The development of a malignant tumor depends upon alterations in gene expression that lead to metastasis. The focus of this grant has been to identify a gene product that is required for the development of metastasis and to use this gene as a paradigm for analyzing gene expression during tumor progression. We have shown that the protease, matrix metalloproteinase-9 (gelatinase B or 92 kDa collagenase/gelatinase) is highly expressed in the metastatic cells in a sarcoma model system and a murine prostate model system but not in the poorly metastatic cells. We have extended this observation beyond a correlation by showing that augmentation of matrix metalloproteinase-9 (MMP-9 expression) an enhance metastasis and that specific down-regulation of MMP-9 inhibits metastasis. Since MMP-9 is expressed by many (but not all) human metastatic and malignant tumors, these observations indicate that the induction of expression of MMP-9 may play an important role in the development of metastasis during tumor progression. These observation raise several questions including asking at which points during MMP-9 plays a role in vivo and what factors control the expression of MMP-9 during tumor progression. We propose to address these questions by examining tumor progression in both skin carcinogenesis and prostate cancer development using MMP-9 knockout mice. We will also explore the promoter elements that contribute to MMP-9 expression in tumor cells both in tissue culture and in vivo with a transgenic mouse. Lastly we have documented the occurrence of post-transcriptional regulation of MMP-9 and will investigate the mechanisms underlying this mode of regulation in tumor cells.
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