Abstract It is predicted that 66,290 new cases of primary central nervous system (CNS) tumors will be diagnosed in the United States in 2012. Of these, glioblastoma multiforme (GBM) is among the most aggressive tumors. The extraordinary invasiveness of GBM contributes to treatment failure and the grim prognosis of patients diagnosed with this tumor. Consequently, it is imperative to define further the cellular and molecular mechanisms that control GBM invasion and identify promising novel therapeutic targets. Melanoma differentiation associated gene-9 (MDA-9/syntenin) is a highly conserved PDZ domain-containing scaffolding protein that promotes invasion and metastasis in in vitro and in vivo in human melanoma models. The ability of single high-grade glioma cells to invade the surrounding normal brain tissue is an important characteristic that makes treating these tumors so difficult. Additionally, the highly angiogenic nature of GBM tumors contributes to their malignancy. Therefore, if MDA-9/syntenin plays a role in GBM invasion and angiogenesis, this gene or its downstream-regulated molecules could represent new targets that will aid in furthering the efficacy of current and future therapeutics. The objectives of our studies were to: (1) Determine the expression of MDA-9/syntenin in astrocytic tumors, (2) Assess the role of MDA-9/syntenin on the invasive ability of astrocytomas in vitro and in vivo, (3) Elucidate important molecular signaling events associated with mda-9/syntenin, and (4) Assess the role of MDA-9/syntenin on angiogenic potential in malignant astrocytomas. To achieve these objectives we have employed gain-of-function (GOF) and Loss-of-function (LOF) strategies that incorporate both Genetic and Pharmacological approaches. We now demonstrate that in primary human patient samples, MDA-9/syntenin is overexpressed in a large proportion of high-grade astrocytomas and this expression pattern correlates with tumor grade. Forced overexpression (GOF) of MDA-9/syntenin through an adenoviral vector enhanced Matrigel invasion, while knockdown (LOF) of MDA-9/syntenin inhibited invasion, suppressed migration as measured by rate of gap closure, and reduced anchorage-independent growth in soft agar. Moreover, overexpression of MDA-9/syntenin in cells with low endogenous levels (Sw1783, a grade III astrocytoma, and GBM5) increased activation of c-Src, p-P38MAPK, and NF-κB, leading to elevated MMP2 expression. Conversely, the knockdown of MDA-9/syntenin in GBM cell lines with high levels of MDA-9/syntenin, T98G and U87MG, resulted in reduced levels of p-Src, p-IκBα, and MMP2. GBM6 cells that stably express shmda-9 had decreased invasive ability and formed smaller tumors in a mouse xenograft model. Furthermore, knockdown of MDA-9/syntenin was found to decrease the production and secretion of IL-8, a known angiogenic cytokine. Using intracranial orthotopic xenografts, MDA-9/syntenin knockdown resulted in a less invasive tumor phenotype with decreased CD31 expression. Our findings indicate that MDA-9/syntenin is a novel and important mediator of invasion and angiogenesis, key regulators of pathogenesis, in GBM and this gene represents a potential target for anti-invasive treatment in human astrocytomas. Citation Format: Timothy P. Kegelman, Swadesh K. Das, Bin Hu, Mitchell Menezes, Luni Emdad, Santanu Dasgupta, Albert S. Baldwin, Jr., Jeffery N. Bruce, Paul Dent, Maurizio Pellecchia, Devanand Sarkar, Paul B. Fisher. MDA-9/syntenin is a key regulator of glioma pathogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B85.
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Jun 28, 2013
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