Matrix Metalloproteinases: Regulators of the Tumor Microenvironment

Abstract

Extracellular proteolysis mediates tissue homeostasis. In cancer, altered proteolysis leads to unregulated tumor growth, tissue remodeling, inflammation, tissue invasion, and metastasis. The matrix metalloproteinases (MMPs) represent the most prominent family of proteinases associated with tumorigenesis. Recent technological developments have markedly advanced our understanding of MMPs as modulators of the tumor microenvironment. In addition to their role in extracellular matrix turnover and cancer cell migration, MMPs regulate signaling pathways that control cell growth, inflammation, or angiogenesis and may even work in a nonproteolytic manner. These aspects of MMP function are reorienting our approaches to cancer therapy.

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“…Similarities in the pathologies of autoimmune diseases and cancer have been noted in studies conducted within the preceding 30 years 85, 86. Inflammatory cytokines and growth factors mediate cell proliferation, and proteinases—especially the collagenase matrix metalloproteinase‐1 (MMP‐1)—contribute to disease progression by remodeling the extracellular matrix and modulating the microenvironment 87, 88. Autoimmune disorders may activate stromal cells found in these diseases and cancers 85, 86, 87, 88.…”

“…Finally, new therapeutic agents directed at MMP‐1 and G protein‐coupled receptors might be emerging. These targets underscore fundamental similarities between autoimmune diseases and some cancers 87, 88…”

“…Inflammatory cytokines and growth factors mediate cell proliferation, and proteinases—especially the collagenase matrix metalloproteinase‐1 (MMP‐1)—contribute to disease progression by remodeling the extracellular matrix and modulating the microenvironment 87, 88. Autoimmune disorders may activate stromal cells found in these diseases and cancers 85, 86, 87, 88. MMP‐1 was originally thought to function not only to degrade interstitial collagens; in addition, novel roles for MMP‐1 have been revealed, involving G protein‐coupled receptors, namely the chemokine receptor CXCR‐4 and protease‐activated receptor‐1 (PAR‐1).…”

“…MMP‐1 was originally thought to function not only to degrade interstitial collagens; in addition, novel roles for MMP‐1 have been revealed, involving G protein‐coupled receptors, namely the chemokine receptor CXCR‐4 and protease‐activated receptor‐1 (PAR‐1). Coordination between MMP‐1 and CXCR4 or stromal‐derived factor‐1 signaling influences the behavior of activated fibroblasts in autoimmune diseases and cancers 85, 86, 87, 88. In addition, MMP‐1 is a vital part of an autocrine‐paracrine MMP‐1‐PAR‐1 signal transduction axis—a role that amplifies the potential of MMP‐1 to remodel the matrix and modify cell behavior 87, 88.…”

“…Coordination between MMP‐1 and CXCR4 or stromal‐derived factor‐1 signaling influences the behavior of activated fibroblasts in autoimmune diseases and cancers 85, 86, 87, 88. In addition, MMP‐1 is a vital part of an autocrine‐paracrine MMP‐1‐PAR‐1 signal transduction axis—a role that amplifies the potential of MMP‐1 to remodel the matrix and modify cell behavior 87, 88. Finally, new therapeutic agents directed at MMP‐1 and G protein‐coupled receptors might be emerging.…”