCC), transitioning from viral to metabolic liver diseases. Besides the degree of liver fibrosis, several modifiable lifestyle risk factors, such as type 2 diabetes, obesity, alcohol use, smoking, and HBV, HCV infection contribute to the pathogenesis of HCC. Moreover gut microbiota and genetic variants may contribute to HCC development.The pathophysiological link between MAFLD and HCC involves metabolic dysregulation, impairing glucose and lipid metabolism, inflammation and oxidative stress. Silent presentation poses challenges in early MAFLD-HCC diagnosis. Imaging, biopsy, and AI-assisted techniques aid diagnosis, while HCC surveillance in non-cirrhotic MAFLD patients remains debated.ITA.LI.CA. group proposes a survival-based algorithm for treatment based on Barcelona clinic liver cancer (BCLC) algorithm. Liver resection, transplantation, ablation, and locoregional therapies are applied based on the disease stage. Systemic treatments is promising, with initial immunotherapy results indicating a less favorable response in MAFLD-related HCC.Adopting lifestyle interventions and chemopreventive measures with medications, including aspirin, metformin, and statins, constitute promising approaches for the primary prevention of HCC.Prognosis is influenced by multiple factors, with MAFLD-HCC associated with prolonged survival. Emerging diagnostic biomarkers and epigenomic markers, show promising results for early HCC detection in the MAFLD population.
140A review of lifestyle and environment risk factors for pancreatic cancer.PubMed
Sara Zanini, Serena Renzi, Antonina R Limongi, et al.
Eur J Cancer. 2021 Mar;145:53-70. doi: 10.1016/j.ejca.2020.11.040. Epub 2021 Jan 7.
Pancreatic cancer (PaCa) is one of the deadliest cancers known and its incidence is increasing in the developed countries. Because of the lack of biomarkers that allow early detection and the tendency of the disease to be asymptomatic, the diagnosis comes often too late for effective surgical or chemotherapy intervention. Lifestyle factors, that may cause common genetic modifications occurring in the disease, interfere with pancreatic physiology or function, and play a role in PaCa development, have been of concern recently, since a strategy to prevent this severe cancer is needed. This review identifies the latest evidences related to increased risk of developing PaCa due to dietary habits such as high alcohol, fructose and red or processed meat intake, and pathological conditions such as diabetes, obesity and infections in addition to stress and smoking behaviour. It aims to highlight the importance of intervening on modifiable risk factors: the action on these factors could prevent a considerable number of new cases of PaCa.
141Rethinking Environmental Carcinogenesis.PubMed
Margaret Kripke, Julia Green Brody, Ernest Hawk, et al.
Cancer Epidemiol Biomarkers Prev. 2020 Oct;29(10):1870-1875. doi: 10.1158/1055-9965.EPI-20-0541.
The 2010 report of the President's Cancer Panel concluded that the burden of cancer from chemical exposures is substantial, while the programs for testing and regulation of carcinogens remain inadequate. New research on the role of early life exposures and the ability of chemicals to act via multiple biological pathways, including immunosuppression, inflammation, and endocrine disruption as well as mutagenesis, further supports the potential for chemicals and chemical mixtures to influence disease. Epidemiologic observations, such as higher leukemia incidence in children living near roadways and industrial sources of air pollution, and new technologies that decode carcinogenesis at the molecular level, illustrate the diverse evidence that primary prevention of some cancers may be achieved by reducing harmful chemical exposures. The path forward requires cross-disciplinary approaches, increased environmental research investment, system-wide collaboration to develop safer economic alternatives, and community engagement to support evidence-informed action. Engagement by cancer researchers to integrate environmental risk factors into prevention initiatives holds tremendous promise for reducing the rates of disease.
142Pancreatic cancer and obesity: epidemiology, mechanism, and preventive strategies.PubMed
Prashanth Rawla, Krishna Chaitanya Thandra, Tagore Sunkara
Clin J Gastroenterol. 2019 Aug;12(4):285-291. doi: 10.1007/s12328-019-00953-3. Epub 2019 Feb 20.
The prevalence of obesity has seen a global increase in the past decades, escalating to one of the major epidemiological challenges today. Global economic growth has caused changes in dietary and physical activity patterns fueling obesity across age, gender, and income groups. The implications are many, as obesity has been associated with numerous serious health conditions, ultimately affecting morbidity and mortality. There is a growing recognition of the risk a high body mass index confers on the development and outcome of several malignancies, including pancreatic cancer. Pancreatic cancer is a highly lethal disease with exceptionally poor outcome, with incidences rising worldwide. Due to vague symptoms and no screening recommendations, a vast majority of patients are diagnosed at late stages, with already advanced disease and no opportunity for surgical intervention. Obesity mediates risk for pancreatic cancer through insufficiently understood mechanisms, possibly including inflammation and hormonal misbalance. As excess abdominal adiposity is among the few modifiable risk factors for pancreatic cancer onset, enduring weight loss could manifest an effective preventive measure. Lifestyle modifications on a population level aimed to reduce obesity could also scale down the grim pancreatic cancer rates. In cases when these measures alone are insufficiently effective, bariatric surgery can be an advantageous alternative. Extremely obese patients exhibit many health benefits following bariatric surgery along with weight loss, consequently reducing the chances of pancreatic cancer, especially if additionally adopting healthy lifestyle habits.
