Metastasis is the major cause of death in cancer patients. The objective of our research is to determine whether this process can be inhibited and ultimately suppressed. It has become apparent that in addition to genetic changes, important changes in the extracellular environment occur during cancer progression and dissemination. Our research focuses on the role of a family of inhibitors of matrix degrading metalloproteinases designated tissue inhibitor of metalloproteinases (TIMP). We postulate that during cancer progression and dissemination the balance between matrix metalloprotcinases and their corresponding inhibitors is shifted toward the proteases. This shift results in an excessive degradation of the extracellular matrix (ECM) and a subsequent loss of control by the ECM over tumor growth and dissemination. In support of thin hypothesis we have shown that TlMP-2--an inhibitor of metalloproteinases identified and studied in our laboratory--can inhibit not only tumor invasion and metastasis but also tumor growth in vivo. This proposal examines the biological role of TIMP-2 by investigating its tissue and cell-type specific expression and identifying molecular mechanisms that contribute to the transcriptional regulation of this gene. The 5'-flanking region of the gene will be characterized and its regulatory activity will be examined in vitro using reporter gene assays. We will also determine whether increased expression of TIMP-2 in normal tissues can prevent tumor growth, invasion and metastasis. Finally, we will analyze the expression of TIMP-2 and changes in the metalloproteinase-TIMP balance in a series of archival pediatric tumor specimens by Northern blot analysis, in situ hybridization and immunohistochemistry. Data will be correlated with indicators of clinical and biological behavior such as stage, histopathology, survival, N-myc amplification, nm23 mutation and expression of high affinity nerve growth factor. These studies will deepen our understanding of the biological role of TIMP-2 and determine whether this inhibitor can restore the control by the ECM over tumor progression in vivo. This knowledge could potentially lead to novel approaches to prevent the dissemination of cancer cells.
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