Control of Tumor Growth by the MMP/Angiostatin Pathway

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Angiogenesis is essential for tumor growth and blocking this process is viewed as a valid tool for the control of cancer growth. We showed that in integrin _l-null mice tumor angiogenesis is reduced compared to that of wild type mice. This reduction is due to overexpression of matrix metaUoproteinases (MMPs) in the al-null and consequent generation of angiostatin (an inhibitor of endothelial cell growth) from plasminogen. Our findings, in contrast to the accepted role of MMPs being pro-tumorigenic, suggest that excess synthesis of MMPs may play opposite effects on tumor growth. On one hand, increased MMPs may promote cell migration and metastasis by inducing extracellular matrix degradation. On the other hand, increased MMPs may prevent tumor growth via angiostatin generation. We showed that inhibition of MMP expression in vivo leads to decreased synthesis of angiostatin and consequent increased tumor growth and vascularization. This observation, together with the disappointing results achieved by MMP inhibitors in the treatment of human cancers, suggests that MMP inhibitors used as anti-tumor drugs might in fact cause a paradoxical increase in tumor growth and angiogenesis by preventing the generation of inhibitors of endothelial cell growth. In addition, we also showed that integrin otl is directly involved in the control of cell proliferation suggesting that this receptor may play a synergistic role together with the MMP/angiostatin axis by directly regulating endothelial cell proliferation. The role of integrin o_1 and the MMP/angiostatin axis in tumor progression will be explored in the following aims. 1) Analyze in vivo i) the role of the MMP/angiostatin axis in the control of primary vs. metastatic human tumors, ii) whether MMP inhibitors can be successfully used in the prophylaxis of primary vs. metastatic cancers. II) Distinguish between a direct role of integrin c_l in the control of endothelial cell proliferation and the effect of MMPs or angiostatin by crossing the otl-null mice with the plasminogen- or MMP-null mice. III) Analyze in real time the effect of angiostatin and MMP inhibitors on tumor vascularization using the cutaneous window assay. These studies will help us to determine how stinaulation of the MMP/angiostatin axis can be used as a tool to inhibit specifically tumor vaseularization and growth.