143Diet and cancer risk reduction: The role of diet-microbiota interactions and microbial metabolites.PubMed
Tiffany L Weir, S Raj J Trikha, Henry J Thompson
Semin Cancer Biol. 2021 May;70:53-60. doi: 10.1016/j.semcancer.2020.06.007. Epub 2020 Jun 20.
According to recent estimates, over one third of the human population will be diagnosed with cancer at some point in their lifetime. While genetic factors play a large part in cancer risk, as much as 50 % of cancers may be preventable through various lifestyle modifications. Nutrition is a major modifiable risk factor, both through its impacts on obesity as well as through dietary chemical exposures that can either increase or decrease cancer risk. However, specific associations and mechanistic links between diet and cancer risk are either inconsistent or elusive. New insights regarding the reciprocal interactions between diet and the gut microbiota, the trillions of organisms that reside in our intestines, may help clarify how diet impacts cancer. The gut microbiota is largely shaped by an individual's diet and has far-reaching effects on metabolism, the immune system, and inflammation- important factors in the development and progression of various cancers. Likewise, the microbiota modifies dietary components, and consequently, exposure to metabolites that can influence cancer. This review explores some of these diet-microbiota interactions in the context of their potential impacts on cancer prevention.
144Hepatocellular Carcinoma: Updates to Screening and Diagnosis.PubMed
Anne M Covey
J Natl Compr Canc Netw. 2018 May;16(5S):663-665. doi: 10.6004/jnccn.2018.0052.
In what is considered to be "a global problem," liver cancer has tripled in incidence in the United States over the past 20 to 30 years, and is now present in 7 per 100,000 Americans. Thus, screening for disease should be at the forefront to effectively treat high-risk populations. At the 2018 NCCN 23rd Annual Conference, Dr. Anne M. Covey discussed the updated NCCN Guidelines for the screening and diagnosis of hepatocellular carcinoma, which place ultrasound as the most cost-effective and least toxic primary screening option, with a screening interval of approximately 6 months for individuals considered to be at high risk.
145Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis: A Meta-analysis.PubMed
Kristina Tzartzeva, Joseph Obi, Nicole E Rich, et al.
Gastroenterology. 2018 May;154(6):1706-1718.e1. doi: 10.1053/j.gastro.2018.01.064. Epub 2018 Feb 6.
BACKGROUND & AIMS: Society guidelines differ in their recommendations for surveillance to detect early-stage hepatocellular carcinoma (HCC) in patients with cirrhosis. We compared the performance of surveillance imaging, with or without alpha fetoprotein (AFP), for early detection of HCC in patients with cirrhosis. METHODS: Two reviewers searched MEDLINE and SCOPUS from January 1990 through August 2016 to identify published sensitivity and specificity of surveillance strategies for overall and early detection of HCC. Pooled estimates were calculated and compared using the DerSimonian and Laird method for a random effects model. The study was conducted in accordance with Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. RESULTS: Thirty-two studies (comprising 13,367 patients) characterized sensitivity of imaging with or without AFP measurement for detection of HCC in patients with cirrhosis. Ultrasound detected any stage HCC with 84% sensitivity (95% confidence interval [CI] 76%-92%), but early-stage HCC with only 47% sensitivity (95% CI 33%-61%). In studies comparing ultrasound with vs without AFP measurement, ultrasound detected any stage HCC with a lower level of sensitivity than ultrasound plus AFP measurement (relative risk [RR] 0.88; 95% CI 0.83-0.93) and early-stage HCC with a lower level of sensitivity than ultrasound plus AFP measurement (RR 0.81; 95% CI 0.71-0.93). However, ultrasound alone detected HCC with a higher level of specificity than ultrasound plus AFP measurement (RR 1.08; 95% CI 1.05-1.09). Ultrasound with vs without AFP detected early-stage HCC with 63% sensitivity (95% CI 48%-75%) and 45% sensitivity (95% CI 30%-62%), respectively (P = .002). Only 4 studies evaluated computed tomography or magnetic resonance image-based surveillance, which detected HCC with 84% sensitivity (95% CI 70%-92%). CONCLUSIONS: We found ultrasound alone has a low sensitivity to detect early stage HCC in patients with cirrhosis. Addition of AFP to ultrasound significantly increases sensitivity of early HCC detection in clinical practice.
146Current and Emerging Tools for Hepatocellular Carcinoma Surveillance.PubMed
Nia Adeniji, Renumathy Dhanasekaran
Hepatol Commun. 2021 Dec;5(12):1972-1986. doi: 10.1002/hep4.1823. Epub 2021 Sep 17.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Early detection of HCC enables patients to avail curative therapies that can improve patient survival. Current international guidelines advocate for the enrollment of patients at high risk for HCC, like those with cirrhosis, in surveillance programs that perform ultrasound every 6 months. In recent years, many studies have further characterized the utility of established screening strategies and have introduced new promising tools for HCC surveillance. In this review, we provide an overview of the most promising new imaging modalities and biomarkers for the detection of HCC. We discuss the role of imaging tools like ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) in the early detection of HCC, and describe recent innovations which can potentially enhance their applicability, including contrast enhanced ultrasound, low-dose CT scans, and abbreviated MRI. Next, we outline the data supporting the use of three circulating biomarkers (i.e., alpha-fetoprotein [AFP], AFP lens culinaris agglutinin-reactive fraction, and des-gamma-carboxy prothrombin) in HCC surveillance, and expand on multiple emerging liquid biopsy biomarkers, including methylated cell-free DNA (cfDNA), cfDNA mutations, extracellular vesicles, and circulating tumor cells. These promising new imaging modalities and biomarkers have the potential to improve early detection, and thus improve survival, in patients with HCC.
