Tumor Microenvironment: Extracellular Matrix Alterations Influence Tumor Progression

Abstract

The tumor microenvironment (TME) is composed of various cell types embedded in an altered extracellular matrix (ECM). ECM not only serves as a support for tumor cell but also regulates cell-cell or cell-matrix cross-talks. Alterations in ECM may be induced by hypoxia and acidosis, by oxygen free radicals generated by infiltrating inflammatory cells or by tumor- or stromal cell-secreted proteases. A poorer diagnosis for patients is often associated with ECM alterations. Tumor ECM proteome, also named cancer matrisome, is strongly altered, and different ECM protein signatures may be defined to serve as prognostic biomarkers. Collagen network reorganization facilitates tumor cell invasion. Proteoglycan expression and location are modified in the TME and affect cell invasion and metastatic dissemination. ECM macromolecule degradation by proteases may induce the release of angiogenic growth factors but also the release of proteoglycan-derived or ECM protein fragments, named matrikines or matricryptins. This review will focus on current knowledge and new insights in ECM alterations, degradation, and reticulation through cross-linking enzymes and on the role of ECM fragments in the control of cancer progression and their potential use as biomarkers in cancer diagnosis and prognosis.

Keywords: cancer; extracellular matrix; integrins; matrikines; microenvironment; proteases.

Figure 1

Main metabolic and extracellular matrix (ECM) alterations in the tumor microenvironment (TME) during tumor progression. During cancer progression, tumor cells increase lactate production, leading to an acidification of TME. Tumor cells, cancer-associated fibroblasts (CAFs), polymorphonuclear leukocytes (PMNs), and monocytes secrete proteases, such as matrix metalloproteinases (MMPs), that degrade ECM and release matrikines. CAFs induce a higher secretion of ECM macromolecules that leads to an excessive deposition of ECM components. Tumor cells, PMNs, and monocytes produce reactive oxygen species (ROS) that degrade ECM components and particularly collagen I, facilitating tumor cell migration. They also stimulate the production of MMPs. Hypoxia also induces hypoxia-inducible factor (HIF) stabilization, lysyl oxidase (LOX) and transglutaminase activation, collagen and elastin cross-linking leading to ECM stiffening. These events favor tumor cell migration and cancer progression.

Figure 2

Schematic representation of the main transduction pathways altered by extracellular matrix (ECM) bioactive fragments. Bioactive fragments stimulating the pathway are outlined in green, and fragments with inhibitory activity are outlined in red. Endostatin inhibits the Wnt/β-catenin pathway, while glypican-3 triggers this pathway. Tumstatin, tetrastatin, endostatin, NC1(XIX), and lumcorin inhibit the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway through integrin binding while VGVAPG and IKVAV activate this pathway through elastin receptor complex (ERC) and integrin binding, respectively. VGVAPG and IKVAV also activate the mitogen-activated protein kinase (MAPK) pathways. Arresten and canstatin activate the Bcl-2 pro-apoptotic pathway through integrin binding.