One of the crucial steps in tumor growth and metastasis is proteolytic modification of the extracellular matrix surrounding tumor cells. A major class of proteases that mediates this process is the matrix metalloproteinases (MMPs); inhibition of these enzymes has been shown to prevent tumor progression. Although it was originally thought that tumor MMPs were produced by tumor cells themselves, it is now clear that, in vivo, most tumor MMPs are produced by stromal cells associated with tumors. The tumor cell surface glycoprotein, EMMPRIN, stimulates production of several MMPs by fibroblasts and endothelial cells. Also, EMMPRIN is enriched in malignant tumors relative to normal tissues and elevated expression of EMMPRIN leads to increased tumor growth in vivo. Thus EMMPRIN may be an important regulator of MMP production that serves a crucial role in cancer. Consequently, the focus of this proposal will be the structure, function and mechanism of action of EMMPRIN in tumorigenesis. The role of EMMPRIN in various aspects of tumor progression will be tested by overexpression, by antisense inhibition of expression, and by testing susceptibility of EMMPRIN-null mice to tumor growth. The potential significance of EMMPRIN stimulation of endothelial MMP production in augmenting tumor angiogenesis, and of EMMPRIN stimulation of fibroblast MMP production in tumor cell growth and invasiveness will be explored. The fibroblast/endothelial cell receptor responsible for transduction of EMMPRIN stimulation of MMP production will be isolated and characterized. Finally, the region of EMMPRIN responsible for interacting with stromal cells and stimulating MMP production will be mapped, and reagents will be designed to facilitate examination of the functions of EMMPRIN and is putative receptor. The results obtained should determine definitively whether or not EMMPRIN is a crucial element in malignancy, and they should begin to resolve the mechanisms whereby its action is regulated and transmitted. Interference with EMMPRIN action may then be an effective way to inhibit tumor progression patients.
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