Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Kitasato 1-15-1, Minami-ku, Sagamihara 252-0374, Japan.
Department of General-Pediatric-Hepatobiliary Pancreatic Surgery, Kitasato University School of Medicine, Sagamihara 252-0374, Japan.
Int J Mol Sci. 2024 May 30;25(11):6003. doi: 10.3390/ijms25116003.
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive cancer with striking fibrosis, and its mortality rate is ranked second across human cancers. Cancer-associated fibroblasts (CAFs) play a critical role in PDAC progression, and we reviewed the molecular understanding of PDAC CAFs and novel therapeutic potential at present. CAFs-associated genes (CAFGs) were tentatively classified into three categories by stroma specificity representing stroma/epithelia expression ratios (SE ratios). The recent classification using single cell transcriptome technology clarified that CAFs were composed of myofibroblasts (myCAFs), inflammatory CAFs (iCAFs), and other minor ones (e.g., POSTN-CAFs and antigen presenting CAFs, apCAFs). is a myCAFs marker, and myCAFs depletion by diphtheria toxin induces the rapid accumulation of cytotoxic T lymphocytes (CTLs) and therefore augment PDL1 antibody treatments. This finding proposes that myCAFs may be a critical regulator of tumor immunity in terms of PDAC progression. myCAFs are located in CAFs adjacent to tumor cells, while iCAFs marked by and/or are distant from tumor cells, where hypoxic and acidic environments being located in iCAFs putatively due to poor blood supply is consistent with and expressions. iCAFs may be shared with SASP (secretion-associated phenotypes) in senescent CAFs. myCAFs are classically characterized by CAFGs induced by , while chemoresistant CAFs with SASP may dependent on expression and accompanied by STAT3 activation. Recently, it was found that the unique metabolism of CAFs can be targeted to prevent PDAC progression, where PDAC cells utilize glucose, whereas CAFs in turn utilize lactate, which may be epigenetically regulated, mediated by its target genes including . In summary, CAFs have unique molecular characteristics, which have been rigorously clarified as novel therapeutic targets of PDAC progression.
胰腺导管腺癌 (PDAC) 是最具侵袭性的癌症，伴有明显的纤维化，其死亡率在人类癌症中排名第二。癌相关成纤维细胞 (CAFs) 在 PDAC 进展中发挥关键作用，我们目前综述了对 PDAC CAFs 的分子认识和新的治疗潜力。CAFs 相关基因 (CAFGs) 被暂定分为三类，根据基质特异性代表基质/上皮表达比 (SE 比)。最近使用单细胞转录组技术的分类阐明了 CAFs 由肌成纤维细胞 (myCAFs)、炎性 CAFs (iCAFs) 和其他少量 CAFs (如 POSTN-CAFs 和抗原呈递 CAFs、apCAFs) 组成。是 myCAFs 的标志物，用白喉毒素耗竭 myCAFs 会诱导细胞毒性 T 淋巴细胞 (CTL) 的快速积累，从而增强 PD-L1 抗体治疗效果。这一发现表明，myCAFs 可能是 PDAC 进展中肿瘤免疫的关键调节因子。myCAFs 位于与肿瘤细胞相邻的 CAFs 中，而由 和/或 标记的 iCAFs 远离肿瘤细胞，由于 iCAFs 中供血不足，可能存在缺氧和酸性环境，这与 和 的表达一致。iCAFs 可能与衰老 CAFs 中的 SASP (分泌相关表型) 共享。myCAFs 的特征是经典地由 TGFβ 诱导的 CAFGs 引起，而具有 SASP 的化学抗性 CAFs 可能依赖于 表达，并伴有 STAT3 激活。最近发现，CAFs 的独特代谢可以被靶向以阻止 PDAC 进展，其中 PDAC 细胞利用葡萄糖，而 CAFs 反过来利用乳酸，这可能是通过其靶基因包括 进行表观遗传调控的。总之，CAFs 具有独特的分子特征，已被严格阐明为 PDAC 进展的新治疗靶点。
