Abstract 5285: ADAM12: A novel mediator of tumor angiogenesis

Abstract

Abstract ADAM12 (a disintegrin and metalloprotease) is a member of a family of integral membrane and secreted Zn-dependent metalloproteases that have diverse roles in normal and pathological states. Human ADAM12 is expressed as two alternatively spliced forms, a membrane-anchored long form (ADAM12-L), and a short secreted form (ADAM12-S). Increased levels of ADAM12 mRNA and protein have been reported in a variety of cancers including colon, hepatocellular, lung, gastric and glioblastoma. We have previously reported that urinary ADAM12 is predictive of disease status and stage in breast cancer. We have also demonstrated that expression of ADAM12 isoforms in breast tumor cells results in a higher rate of tumor take, increased tumor size and endocrine resistance. ADAM12-S expression stimulated migration and invasion of breast tumor cells in vitro and local and distant tumor invasion in vivo. In the course of these studies, we observed that ADAM12 is upregulated in the vessels of aggressive breast tumors as compared to normal adjacent breast tissue. ADAM12-overexpressing breast tumors also displayed a higher microvascular density. Furthermore, we found that angiogenic tumors express higher levels of ADAM12 compared to their preangiogenic counterparts. The goal of the present study was to determine whether ADAM12 regulates tumor angiogenesis. Basal levels of ADAM12-L expression in HUVEC and HMVEC are relatively low, however, both ADAM12 protein and mRNA expression is significantly increased when cells are stimulated with growth factors such as VEGF, bFGF or inflammatory cytokines such as TNFα, TGFβ or IL1α. Interestingly, VEGF stimulation of endothelial cells (EC) resulted in ADAM12 protein expression and/or localization specifically along the invadopodia of these cells. Consistent with these results, we found that ADAM12 overexpression in EC resulted in significantly increased rates of migration, capillary tube formation and increased adhesion to fibronectin and type IV collagen but not laminin. In vivo studies demonstrate that ADAM12 significantly increases bFGF-mediated angiogenesis in the mouse corneal pocket assay. Taken together, our data provide evidence supporting a novel role for ADAM12 in the regulation of endothelial cell function and tumor angiogenesis. Studies to investigate the mechanism/s by which ADAM12 may regulate angiogenesis are ongoing. [The authors acknowledge the support of NIH PO1 CA045548, The Breast Cancer Research Foundation and The Simeon J. Fortin Foundation] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5285. doi:1538-7445.AM2012-5285