Cancer has long been believed to be a genetic disease caused by the accumulation of mutations in key genes involved in cellular processes. However, recent advances in sequencing technology have demonstrated that cells with cancer driver mutations are also present in normal tissues in response to aging, environmental damage, and chronic inflammation, suggesting that not only intrinsic factors within cancer cells, but also environmental alterations are important key factors in cancer development and progression. Pancreatic cancer tissue is mostly comprised of stromal cells and immune cells. The desmoplasmic microenvironment characteristic of pancreatic cancer is hypoxic and hypotrophic. Pancreatic cancer cells may adapt to this environment by rewiring their metabolism through epigenomic changes, enhancing intrinsic plasticity, creating an acidic and immunosuppressive tumor microenvironment, and inducing noncancerous cells to become tumor-promoting. In addition, pancreatic cancer has often metastasized to local and distant sites by the time of diagnosis, suggesting that a similar mechanism is operating from the precancerous stage. Here, we review key recent findings on how pancreatic cancers acquire plasticity, undergo metabolic reprogramming, and promote immunosuppressive microenvironment formation during their evolution. Furthermore, we present the following two signaling pathways that we have identified: one based on the small G-protein ARF6 driven byKRAS/TP53mutations, and the other based on the RNA-binding protein Arid5a mediated by inflammatory cytokines, which promote both metabolic reprogramming and immune evasion in pancreatic cancer. Finally, the striking diversity among pancreatic cancers in the relative importance of mutational burden and the tumor microenvironment, their clinical relevance, and the potential for novel therapeutic strategies will be discussed.
长期以来，癌症一直被认为是一种由细胞关键基因突变累积引起的遗传性疾病。然而，近期测序技术的进展表明，携带癌症驱动突变的细胞同样存在于正常组织中，这些突变是机体应对衰老、环境损伤及慢性炎症的结果。这一发现提示，不仅癌细胞的内在因素，环境改变同样是癌症发生与发展过程中的关键要素。胰腺癌组织主要由基质细胞和免疫细胞构成，其特有的促纤维增生微环境呈现低氧与低营养状态。胰腺癌细胞可能通过表观基因组改变重塑代谢途径、增强内在可塑性、营造酸性免疫抑制性肿瘤微环境，并诱导非癌细胞转化为促肿瘤细胞，从而适应这种特殊环境。此外，胰腺癌在确诊时往往已发生局部或远处转移，这表明从癌前阶段开始已有类似机制在发挥作用。本文综述了近期关于胰腺癌在演进过程中如何获得可塑性、进行代谢重编程以及促进免疫抑制微环境形成的关键发现。同时，我们提出已鉴定的两条信号通路：一条由KRAS/TP53突变驱动的小G蛋白ARF6通路，另一条由炎症细胞因子介导的RNA结合蛋白Arid5a通路，这两条通路共同促进胰腺癌的代谢重编程与免疫逃逸。最后，本文将探讨胰腺癌在突变负荷与肿瘤微环境相对重要性方面存在的显著异质性、其临床相关性以及新型治疗策略的潜在可能性。
肿瘤(癌症)患者之家