147Cell-free DNA testing for early hepatocellular carcinoma surveillance.PubMed
Lei Chen, Tong Wu, Rong Fan, et al.
EBioMedicine. 2024 Feb;100:104962. doi: 10.1016/j.ebiom.2023.104962. Epub 2024 Jan 6.
BACKGROUND: Liver cirrhosis (LC) is the highest risk factor for hepatocellular carcinoma (HCC) development worldwide. The efficacy of the guideline-recommended surveillance methods for patients with LC remains unpromising. METHODS: A total of 4367 LCs not previously known to have HCC and 510 HCCs from 16 hospitals across 11 provinces of China were recruited in this multi-center, large-scale, cross-sectional study. Participants were divided into Stage Ⅰ cohort (510 HCCs and 2074 LCs) and Stage Ⅱ cohort (2293 LCs) according to their enrollment time and underwent Tri-phasic CT/enhanced MRI, US, AFP, and cell-free DNA (cfDNA). A screening model called PreCar Score was established based on five features of cfDNA using Stage Ⅰ cohort. Surveillance performance of PreCar Score alone or in combination with US/AFP was evaluated in Stage Ⅱ cohort. FINDINGS: PreCar Score showed a significantly higher sensitivity for the detection of early/very early HCC (Barcelona stage A/0) in contrast to US (sensitivity of 51.32% [95% CI: 39.66%-62.84%] at 95.53% [95% CI: 94.62%-96.38%] specificity for PreCar Score; sensitivity of 23.68% [95% CI: 14.99%-35.07%] at 99.37% [95% CI: 98.91%-99.64%] specificity for US) (P < 0.01, Fisher's exact test). PreCar Score plus US further achieved a higher sensitivity of 60.53% at 95.08% specificity for early/very early HCC screening. INTERPRETATION: Our study developed and validated a cfDNA-based screening tool (PreCar Score) for HCC in cohorts at high risk. The combination of PreCar Score and US can serve as a promising and practical strategy for routine HCC care. FUNDING: A full list of funding bodies that contributed to this study can be found in Acknowledgments section.
148Management of epithelial precancerous conditions and early neoplasia of the stomach (MAPS III): European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter and Microbiota Study Group (EHMSG) and European Society of Pathology (ESP) Guideline update 2025.PubMed
Mário Dinis-Ribeiro, Diogo Libânio, Hugo Uchima, et al.
Endoscopy. 2025 May;57(5):504-554. doi: 10.1055/a-2529-5025. Epub 2025 Mar 20.
At a population level, the European Society of Gastrointestinal Endoscopy (ESGE), the European and Microbiota Study Group (EHMSG), and the European Society of Pathology (ESP) suggest endoscopic screening for gastric cancer (and precancerous conditions) in high-risk regions (age-standardized rate [ASR] > 20 per 100 000 person-years) every 2 to 3 years or, if cost-effectiveness has been proven, in intermediate risk regions (ASR 10-20 per 100 000 person-years) every 5 years, but not in low-risk regions (ASR < 10).ESGE/EHMSG/ESP recommend that irrespective of country of origin, individual gastric risk assessment and stratification of precancerous conditions is recommended for first-time gastroscopy. ESGE/EHMSG/ESP suggest that gastric cancer screening or surveillance in asymptomatic individuals over 80 should be discontinued or not started, and that patients' comorbidities should be considered when treatment of superficial lesions is planned.ESGE/EHMSG/ESP recommend that a high quality endoscopy including the use of virtual chromoendoscopy (VCE), after proper training, is performed for screening, diagnosis, and staging of precancerous conditions (atrophy and intestinal metaplasia) and lesions (dysplasia or cancer), as well as after endoscopic therapy. VCE should be used to guide the sampling site for biopsies in the case of suspected neoplastic lesions as well as to guide biopsies for diagnosis and staging of gastric precancerous conditions, with random biopsies to be taken in the absence of endoscopically suspected changes. When there is a suspected early gastric neoplastic lesion, it should be properly described (location, size, Paris classification, vascular and mucosal pattern), photodocumented, and two targeted biopsies taken.ESGE/EHMSG/ESP do not recommend routine performance of endoscopic ultrasonography (EUS), computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET)-CT prior to endoscopic resection unless there are signs of deep submucosal invasion or if the lesion is not considered suitable for endoscopic resection.ESGE/EHMSG/ESP recommend endoscopic submucosal dissection (ESD) for differentiated gastric lesions clinically staged as dysplastic (low grade and high grade) or as intramucosal carcinoma (of any size if not ulcerated or ≤ 30 mm if ulcerated), with EMR being an alternative for Paris 0-IIa lesions of size ≤ 10 mm with low likelihood of malignancy.ESGE/EHMSG/ESP suggest that a decision about ESD can be considered for malignant lesions clinically staged as having minimal submucosal invasion if differentiated and ≤ 30 mm; or for malignant lesions clinically staged as intramucosal, undifferentiated and ≤ 20 mm; and in both cases with no ulcerative findings.ESGE/EHMSG/ESP recommends patient management based on the following histological risk after endoscopic resection: (lymph node metastasis [LNM] risk < 0.5 %-1 %): en bloc R0 resection; dysplastic/pT1a, differentiated lesion, no lymphovascular invasion, independent of size if no ulceration and ≤ 30 mm if ulcerated. No further staging procedure or treatment is recommended.C (LNM risk < 3 %): en bloc R0 resection; lesion with no lymphovascular invasion and: a) pT1b, invasion ≤ 500 µm, differentiated, size ≤ 30 mm; or b) pT1a, undifferentiated, size ≤ 20 mm and no ulceration. Staging should be completed, and further treatment is generally not necessary, but a multidisciplinary discussion is required. (very low risk of LNM but increased risk of