Fig. 2: Extracellular matrix and tumor microenvironment.
From: Causal contributors to tissue stiffness and clinical relevance in urology
Cell components of the TME (cancer cells, CAFs and TAMs) modulate ECM through different activities. One of these modulations is the topographic reconfiguration of the stroma: ECM anisotropy. By upregulation of LOX, CAFs increase collagen crosslinking, altering ECM topology as well as directionality and mechanical properties. Increased collagen crosslinking induces stiffer microenvironment, which modulates macrophages activation (a). Cancer-associated fibroblasts (CAFs) represent the main source of ECM production and remodeling within the TME where they promote neoangiogenesis and EMT (b). Tumor-associated macrophages (TAMs), microbiome, and extracellular vesicles (EVs) reshape ECM by secreting MMPs and matrix-associated proteins. MMPs release ECM-attached soluble growth factors and cytokines, which promote neoangiogenesis, contributing to tumor growth and potential metastatic spreading (c). Finally, cancer cells migrate along tension-oriented collagen fibers towards the vessels. The alignment of ECM fibers yields a rigid structure that contributes to tumor stiffness and acts as sort of highway for cancer cell migration, leading metastasis (d). ECM extracellular matrix, TME tumor microenvironment, CAFs cancer-associated fibroblasts, EMt epithelial–mesenchymal transition, TAMs tumor-associated macrophage, LOX lysyl oxidase enzyme, MMPs matrix metalloproteinases, EVs extracellular vesicles.
