Department of Hematology and Oncology, Heersink School of Medicine, University of Alabama, Birmingham, AL 35233, USA.
Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Biochim Biophys Acta Rev Cancer. 2024 Jan;1879(1):189065. doi: 10.1016/j.bbcan.2023.189065. Epub 2023 Dec 30.
Pancreatic cancer (PC) remains a leading cause of mortality worldwide due to the absence of early detection methods and the low success rates of traditional therapeutic strategies. Drug resistance in PC is driven by its desmoplastic stroma, which creates a barrier that shields cancer niches and prevents the penetration of drugs. The PC stroma comprises heterogeneous cellular populations and non-cellular components involved in aberrant ECM deposition, immunosuppression, and drug resistance. These components can influence PC development through intricate and complex crosstalk with the PC cells. Understanding how stromal components and cells interact with and influence the invasiveness and refractoriness of PC cells is thus a prerequisite for developing successful stroma-modulating strategies capable of remodeling the PC stroma to alleviate drug resistance and enhance therapeutic outcomes. In this review, we explore how non-cellular and cellular stromal components, including cancer-associated fibroblasts and tumor-associated macrophages, contribute to the immunosuppressive and tumor-promoting effects of the stroma. We also examine the signaling pathways underlying their activation, tumorigenic effects, and interactions with PC cells. Finally, we discuss recent pre-clinical and clinical work aimed at developing and testing novel stroma-modulating agents to alleviate drug resistance and improve therapeutic outcomes in PC.
胰腺癌（PC）仍然是全球主要的死亡原因，这是由于缺乏早期检测方法和传统治疗策略的成功率低。PC 的耐药性是由其促结缔组织增生性基质驱动的，这种基质形成了一个屏障，保护了肿瘤巢并阻止了药物的渗透。PC 基质由参与异常 ECM 沉积、免疫抑制和耐药性的异质细胞群体和非细胞成分组成。这些成分可以通过与 PC 细胞的复杂和复杂的串扰来影响 PC 的发展。因此，了解基质成分和细胞如何相互作用并影响 PC 细胞的侵袭性和耐药性是开发成功的基质调节策略的前提，这种策略能够重塑 PC 基质，减轻耐药性并提高治疗效果。在这篇综述中，我们探讨了非细胞和细胞基质成分，包括癌相关成纤维细胞和肿瘤相关巨噬细胞，如何促进基质的免疫抑制和肿瘤促进作用。我们还研究了它们激活、致瘤作用以及与 PC 细胞相互作用的信号通路。最后，我们讨论了旨在开发和测试新型基质调节剂以减轻 PC 耐药性并改善治疗效果的最近的临床前和临床工作。