local persistence/recurrence): Piecemeal resection or tumor-positive horizontal margin of a lesion otherwise meeting curative/very low-risk criteria (or meeting low-risk criteria provided that there is no submucosal invasive tumor at the resection margin in the case of piecemeal resection or tumor-positive horizontal margin for pT1b lesions [invasion ≤ 500 µm; well-differentiated; size ≤ 30 mm, and VM0]). Endoscopic surveillance/re-treatment is recommended rather than other additional treatment. (noncurative): Any lesion with any of the following: (a) a positive vertical margin (if carcinoma) or lymphovascular invasion or deep submucosal invasion (> 500 µm from the muscularis mucosae); (b) poorly differentiated lesions if ulceration or size > 20 mm; (c) pT1b differentiated lesions with submucosal invasion ≤ 500 µm with size > 30 mm; or (d) intramucosal ulcerative lesion with size > 30 mm. Complete staging and strong consideration for additional treatments (surgery) in multidisciplinary discussion.ESGE/EHMSG/ESP suggest the use of validated endoscopic classifications of atrophy (e. g. Kimura-Takemoto) or intestinal metaplasia (e. g. endoscopic grading of gastric intestinal metaplasia [EGGIM]) to endoscopically stage precancerous conditions and stratify the risk for gastric cancer.ESGE/EHMSG/ESP recommend that biopsies should be taken from at least two topographic sites (2 biopsies from the antrum/incisura and 2 from the corpus, guided by VCE) in two separate, clearly labeled vials. Additional biopsy from the incisura is optional.ESGE/EHMSG/ESP recommend that patients with extensive endoscopic changes (Kimura C3 + or EGGIM 5 +) or advanced histological stages of atrophic gastritis (severe atrophic changes or intestinal metaplasia, or changes in both antrum and corpus, operative link on gastritis assessment/operative link on gastric intestinal metaplasia [OLGA/OLGIM] III/IV) should be followed up with high quality endoscopy every 3 years, irrespective of the individual's country of origin.ESGE/EHMSG/ESP recommend that no surveillance is proposed for patients with mild to moderate atrophy or intestinal metaplasia restricted to the antrum, in the absence of endoscopic signs of extensive lesions or other risk factors (family history, incomplete intestinal metaplasia, persistent infection). This group constitutes most individuals found in clinical practice.ESGE/EHMSG/ESP recommend eradication for patients with precancerous conditions and after endoscopic or surgical therapy.ESGE/EHMSG/ESP recommend that patients should be advised to stop smoking and low-dose daily aspirin use may be considered for the prevention of gastric cancer in selected individuals with high risk for cardiovascular events.
149AGA Clinical Practice Update on Screening and Surveillance in Individuals at Increased Risk for Gastric Cancer in the United States: Expert Review.PubMed
Shailja C Shah, Andrew Y Wang, Michael B Wallace, et al.
Gastroenterology. 2025 Feb;168(2):405-416.e1. doi: 10.1053/j.gastro.2024.11.001. Epub 2024 Dec 23.
DESCRIPTION: Gastric cancer (GC) is a leading cause of preventable cancer and mortality in certain US populations. The most impactful way to reduce GC mortality is via primary prevention, namely Helicobacter pylori eradication, and secondary prevention, namely endoscopic screening and surveillance of precancerous conditions, such as gastric intestinal metaplasia (GIM). An emerging body of evidence supports the possible impact of these strategies on GC incidence and mortality in identifiable high-risk populations in the United States. Accordingly, the primary objective of this American Gastroenterological Association (AGA) Clinical Practice Update (CPU) Expert Review is to provide best practice advice for primary and secondary prevention of GC in the context of current clinical practice and evidence in the United States. METHODS: This CPU Expert Review was commissioned and approved by the AGA Institute CPU Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPU Committee and external peer review through standard procedures of Gastroenterology. These best practice advice statements were drawn from a review of the published literature and expert opinion. Because systematic reviews were not performed, these best practice advice statements do not carry formal ratings regarding the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: There are identifiable high-risk groups in the United States who should be considered for GC screening. These include first-generation immigrants from high-incidence GC regions and possibly other non-White racial and ethnic groups, those with a family history of GC in a first-degree relative, and individuals with certain hereditary gastrointestinal polyposis or hereditary cancer syndromes. BEST PRACTICE ADVICE 2: Endoscopy is the best test for screening or surveillance in individuals at increased risk for GC. Endoscopy enables direct visualization to endoscopically stage the mucosa and identify areas concerning for neoplasia, as well as enables biopsies for further histologic examination and mucosal staging. Both endoscopic and histologic staging are key for risk stratification and determining whether ongoing surveillance is indicated and at what interval. BEST PRACTICE ADVICE 3: High-quality upper endoscopy for the detection of premalignant and malignant gastric lesions should include the use of a high-definition white-light endoscopy system with image enhancement, gastric mucosal cleansing, and insufflation to achieve optimal mucosal visualization, in addition to adequate visual inspection time, photodocumentation, and use of a systematic biopsy protocol for mucosal staging when appropriate. BEST PRACTICE ADVICE 4: H pylori eradication is essential and serves as an