Extracellular Matrix Degradation During Invasion

Proteolytic modification of the cell surface and the extracellular matrix is believed to be an essential component of invasion (Liotta et al, 1980), both neoplastic and physiological. The major enzymes that degrade the ECM and cell-associated proteins are (1) the matrix metalloproteinases (MMPs), a family of secreted and membrane anchored proteinases, (2) the adamalysin-related membrane proteinases, (3) the bone morphogenetic protein 1 type metallo-proteinases and (4) tissue serine proteinases including tissue plasminogen activator, urokinase, thrombin and plasmin

(Werb, 1997). Major ECM barrier substrates for degradative enzymes include collagens (more than 13 types), proteo-glycans, laminin, fibronectin and vitronectin. Each compartment of the ECM contains a different complement of matrix molecules. Collagens I and III are examples of collagens preferentially localized to stroma, while collagens IV and V are predominant in the basement membrane, which forms the border between epithelium and stroma. Proteolysis of the ECM is observed in trophoblast implantation, embryo morphogenesis, wound healing, tissue remodelling and angiogenesis. An imbalance in the ratio of proteinases to protease inhibitor can regulate vascular morphogenesis and invasion (Ura et al., 1989). All classes (serine, aspartyl, cysteinyl and metallo) of matrix-degrading proteinases participate, and coactivate each other, in the tumour-host invasion field (Nakajima et al., 1987; Ostrowski et al., 1988; Reich et al., 1988). Evidence also exists that proteases inside the cell may also be involved during invasion (Koblinski et al., 2000).

A large body of literature exists correlating degradative enzyme activity with cancer invasion and metastasis. The most studied proteases include tissue-type plasminogen activator (tPA), plasmin, cathepsin-D, -B, -L and -G, the urokinase plasminogen activator (uPA), metalloproteinases and the heparanases. Urokinase plasminogen activator, a serine protease, has been shown to correlate with a meta-static phenotype of cells. Antibodies against uPA block human HEP-3 cell invasion and murine B16-F10 melanoma cell metastasis after tail vain injection (Ossowski and Reich 1983; Esheicher et al., 1989). Moreover, overexpression of uPA in H-ras transformed cell lines enhance lung metastases (Axelrod et al., 1989). Inhibition of metalloproteinases has been demonstrated to inhibit cell invasion (DeClerck et al., 1991). MMPs can be divided into three general classes: (1) interstitial collagenases, (2) stromelysins and (3) gelatinases. Interstitial collagenase degrades type I, II, III and VII collagens. Stromelysins degrade type I, III, IV, V and IX collagens, laminin, fibronectin, and gelatin. The third group of the MMP family, the gelatinases (MMP-2 and MMP-9), can degrade collagen type I, II, III, IV, V, VII, IX and X and fibronectin (Emonard and Grimaud, 1990). Association of MMP-2 and MMP-9 with the invasive phe-notypes is abundant in the literature. Inhibition of MMP-2 by TIMP-1 reduces cellular invasion in vitro and in vivo. Induction of H-ras oncogene enhances expression of MMP-2 and MMP-9. Invasive colonic, gastric, ovarian and thyroid adenocarcinomas showed positive immunoreactivity for MMP-2, whereas normal colorectal, gastric mucosa and benign ovarian cysts showed reduced or negative staining (Monteagudo et al., 1990; Levy et al., 1991). A delicate balance between TIMPs and MMPs may act as a positive and negative feedback control regulating vascular morphogenesis and invasion (Mignatti et al., 1986). MMPs and TIMPs have direct, and indirect, effects on angiogenesis, which are separate from their proteolytic functions (Chambers et al., 1997; Hoegy et al., 2001). Heparan sulfate proteoglycans (HSPGs), major and ubiquitous components of the ECM, are substrates for heparanases, which cleave heparan sulfate glycosaminoglycan side chains. Augmentation of heparanase activity has been associated with tumour aggressiveness (Nakajima et al., 1988; Vlodavsky et al., 1995). Heparin and similar polysaccharides inhibit metastasis (Parish et al., 1987). Transfection of nonmeta-static murine T-lymphoma Eb cell lines with full-length human heparanase cDNA (Vlodavsky etal., 1999) enhances the metastatic phenotype in animal models. (See the chapters on Models for Tumour Cell Adhesion and Invasion and Tumour Metastasis Models.)

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