Fibrotic Fortresses and Therapeutic Frontiers: Pancreatic Stellate Cells and the Extracellular Matrix in Pancreatic Cancer

IF 2.9 2区医学 Q2 ONCOLOGY

Cancer Medicine Pub Date : 2025-05-28 DOI:10.1002/cam4.70788

Sila Sigirli, Didem Karakas

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引用次数: 0

Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a unique tumor microenvironment (TME) that plays pivotal roles in cancer progression, angiogenesis, metastasis, and drug resistance. This complex and dynamic ecosystem comprises cancer cells, stromal cells, and extracellular matrix (ECM) components, which interact synergistically to drive cancer aggressiveness. Among the stromal cells, cancer-associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs), mainly accepted as a group of CAFs, are central players in shaping the desmoplastic, hypoxic, and immunosuppressive stroma of PDAC. PSCs, the most abundant stromal cells in PDAC, are resident pancreatic cells that undergo phenotypic changes upon activation, driving tumor progression through the secretion of cytokines, growth factors, ECM components (e.g., collagen, hyaluronic acid, fibronectin), and matrix metalloproteinases. In addition to cellular elements, ECM components significantly contribute to cancer aggressiveness by forming a physical barrier that hinders drug penetration, activating signaling pathways through specific receptor interactions, and generating peptides originating from the fragmentation of proteins to induce cancer migration. Regarding their critical roles in tumor progression, therapeutic approaches targeting PSCs and the ECM have garnered increasing interest in recent years. However, PSCs and stromal components may exhibit dual roles, with the potential to both promote and suppress tumor progression under different conditions. Therefore, targeting PSCs or stroma may lead to unintended outcomes, including exacerbation of cancer aggressiveness.

Methods

This review focuses on the multifaceted roles of PSCs in PDAC, particularly their interactions with cancer cells and their contributions to therapy resistance. Additionally, we discuss current and emerging therapeutic strategies targeting PSCs and the ECM components, including both preclinical and clinical efforts.

Conclusion

By synthesizing insights from recent literature, this review provides a comprehensive understanding of the role of PSCs in PDAC pathobiology and highlights potential therapeutic approaches targeting PSCs or ECM components to improve patient outcomes.

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纤维化堡垒和治疗前沿：胰腺癌中的胰腺星状细胞和细胞外基质

胰腺导管腺癌（Pancreatic ductal adencarcinoma， PDAC）具有独特的肿瘤微环境（tumor microenvironment， TME），在肿瘤进展、血管生成、转移和耐药中起关键作用。这个复杂而动态的生态系统包括癌细胞、基质细胞和细胞外基质（ECM）成分，它们协同作用以驱动癌症的侵袭性。在基质细胞中，癌症相关成纤维细胞（CAFs）和胰腺星状细胞（PSCs）主要被认为是一组CAFs，它们在形成PDAC的结缔组织增生、缺氧和免疫抑制基质中起着核心作用。PSCs是PDAC中最丰富的基质细胞，是常驻胰腺细胞，激活后发生表型变化，通过分泌细胞因子、生长因子、ECM成分（如胶原蛋白、透明质酸、纤维连接蛋白）和基质金属蛋白酶驱动肿瘤进展。除了细胞成分外，ECM成分还通过形成阻碍药物渗透的物理屏障，通过特定受体相互作用激活信号通路，以及产生源自蛋白质片段的肽来诱导癌症迁移，从而显著促进癌症的侵袭性。鉴于它们在肿瘤进展中的关键作用，针对PSCs和ECM的治疗方法近年来引起了越来越多的兴趣。然而，PSCs和基质成分可能表现出双重作用，在不同条件下具有促进和抑制肿瘤进展的潜力。因此，靶向PSCs或基质可能导致意想不到的结果，包括癌症侵袭性的加剧。方法本文综述了PSCs在PDAC中的多方面作用，特别是它们与癌细胞的相互作用及其对治疗耐药的贡献。此外，我们还讨论了当前和新兴的针对PSCs和ECM成分的治疗策略，包括临床前和临床工作。通过综合近期文献的见解，本综述提供了PSCs在PDAC病理生物学中的作用的全面理解，并强调了针对PSCs或ECM成分的潜在治疗方法，以改善患者的预后。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Medicine ONCOLOGY-

CiteScore

5.50

自引率

2.50%

发文量

907

审稿时长

19 weeks

期刊介绍： Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas: Clinical Cancer Research Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations Cancer Biology: Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery. Cancer Prevention: Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach. Bioinformatics: Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers. Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.