Matrix metalloproteinases (MMPs) are zinc-dependent secreted proteinases that degrade extracellular matrix components under physiological conditions. They are frequently expressed at high levels in advanced tumors and there is direct experimental evidence that these enzymes play a casual role in tumor invasion and metastasis. The studies performed the previous granting period indicate however that the MMP matrilysin exerts an effect much earlier stages of tumor progression using well-defined models of colorectal tumor-derived cell lines resulted in alterations in tumorigenicity following orthotopic injection into nude mice, and matrilysin-null mice demonstrated a substantial retardation in the development of benign intestinal tumors in Apc +/- mice. Two critical mechanistic questions arise from this work- how is matrilysin expression induced in benign tumors, and how does it contribute to further tumor progression? Preliminary data suggest that matrilysin expression correlates with loss of Apc function and an elevation in b-catenin levels, and that matrilysin gene expression is regulated by a complex of b-catenin and an HMG-box transcription factor.
Specific aim 1 of this application is to test the hypothesis that the matrilysin expression is regulated through a signaling pathway involving b-catenin using cultured intestinal epithelial cells. The second specific aim will test the hypothesis that matrilysin contributes to early stage tumor progression via cleavage of cell-surface substrate and disruption of normal cellular proliferation and/or apoptosis.
In specific aim 3, the applicant will extend the in vivo studies to test the hypothesis that metalloproteinase activity in general is required for early stages of intestinal tumorigenesis and preneoplastic lesions. The results of these studies should enhance the understanding of early events in colorectal progression and provide guidance for the application of specific MMP inhibitors in the treatment and possibly the prevention of early-stage tumors.
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