School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, and Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China.
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Adv Drug Deliv Rev. 2021 May;172:37-51. doi: 10.1016/j.addr.2021.02.012. Epub 2021 Mar 8.
A dense desmoplastic stroma formed by abundant extracellular matrix and stromal cells, including cancer-associated fibroblasts (CAFs) and immune cells, is a feature of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal cancer types. As the dominant cellular component of the PDAC stroma, CAFs orchestrate intensive and biologically diverse crosstalk with pancreatic cancer cells and immune cells and contribute to a unique PDAC tumor microenvironment promoting cancer proliferation, metastasis, and resistance against both chemo- and immunotherapies. Therefore, CAFs and CAF-related mechanisms have emerged as promising targets for PDAC therapy. However, several clinical setbacks and accumulating knowledge of the PDAC stroma have revealed the heterogeneity and multifaceted biological roles of CAFs, and concerns regarding "what to deliver" and "how to deliver" have arisen when designing CAF-targeted drug delivery systems to specifically inhibit tumor-supporting CAFs without impairing tumor-restricting CAFs. In this review, we will discuss the complexity of CAFs in the PDAC stroma as well as the potential opportunities and common misconceptions regarding drug delivery efforts targeting PDAC CAFs.
富含细胞外基质和基质细胞的致密促结缔组织增生型基质是胰腺导管腺癌 (PDAC) 的特征之一，PDAC 是最致命的癌症类型之一。作为 PDAC 基质的主要细胞成分，癌相关成纤维细胞 (CAFs) 与胰腺癌细胞和免疫细胞进行密集而具有生物学多样性的相互作用，并有助于形成独特的 PDAC 肿瘤微环境，促进癌症增殖、转移以及对化疗和免疫治疗的抵抗。因此，CAFs 及其相关机制已成为 PDAC 治疗的有前途的靶点。然而，一些临床挫折和对 PDAC 基质的不断积累的认识揭示了 CAFs 的异质性和多方面的生物学作用，并且在设计针对 CAF 的药物递送系统以专门抑制支持肿瘤的 CAFs 而不损害限制肿瘤的 CAFs 时，出现了“输送什么”和“如何输送”的问题。在这篇综述中，我们将讨论 PDAC 基质中 CAFs 的复杂性，以及针对 PDAC CAFs 的药物输送工作的潜在机会和常见误解。
