title: MDA-9/syntenin and IGFBP-2 promote angiogenesis in human melanoma.
abstract: 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).
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia 23298, USA.
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Sujit K
authors.initials: SK
authors.lastname: Bhutia
authors.forename: Belal
authors.initials: B
authors.lastname: Azab
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Kegelman
authors.forename: Leyla
authors.initials: L
authors.lastname: Peachy
authors.forename: Prasanna K
authors.initials: PK
authors.lastname: Santhekadur
authors.forename: Santanu
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Rupesh
authors.initials: R
authors.lastname: Dash
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000098:blood supply*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D053676:Syntenins / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D018971:Insulin-Like Growth Factor Binding Protein 2; D053676:Syntenins