adjunct to endoscopic screening and surveillance for primary and secondary prevention of GC. Opportunistic screening for H pylori infection should be considered in individuals deemed to be at increased risk for GC (refer to Best Practice Advice 1). Screening for H pylori infection in adult household members of individuals who test positive for H pylori (so-called "familial-based testing") should also be considered. BEST PRACTICE ADVICE 5: In individuals with suspected gastric atrophy with or without intestinal metaplasia, gastric biopsies should be obtained according to a systematic protocol (eg, updated Sydney System) to enable histologic confirmation and staging. A minimum of 5 total biopsies should be obtained, with samples from the antrum/incisura and corpus placed in separately labeled jars (eg, jar 1, "antrum/incisura" and jar 2, "corpus"). Any suspicious areas should be described and biopsied separately. BEST PRACTICE ADVICE 6: GIM and dysplasia are endoscopically detectable. However, these findings often go undiagnosed when endoscopists are unfamiliar with the characteristic visual features; accordingly, there is an unmet need for improved training, especially in the United States. Artificial intelligence tools appear promising for the detection of early gastric neoplasia in the adequately visualized stomach, but data are too preliminary to recommend routine use. BEST PRACTICE ADVICE 7: Endoscopists should work with their local pathologists to achieve consensus for consistent documentation of histologic risk-stratification parameters when atrophic gastritis with or without metaplasia is diagnosed. At a minimum, the presence or absence of H pylori infection, severity of atrophy and/or metaplasia, and histologic subtyping of GIM, if applicable, should be documented to inform clinical decision making. BEST PRACTICE ADVICE 8: If the index screening endoscopy performed in an individual at increased risk for GC (refer to Best Practice Advice 1) does not identify atrophy, GIM, or neoplasia, then the decision to continue screening should be based on that individual's risk factors and preferences. If the individual has a family history of GC or multiple risk factors for GC, then ongoing screening should be considered. The optimal screening intervals in such scenarios are not well defined. BEST PRACTICE ADVICE 9: Endoscopists should ensure that all individuals with confirmed gastric atrophy with or without GIM undergo risk stratification. Individuals with severe atrophic gastritis and/or multifocal or incomplete GIM are likely to benefit from endoscopic surveillance, particularly if they have other risk factors for GC (eg, family history). Endoscopic surveillance should be considered every 3 years; however, intervals are not well defined and shorter intervals may be advisable in those with multiple risk factors, such as severe GIM that is anatomically extensive. BEST PRACTICE ADVICE 10: Indefinite and low-grade dysplasia can be difficult to reproducibly identify by endoscopy and accurately diagnose on histopathology. Accordingly, all dysplasia should be confirmed by an experienced gastrointestinal pathologist, and clinicians should refer patients with visible or nonvisible dysplasia to an endoscopist or center with expertise in the diagnosis and management of gastric neoplasia. Individuals with indefinite or low-grade dysplasia who are infected with H pylori should be treated and have eradication confirmed, followed by repeat endoscopy and biopsies by an experienced endoscopist, as visual and histologic discernment may improve once inflammation subsides. BEST PRACTICE ADVICE 11: Individuals with suspected high-grade dysplasia or early GC should undergo endoscopic submucosal dissection with the goal of en bloc, R0 resection to enable accurate pathologic staging with curative intent. Eradication of active H pylori infection is essential, but should not delay endoscopic intervention. Endoscopic submucosal dissection should be performed at a center with endoscopic and pathologic expertise. BEST PRACTICE ADVICE 12: Individuals with a history of successfully resected gastric dysplasia or cancer require ongoing endoscopic surveillance. Suggested surveillance intervals exist, but additional data are required to refine surveillance recommendations, particularly in the United States. BEST PRACTICE ADVICE 13: Type I gastric carcinoids in individuals with atrophic gastritis are typically indolent, especially if <1 cm. Endoscopists may consider resecting gastric carcinoids <1 cm and should endoscopically resect lesions measuring 1-2 cm. Individuals with type I gastric carcinoids >2 cm should undergo cross-sectional imaging and be referred for surgical resection, given the risk of metastasis. Individuals with type I gastric carcinoids should undergo surveillance, but the intervals are not well defined. BEST PRACTICE ADVICE 14: In general, only individuals who are fit for endoscopic or potentially surgical treatment should be screened for GC and continued surveillance of premalignant gastric conditions. If a person is no longer fit for endoscopic or surgical treatment, then screening and surveillance should be stopped. BEST PRACTICE ADVICE 15: To achieve health equity, a personalized approach should be taken to assess an individual's risk for GC to determine whether screening and surveillance should be pursued. In conjunction, modifiable risk factors for GC should be distinctly addressed, as most of these risk factors disproportionately impact people at high risk for GC and represent health care disparities.
150[Pancreatic cancer-screening or surveillance?].PubMed
Simon Sirtl, Marlies Vornhülz, Felix O Hofmann, et al.
Radiologie (Heidelb). 2023 Dec;63(12):908-915. doi: 10.1007/s00117-023-01227-3.
