Melanoma differentiation-associated gene-9 (mda-9/
syntenin) encodes an adapter scaffold
protein whose expression correlates with and mediates
melanoma progression and
metastasis.
Tumor angiogenesis represents an integral component of
cancer metastasis prompting us to investigate a possible role of mda-9/
syntenin in inducing angiogenesis. Genetic (gain-of-function and loss-of-function) and pharmacologic approaches were used 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, chorioallantoic membrane (CAM) assays and xenograft
tumor animal models. Gain-of-function and loss-of-function experiments confirm that MDA-9/
syntenin induces angiogenesis by augmenting expression of several proangiogenic factors/genes. Experimental evidence is provided for a model of angiogenesis induction by MDA-9/
syntenin in which MDA-9/
syntenin interacts with the extracellular matrix (ECM), activating Src and FAK resulting in activation by phosphorylation of Akt, which induces
hypoxia inducible factor 1-α (HIF-1α). The HIF-1α activates transcription of
insulin growth factor-binding protein-2 (IGFBP-2), which is secreted thereby promoting angiogenesis and further induces endothelial cells to produce and secrete
VEGF-A augmenting
tumor angiogenesis. Our studies delineate an unanticipated cell nonautonomous function of MDA-9/
syntenin in the context of angiogenesis, which may directly contribute to its
metastasis-promoting properties. 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 (nonautonomous).