Extracellular matrix (ECM) remodeling plays a critical role in tissue reorganization. Understanding mechanisms that regulate ECM proteolysis during tumor development and angiogenesis is of paramount importance to the treatment of malignancies. Our studies will provide valuable information about mechanisms which control ECM proteolysis. Our hypothesis is that specific interactions of MMPs with molecular receptors on the cell surface govern ECM remodeling involved in tumor growth and angiogenesis. Our data suggest that MT1-MMP, TIMP-2, and alphavbeta3 integrin jointly control the activation and docking of secretory MMP-2. MT1-MMP initiates activation of MMP-2 and alphavbeta3 facilitates autocatalytic maturation of MMP-2. Furthermore, MT1-MMP mediates generation of the modified beta3 integrin subunit which correlates with increased migration of tumor cells. A disulfide bridge with an intracellular, presumably cytoskeletal, protein can direct MT1-MMP to discrete regions on the cell surface in an immediate proximity to alphavbeta3. The identified mechanisms could be a link in joining continually changing cell shape, cytoskeleton, and focal proteolysis of the ECM. According to our model, docking of MMP-2 co-exists with its activation at the cell surface, thereby illustrating how latent MMP-2 produced by the stroma could be specifically localized at tumor cells as the mature enzyme. We suggest that these are basic mechanisms employed not only by tumor cells, but also by endothelial cells to spatially and temporally control ECM proteolysis during tumor development.
Our aims are: 1) To enzymologically characterize MT1-MMP and to complete the characterization of the MMP-2 activation cascade. 2) To functionally and structurally characterize a novel species of the beta3 integrin subunit. 3) To establish specific roles of MT1-MMP, MMP-2, and alphavbeta3 in tumor angiogenesis and to identify novel targets for inhibition of tumor neovascularization. 4) To generate novel angiogenic inhibitors derived from critical functional and structural elements of the C-terminal domains of MMP-2 and MT1-MMP. We anticipate our studies will lead to novel methods of cancer therapy based on the modulation of ECM remodeling and inhibition of tumor angiogenesis.
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