BACKGROUND: Despite continuous improvement of diagnostic and therapeutic procedures, the number of new pancreatic ductal adenocarcinoma (PDAC) cases diagnosed annually almost equals the number of PDAC-related deaths. Prerequisite for curative treatment is a resectable tumor at the time of diagnosis. Individuals with genetic and/or familial risk profiles should therefore be screened and included in structured surveillance programs. OBJECTIVES: Description of the status quo and usefulness of current PDAC screening and surveillance concepts. METHODS: A selective literature search of current national and international guidelines including underlying literature was performed. RESULTS: Nearly half of pancreatic cancer cases are missed by currently available surveillance programs, even in high-risk cohorts. Magnetic resonance imaging and endoscopic ultrasound supplemented by CA19‑9 (± HbA) are not accurate enough to ensure robust earlier pancreatic cancer detection. Complementary biomarker panels will take on a crucial diagnostic role in the future.
151Diagnostic evaluation and staging of pancreatic ductal adenocarcinoma.PubMed
Caitlin A McIntyre, Jordan M Winter
Semin Oncol. 2015 Feb;42(1):19-27. doi: 10.1053/j.seminoncol.2014.12.003. Epub 2014 Dec 9.
Pancreatic ductal adenocarcinoma (PDA) frequently presents at an advanced and incurable stage of the disease. Common signs and symptoms of PDA include abdominal or back pain, jaundice, weight loss, pruritus, and nausea/vomiting. Diagnostic workup includes serum chemistries and CA19-9, primarily to monitor disease status and response to treatment. Imaging studies are performed to assess resectability and stage disease, and pancreatic protocol computed tomography (CT) scan or magnetic resonance imaging (MRI) are the preferred imaging studies for this purpose. Conventional staging is based on the American Joint Cancer Committee (AJCC) Staging System, 7th Edition and informs prognosis, while surgical staging systems focus specifically on assessing the likelihood of a complete (negative margins) resection with operative management. Herein, we review the presenting signs and symptoms, the diagnostic evaluation, and staging of PDA.
152Diagnosis and management of pancreatic cancer.PubMed
A Collins, M Bloomston
Minerva Gastroenterol Dietol. 2009 Dec;55(4):445-54.
Pancreatic adenocarcinoma is an aggressive malignancy with the majority of patients dying within one year of diagnosis. While surgical resection with negative margins offers the only hope for cure only a small minority of patients are amenable to resection at the time of diagnosis owing to the propensity for early metastasis. While most advances in the last several decades have revolved around improvements in surgical techniques and postoperative outcomes, some modest inroads have been made with modern chemotherapy. This review discusses the diagnosis and management of pancreatic cancer and highlights some of the current issues. A Medline database search was performed to identify relevant articles using the keywords "pancreatic adenocarcinoma", "diagnosis", "CA19-9", "pancreaticoduodenectomy", "adjuvant therapy", "chemotherapy", and "microRNA". Additional papers were then identified by a manual search of the references from the key articles. While high quality CT is often the only imaging modality needed for preoperative evaluation, magnetic resonance imaging (MRI), cholangiography, and endoscopic ultrasound (EUS) have been utilized for diagnosis, staging, and/ or palliation. The controversies of pylorus preservation, extended lymphadenectomy, and laparoscopic pancreaticoduodenectomy are discussed. Randomized controlled trials regarding the use of 5-fluorouracil and gemcitabine are also reviewed. Early detection and aggressive surgical resection in combination with protocol-driven adjuvant therapy and novel molecular approaches are the only hope for cure. This review summarizes the recent literature on the abovementioned topics.
153Magnetic resonance elastography-derived stiffness: potential imaging biomarker for differentiation of benign and malignant pancreatic masses.PubMed
Dingxia Liu, Jiejun Chen, Yunfei Zhang, et al.
Abdom Radiol (NY). 2023 Aug;48(8):2604-2614. doi: 10.1007/s00261-023-03956-4. Epub 2023 May 26.
OBJECTIVE: This study sought to determine the diagnostic performance of magnetic resonance elastography (MRE) for pancreatic solid masses, compared with diffusion-weighted imaging (DWI) and serum CA19-9, to establish a threshold for differentiating between pancreatic ductal adenocarcinoma (PDAC) and benign tumors in pancreas. MATERIALS AND METHODS: Between July 2021 to January 2023, 75 adult patients confirmed with pancreatic solid tumors were enrolled in this prospective and consecutive study. All patients underwent MRE and DWI examinations that were both performed with a spin echo-EPI sequence. Stiffness maps and apparent diffusion coefficient (ADC) maps were generated, with MRE-derived mass stiffness and stiffness ratio (computing as the ratio of mass stiffness to the parenchyma stiffness) and DWI-derived ADC values obtained by placing regions of interest over the focal tumors on stiffness and ADC maps. Further analysis of comparing diagnostic performances was assessed by calculating the area under ROC curves. RESULTS: PDAC had significantly higher tumor stiffness [3.795 (2.879-4.438) kPa vs. 2.359 (2.01-3.507) kPa, P = 0.0003], stiffness ratio [1.939 (1.562-2.511) vs. 1.187 (1.031-1.453), P < 0.0001] and serum CA19-9 level [276 (31.73-1055) vs. 10.45 (7.825-14.15), P < 0.0001] than other pancreatic masses. Mass stiffness, stiffness ratio and serum CA19-9 showed good diagnostic performance for differentiation with AUC of 0.7895, 0.8392 and 0.9136 respectively. The sensitivity/specificity/positive predictive value/negative predictive value for differentiating malignant from benign pancreatic tumors with mass stiffness (cutoff, > 2.8211 kPa) and stiffness ratio (cutoff, > 1.5117) were 78.4/66.7/82.9/60% and 77.8/83.3/90.3/65.2% respectively. The combined performance of Mass stiffness, stiffness ratio and serum CA19-9 got an AUC of 0.9758. CONCLUSION: MRE holds excellent clinical potential in discriminating pancreatic ductal adenocarcinoma from other pancreatic solid masses according to their mechanical properties.
