Finger Anna-Marie, Hendley Audrey Marie, Figueroa Diego, Gonzalez Hugo, Weaver Valerie Marie
Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA 94143; Current address: Liver Disease Research, Global Drug Discovery, Novo Nordisk A/S, Malov, Denmark.
Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA 94143.
Trends Cancer. 2025 Aug;11(8):806-824. doi: 10.1016/j.trecan.2025.04.004. Epub 2025 Apr 29.
Tumorigenesis ensues within a heterogeneous tissue microenvironment that promotes malignant transformation, metastasis and treatment resistance. A major feature of the tumor microenvironment is the heterogeneous population of cancer-associated fibroblasts and myeloid cells that stiffen the extracellular matrix. The heterogeneously stiffened extracellular matrix in turn activates cellular mechanotransduction and creates a hypoxic and metabolically hostile microenvironment. The stiffened extracellular matrix and elevated mechanosignaling also drive tumor aggression by fostering tumor cell growth, survival, and invasion, compromising antitumor immunity, expanding cancer stem cell frequency, and increasing mutational burden, which promote intratumor heterogeneity. Delineating the molecular mechanisms whereby tissue mechanics regulate these phenotypes should help to clarify the basis for tumor heterogeneity and cancer aggression and identify novel therapeutic targets that could improve patient outcome. Here, we discuss the role of the extracellular matrix in driving cancer aggression through its impact on tumor heterogeneity.
肿瘤发生在促进恶性转化、转移和治疗抵抗的异质性组织微环境中。肿瘤微环境的一个主要特征是癌症相关成纤维细胞和髓样细胞的异质性群体，它们会使细胞外基质变硬。而异质性变硬的细胞外基质反过来又会激活细胞机械转导，并创造一个缺氧和代谢不利的微环境。变硬的细胞外基质和增强的机械信号传导还通过促进肿瘤细胞生长、存活和侵袭来驱动肿瘤侵袭，损害抗肿瘤免疫力，扩大癌症干细胞频率，并增加突变负担，从而促进肿瘤内异质性。阐明组织力学调节这些表型的分子机制，应有助于阐明肿瘤异质性和癌症侵袭的基础，并确定可改善患者预后的新治疗靶点。在此，我们讨论细胞外基质通过其对肿瘤异质性的影响在驱动癌症侵袭中的作用。
