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ADAM12: A Novel Mediator of Tumor Angiogenesis

We have previously demonstrated that urinary ADAM12 (a disintegrin and metalloprotease) is predictive of breast cancer status and stage and that expression of ADAM12 in breast tumors results in increased tumor take, tumor size and metastasis. ADAM12 expression is upregulated in the vessels of aggressive human breast tumors as compared to those of normal adjacent tissue. ADAM12‐overexpressing breast tumors also displayed a higher microvascular density. The goal of this study was to determine the mechanism by which ADAM12 may regulate tumor angiogenesis. Increased ADAM12 expression in breast tumors resulted in a significant upregulation of proangiogenic factors such as VEGFA, MMP‐9, and MCP‐1 while antiangiogenic factors such as TIMP‐1 and Thrombospondin 1 were downregulated. Conditioned media from ADAM12‐expressing tumor cells promoted human endothelial cell (EC) migration and tube formation. EC treated with recombinant ADAM12 showed significantly increased migration, tube formation and adhesion to matrix. Our findings suggest that elevated ADAM12 expression in tumor cells induces a proangiogenic/proinflammatory microenvironment which in turn facilitates angiogenesis and tumor growth. This suggests that the inhibition of ADAM12 may represent a novel strategy to target tumor angiogenesis. [Supported by NIH PO1 CA045548, The Breast Cancer Research Foundation and The Simeon J. Fortin Foundation]