154Comparative efficacy of novel combination strategies for unresectable hepatocellular carcinoma: A network metanalysis of phase III trials.PubMed
Claudia A M Fulgenzi, Antonio D'Alessio, Chiara Airoldi, et al.
Eur J Cancer. 2022 Oct;174:57-67. doi: 10.1016/j.ejca.2022.06.058. Epub 2022 Aug 12.
BACKGROUND: Dual programmed cell death-1 and vascular endothelial growth factor pathway inhibition is the novel standard of care for patients with unresectable hepatocellular carcinoma. Direct comparisons between first-line treatments are lacking. METHOD: We conducted a literature search in MEDLINE (https://pubmed.ncbi.nlm.nih.gov), the Cochrane library (https://www.cochranelibrary.com) and Embase (www.embase.com) between January 2007 and February 2022. We included phase III randomised controlled trials that tested immune-checkpoint inhibitors or tyrosine kinase inhibitors, including sorafenib, lenvatinib and donafenib, and evaluated as primary end-point overall survival (OS) or progression-free survival (PFS). Studies testing loco-regional therapies were excluded. The primary end-point was to compare the efficacy of first-line options in terms of OS and PFS. We extracted Hazard ratios (HR) and 95% confidence intervals (95% CI) for OS and PFS and performed a frequentist network meta-analysis with fixed effect multivariable meta-regression models. The research protocol was registered in PROSPERO, an international prospective register of systematic reviews (registration code CRD42022312489). FINDINGS: Literature review yielded 13709 results, after duplicates removal and exclusion of not relevant studies, 70 papers were available for screening. After full-text review, 9 studies were eligible for analysis. Atezolizumab plus bevacizumab reduced the risk of death compared to placebo (HR 0·40; 95% CI 0·28-0·57), sorafenib (HR 0·58; 95% CI 0·42-0·80), lenvatinib (HR 0·63; 95% CI 0·44-0·89), atezolizumab plus cabozantinib (HR 0·64; 95% CI 0·43-0·97), nivolumab (HR 0·68; 95% CI 0·48-0·98) and donafenib (HR 0·69; 95% CI 0·48-0·99). Atezolizumab plus bevacizumab was not statistically superior to durvalumab plus tremelimumab (HR 0·74; 95% CI 0·52-1·06) and sintilimab plus IBI305 (HR 1·02; 95% CI 0·67-1·55) in reducing the risk of death. Efficacy was associated with a higher risk of grade 3 adverse events.
155The Trend of the Treatment of Advanced Hepatocellular Carcinoma: Combination of Immunotherapy and Targeted Therapy.PubMed
Heng Dong, Zhengguo Zhang, Mengjie Ni, et al.
Curr Treat Options Oncol. 2024 Oct;25(10):1239-1256. doi: 10.1007/s11864-024-01246-9. Epub 2024 Sep 11.
Hepatocellular carcinoma (HCC) is a common type of tumor worldwide. The development of systemic treatment of advanced HCC has remained stagnant for a considerable period. During the last years, a series of new treatment regimens based on the combination of immunotherapeutic drugs and targeted drugs have been gradually developed, increased the objective response rate (ORR), overall survival (OS), and progression free survival (PFS) of HCC patients. Among the different combination therapy groups, atezolizumab plus bevacizumab and sintilimab plus IBI-305 seem to have unique advantages, while head-to-head comparisons are still needed. A comprehensive understanding of the developments, the ongoing clinical trials and the mechanisms of combination of immunotherapy and targeted therapy might lead to the development of new combination strategies and solving current challenges such as the molecular biomarkers, the clinical administration order of drugs and the second-line treatments after combination therapy.
156Case Report: Successful immune checkpoint inhibitor rechallenge after sintilimab-induced Guillain-Barré syndrome.PubMed
Lin Ye, Wan Rong Yue, Hao Shi, et al.
Front Immunol. 2025 Mar 19;16:1546886. doi: 10.3389/fimmu.2025.1546886. eCollection 2025.
Immune checkpoint inhibitors (ICIs) have revolutionized hepatocellular carcinoma (HCC) treatment, while immune-related adverse events (IRAEs) pose significant challenges. We report a 60-year-old male with unresectable HCC who developed Guillain-Barré syndrome (GBS), a rare but severe neurologic complication, after three cycles of sintilimab plus bevacizumab biosimilar and conventional transarterial chemoembolization (c-TACE). The patient presented with progressive ascending weakness, reaching symmetric quadriparesis with proximal muscle strength of 2/5 in upper limbs and 1/5 in lower limbs. Following sintilimab discontinuation, treatment with intravenous immunoglobulin (2 g/kg) and oral prednisone (30 mg/day) achieved complete neurological recovery within one month. Given the patient's favorable initial tumor response and strong request, immunotherapy was cautiously reinstated using tislelizumab after thorough clinical evaluation. Following four cycles of treatment, significant tumor response enabled successful conversion surgery with major pathological response (necrosis rate >70%). With 26-month survival and no evidence of recurrence, this case demonstrates the potential feasibility of ICI rechallenge with an alternative PD-1 inhibitor following sintilimab-induced GBS. Our experience suggests that ICI-related neurological adverse events may be drug-specific rather than class-specific, potentially providing valuable treatment options for patients showing favorable tumor response despite experiencing severe IRAEs, though larger studies are needed for validation.
