Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA.
Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, USA.
Hepatol Commun. 2024 Aug 5;8(8). doi: 10.1097/HC9.0000000000000502. eCollection 2024 Aug 1.
Cholangiocarcinoma (CCA) features highly desmoplastic stroma that promotes structural and functional resistance to therapy. Lysyl oxidases (LOX, LOXL1-4) catalyze collagen cross-linking, thereby increasing stromal rigidity and facilitating therapeutic resistance. Here, we evaluate the role of lysyl oxidases in stromal desmoplasia and the effects of pan-lysyl oxidase (pan-LOX) inhibition in CCA.
Resected CCA and normal liver specimens were analyzed from archival tissues. Spontaneous and orthotopic murine models of intrahepatic CCA (iCCA) were used to assess the impact of the pan-LOX inhibitor PXS-5505 in treatment and correlative studies. The functional role of pan-LOX inhibition was interrogated through in vivo and ex vivo assays.
All 5 lysyl oxidases are upregulated in CCA and reduced lysyl oxidase expression is correlated with an improved prognosis in resected patients with CCA. Spontaneous and orthotopic murine models of intrahepatic cholangiocarcinoma upregulate all 5 lysyl oxidase isoforms. Pan-LOX inhibition reversed mechanical compression of tumor vasculature, resulting in improved chemotherapeutic penetrance and cytotoxic efficacy. The combination of chemotherapy with pan-LOX inhibition increased damage-associated molecular pattern release, which was associated with improved antitumor T-cell responses. Pan-LOX inhibition downregulated macrophage invasive signatures in vitro, rendering tumor-associated macrophages more susceptible to chemotherapy. Mice bearing orthotopic and spontaneously occurring intrahepatic cholangiocarcinoma tumors exhibited delayed tumor growth and improved survival following a combination of pan-LOX inhibition with chemotherapy.
CCA upregulates all 5 lysyl oxidase isoforms, and pan-LOX inhibition reverses tumor-induced mechanical forces associated with chemotherapy resistance to improve chemotherapeutic efficacy and reprogram antitumor immune responses. Thus, combination therapy with pan-LOX inhibition represents an innovative therapeutic strategy in CCA.
胆管癌（CCA）的特征是高度细胞外基质增生，这促进了治疗的结构和功能抵抗。赖氨酰氧化酶（LOX，LOXL1-4）催化胶原交联，从而增加基质刚性并促进治疗抵抗。在这里，我们评估赖氨酰氧化酶在基质纤维化中的作用以及泛赖氨酰氧化酶（pan-LOX）抑制在 CCA 中的作用。
分析了来自存档组织的 CCA 和正常肝脏标本。使用自发性和原位肝内胆管癌（iCCA）小鼠模型来评估泛 LOX 抑制剂 PXS-5505 在治疗和相关研究中的作用。通过体内和体外测定来探究泛 LOX 抑制的功能作用。
CCA 中所有 5 种赖氨酰氧化酶均上调，而在接受切除治疗的 CCA 患者中，下调赖氨酰氧化酶表达与改善预后相关。自发性和原位肝内胆管癌小鼠模型上调了所有 5 种赖氨酰氧化酶同工型。泛 LOX 抑制逆转了肿瘤血管的机械压缩，从而提高了化疗药物的渗透性和细胞毒性作用。化疗与泛 LOX 抑制的联合使用增加了损伤相关分子模式的释放，这与增强抗肿瘤 T 细胞反应相关。泛 LOX 抑制在体外下调了肿瘤相关巨噬细胞的侵袭特征，使肿瘤相关巨噬细胞对化疗更敏感。接受原位和自发性肝内胆管癌肿瘤的小鼠在接受泛 LOX 抑制联合化疗后，肿瘤生长延迟，存活率提高。
CCA 上调了所有 5 种赖氨酰氧化酶同工型，泛 LOX 抑制逆转了与化疗耐药相关的肿瘤诱导的机械力，从而提高了化疗效果并重新编程了抗肿瘤免疫反应。因此，泛 LOX 抑制联合治疗代表了 CCA 的一种创新治疗策略。
