Proteases, extracellular matrix, and cancer: a workshop of the path B study section

Abstract

The role of the extracellular matrix (ECM) in the tumor microenvironment is not limited to being a barrier against tumor invasion. The ECM is a reservoir of cell binding proteins and growth factors that affect tumor cell behavior. It is also substantially modified by proteases produced by tumor cells or stroma cells. As a result of the activity of these proteases, cell-cell and cell-ECM interactions are altered, new biologically active ECM molecules are generated, and the bioavailability and activity of many growth factors, growth factor receptors, and cytokines are modified. ECM-degrading proteases also play a critical role in angiogenesis, where they can act as positive as well as negative regulators of endothelial cell proliferation and vascular morphogenesis. This review article summarizes some of the most relevant findings made over the recent years that were discussed at a workshop organized by the Path B Study Section of the National Institutes of Health in October 2002.

Figure 1

Changes in cell-cell to cell-ECM interaction during EMT. Release of α4β6 integrin from hemidesmosomes (top left) allow interaction between α4β6 and ECM proteins that stimulate tumor cell proliferation by an autocrine mechanism that involves VEGF and its receptor neuropilin-1 (bottom left). Association between α3β1 and uPAR (top right) stimulates ERK1/2 and results in up-regulation of MMP-9 and uPA and promotes E-cadherin dissociation (bottom right). Interaction between α3β1 and laminin also promotes intravascular arrest of intravasated cells.

Figure 2

The effect of MMP-7 proteolytic activity on tumor behavior is a function of the substrate. Cleavage of Fas-L by MMP-7 releases cell-associated Fas-L and increases Fas-L/Fas interaction and promotes apoptosis in pre-malignant cells. Constitutive expression of MMP-7 by the same cells results in the selection of a subpopulation with reduced sensitivity to Fas-mediated apoptosis (top). Degradation of E-cadherin by MMP-7 promotes cell-cell dissociation, EMT, and motility (bottom). Degradation of basement membrane proteins by MMP-7 promotes invasion and metastasis.

Figure 3

Complex interaction between proteases, protease inhibitors and ECM proteins in angiogenesis and tumorigenesis. The balance between MT1-MMP free of TIMP-2 and MT1-MMP/TIMP-2/proMMP-2 complex determines the degree of proMMP-2 activation, αvβ3 activation, pericellular fibrinolysis, and VEGF transcription (bottom left). The balance between uPA bound PAI-1 and vitronectin (Vn) bound PAI-1 controls uPA-mediated proteolysis. Vn bound PAI-1 promotes the migration of endothelial cells from Vn toward Fn (bottom right). MT1-MMP and MMP-2 cleave laminin 5 γ2 to generate cleavage products (Ln5 γ2 and Ln5 γ2x) which promote the migratory and invasive ability of melanoma cells expressing a vascular phenotype (vascular mimicry) (middle). MMP-9 produced by mast cells and inflammatory cells releases VEGF from the ECM and promotes VEGF/VEGFR interaction (top right). MT1-MMP and MMP-1 degrade interstitial type I collagen which when intact, inhibits tumorigenesis.