157Promising first-line immuno-combination therapies for unresectable hepatocellular carcinoma: A cost-effectiveness analysis.PubMed
Feng Wen, Peng Huang, Qiuji Wu, et al.
Cancer Med. 2024 Aug;13(16):e70094. doi: 10.1002/cam4.70094.
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death all over the world, and brings a heavy social economic burden especially in China. Several immuno-combination therapies have shown promising efficacy in the first-line treatment of unresectable HCC and are widely used in clinical practice. Nevertheless, which combination is the most affordable one is unknown. Our study assessed the cost-effectiveness of the immuno-combinations as first-line treatment for patients with unresectable HCC from the perspective of Chinese payers. METHODS: A Markov model was built according to five multicenter, phase III, open-label, randomized trials (Himalaya, IMbrave150, ORIENT-32, CARES-310, LEAP-002) to investigate the cost-effectiveness of tremelimumab plus durvalumab (STRIDE), atezolizumab plus bevacizumab (A + B), sintilimab plus bevacizumab biosimilar (IBI305) (S + B), camrelizumab plus rivoceranib (C + R), and pembrolizumab plus lenvatinib (P + L). Three disease states were included: progression free survival (PFS), progressive disease (PD) as well as death. Medical costs were searched from West China Hospital, published literatures or the Red Book. Cost-effectiveness ratios (CERs) and incremental cost-effectiveness ratios (ICERs) were evaluated to compare costs among different combinations. Sensitivity analyses were performed to assess the robust of the model. RESULTS: The total cost and quality-adjusted life years (QALYs) of C + R, S + B, P + L, A + B and STRIDE were $12,109.27 and 0.91, $26,961.60 and 1.12, $55,382.53 and 0.83, $70,985.06 and 0.90, $84,589.01 and 0.73, respectively, resulting in the most cost-effective strategy of C + R with CER of $13,306.89 per QALY followed by S + B with CER of $24,072.86 per QALY. Compared with C + R, the ICER of S + B strategy was $70,725.38 per QALY, which would become the most cost-effective when the willing-to-pay threshold exceeded $73,500/QALY. In the subgroup analysis, with the application of Asia results in Leap-002 trial, the model results were the same as global data. In the sensitivity analysis, with the variation of parameters, the results were robust. CONCLUSION: As one of the promising immuno-combination therapies in the first-line systemic treatment of HCC, camrelizumab plus rivoceranib demonstrated the potential to be the most cost-effective strategy, which warranted further studies to best inform the real-world clinical practices.
158Single-Cell RNA Sequencing Reveals Stromal Evolution into LRRC15 Myofibroblasts as a Determinant of Patient Response to Cancer Immunotherapy.PubMed
Claudia X Dominguez, Sören Müller, Shilpa Keerthivasan, et al.
Cancer Discov. 2020 Feb;10(2):232-253. doi: 10.1158/2159-8290.CD-19-0644. Epub 2019 Nov 7.
With only a fraction of patients responding to cancer immunotherapy, a better understanding of the entire tumor microenvironment is needed. Using single-cell transcriptomics, we chart the fibroblastic landscape during pancreatic ductal adenocarcinoma (PDAC) progression in animal models. We identify a population of carcinoma-associated fibroblasts (CAF) that are programmed by TGFβ and express the leucine-rich repeat containing 15 (LRRC15) protein. These LRRC15 CAFs surround tumor islets and are absent from normal pancreatic tissue. The presence of LRRC15 CAFs in human patients was confirmed in >80,000 single cells from 22 patients with PDAC as well as by using IHC on samples from 70 patients. Furthermore, immunotherapy clinical trials comprising more than 600 patients across six cancer types revealed elevated levels of the LRRC15 CAF signature correlated with poor response to anti-PD-L1 therapy. This work has important implications for targeting nonimmune elements of the tumor microenvironment to boost responses of patients with cancer to immune checkpoint blockade therapy. SIGNIFICANCE: This study describes the single-cell landscape of CAFs in pancreatic cancer during tumor evolution. A TGFβ-driven, LRRC15 CAF lineage is associated with poor outcome in immunotherapy trial data comprising multiple solid-tumor entities and represents a target for combinatorial therapy..
159myCAFs are better than yours: targeting myofibroblasts potentiates immunotherapy.PubMed
Lea Monteran, Neta Erez
Trends Cancer. 2023 Jan;9(1):1-2. doi: 10.1016/j.trecan.2022.11.001. Epub 2022 Nov 9.
New findings (Krishnamurty et al.) implicate a subset of cancer-associated fibroblasts (CAFs) that express leucine-rich repeat containing 15 (LRRC15) in promoting tumor growth in pancreatic adenocarcinoma (PDAC), by suppressing the antitumor immunity of cytotoxic T cells. Genetic ablation of LRRC15+ CAFs resulted in better response to immune checkpoint blockade, suggesting they may be a novel target for therapy.