This application is a continuation of studies focused on the role of the matrix metalloproteinase MMP-7 (matrilysin) in colorectal cancer. In previous funding periods, we demonstrated that MMP-7 gene expression is directly regulated by signal transduction pathways activated by the loss of function of the """"""""gatekeeper"""""""" APC gene, and that the induction of the MMP-7 gene product significantly contributes to early stage intestinal tumorigenesis. Pharmacological or genetic elimination of MMP-7 results in fewer adenomas and prolonged survival in a mouse model of hereditary polyposis. Synthetic MMP inhibitors have been tested in Phase III clinical trials in advanced cancer settings with disappointing results. The overall goal of this application is to apply the lessons learned from the initial clinical trials to optimize the use of MMPIs for colon cancer prevention and treatment, and to identify novel targets for the development of chemopreventive agents to treat patients at risk for colon cancer.
In aim 1, we will develop a surrogate assay for inhibition of MMP activity and optimize the use of MMPIs in the prevention of intestinal adenomas and the control of liver metastasis.
In aim 2, we will determine if the tumor promoting effects of MMP-7 are mediated by a direct effect on intestinal epithelial cells or are dependent on microenvironmental influences using a cellular reconstitution assay.
In aim 3, we will use tissue proteomics to identify MMP-7 substrates relevant to intestinal tumorigenesis.
In aim 4, in conjunction with the """"""""Protease Consortium"""""""", we will test the hypothesis that multiple proteolytic pathways contribute to intestinal tumor progression by using oligonucleotide microarrays to identify extracellular proteases that are upregulated in adenomas, and determine their potential as targets for the prevention of colorectal cancer.
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