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The proteolytic cleavage fragments of vascular basement membrane (VBM) were found to inhibit the endothelial cell proliferation migration tube formation and their corresponding antibodies reversed these inhibitory effects. α1(IV)NC1, which is efficiently generated from VBM or Col Type IV by matrix metalloproteinase 2. In endothelial cells, recombinant human α1(IV)NC1 binds to α1β1 integrin and inhibits focal adhesion kinase/c-Raf/MAPK pathway, affecting HIF-1α and VEGF expression. α1(IV)NC1 influences MMP-2 activation in a non-cell specific way by forming a tight complex with the catalytic domain causing inhibition of endothelial and tumor cell invasion in reconstituted basement membrane. Consistent with this, in vivo tumor and matrigel studies in mice deficient in α1 integrin shows inhibition of tumor growth at higher dose of α1(IV)NC1 treatment. In addition α1(IV)NC1 was also found to regulate TIMP-2, MT1-MMP and elastase expressions. Collectively our in vitro and in vivo data is the first evidence describing that proteases generated fragments of VBM have dual function in integrin and non-integrin mediated suppression of tumor angiogenesis.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA