Abstract 3902: MDA-9/syntenin and IGFBP-2 promote angiogenesis in human melanoma.
Authors: Das Swadesh K. , Kegelman Timothy P. , Santhekadur Prasanna K. , Dasgupta Santanu , Dent Paul , Grant Steven , Emdad Luni , Sarkar Devanand , Fisher Paul B. , Pellecchia Maurizio 
Published: August 2014

Vascularization of tumors promotes not only their survival and growth, but also facilitates metastases from primary to distant sites. For that reason, understanding the molecular determinants controlling tumor angiogenesis is mandatory to develop clinically efficacious angiogenesis inhibitors for cancer therapy. Melanoma differentiation associated gene or mda-9, also known as syntenin, is a multifunctional scaffold protein that cross talks with a plethora of proteins and regulates diverse physiological and pathological processes, including tumor progression and metastasis. Since, tumor angiogenesis promotes metastasis, we hypothesized that in addition to augmenting invasion and migration, MDA-9/Syntenin might also promote angiogenesis thereby facilitating tumor progression and metastasis.

Genetic (gain-of-function and loss-of-function) and pharmacological approaches were employed to modify mda-9/syntenin expression in normal immortal melanocytes, early radial growth phase melanoma and metastatic melanoma cells. The consequence of modifying mda-9/syntenin expression on angiogenesis was evaluated using both in vitro and in vivo assays, including tube formation assays using human vascular endothelial cells, chicken choriallantoic membrane assays (CAM assays) and xenograft tumor animal models.

Employing both genetic and chemical approaches we now demonstrate that MDA-9/Syntenin expression correlates with in vitro and in vivo (tumorigenic/metastatic) transformed/invasive phenotypes of human melanoma. Additionally, our immunohistochemical and in vivo CAM assays confirm that angiogenesis is an essential component of MDA-9/Syntenin-induced tumor progression. To define how MDA-9/Syntenin regulates angiogenesis we identified and analyzed several potential downstream gene targets of MDA-9/Syntenin. One gene implicated in induction of vasculogenesis is insulin growth factor binding protein-2 (IGFBP-2), which is transcriptionally regulated by hypoxia inducible factor-1 as a consequence of MDA-9/Syntenin and Src interaction. IGFBP-2 transcriptionally regulates VEGF-A in an AKT-dependent manner through interaction with V3 integrin resulting in angiogenesis.

Our studies delineate an unanticipated cell non-autonomous function of MDA-9/Syntenin in the context of angiogenesis by augmenting expression of several pro-angiogenic factors including IGFBP-2, which may provide a complementary way to promote metastasis. As a result, targeting MDA-9/syntenin or its downstream-regulated molecules may provide a means of simultaneously impeding metastasis by both directly inhibiting tumor cell transformed properties (autonomous) and indirectly by blocking angiogenesis (non-autonomous).

Citation Format: Swadesh K. Das, Timothy P. Kegelman, Prasanna K. Santhekadur, Santanu Dasgupta, Paul Dent, Steven Grant, Luni Emdad, Devanand Sarkar, Paul B. Fisher, Maurizio Pellecchia. MDA-9/syntenin and IGFBP-2 promote angiogenesis in human melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3902. doi:10.1158/1538-7445.AM2013-3902