InhibitionofMatrixMetalloproteinases

Cellular transformation is accompanied by many cellular changes, including uncontrolled proliferation, loss of the differentiated cell morphology, and invasion of the extracellular matrix. Degradation of the extracellular matrix is a key component of tumor cell invasion into surrounding tissues. Matrix metalloproteinases (MMPs) are a class of proteases secreted by tumor cells, degrading the proteins of the extracellular matrix and allowing metastasis. Drug inhibitors of MMPs are one strategy to control cancer and block metastasis. In searching for genes that reverse the rounded morphology of transformed cells in culture, RECK was identified (reversion-inducing, cysteine-rich protein with Kazal motifs). RECK is a membrane-anchored inhibitor of matrix metalloproteinases, inhibiting MMP-2, MMP-9 and MT1-MMP. The processing of MMPs to their active form occurs at the plasma membrane, making the localization of RECK at the membrane a key to its potent activity as an inhibitor of MMP activity. Soluble secreted MMP inhibitors have also been identified, TIMPs, which appear to be less active at inhibiting MMPs and even perhaps to be essential for MMP maturation. The inhibition of MMPs by RECK inhibits invasion of tissues, metastasis and tumor angiogenesis, and is essential for normal development. In addition to playing a role in tissue invasion in cancer, the activity of MMPs in angiogenesis, inflammation, and development is regulated by inhibitors such as RECK and TIMPs. RECK expression is inhibited by ras, suggesting one component by which ras induces transformation. High levels of RECK expression in tumors is correlated with cancer patient survival and overexpression of RECK may offer a therapeutic strategy for the control of cancer.

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