Glycosphingolipid Effects on Brain Tumor Angiogenesis

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DESCRIPTION (provided by applicant): The objective of this research is to define the role of glycosphingolipids in brain tumor growth and vascularity (i.e., angiogenesis). Gangliosides are sialic acid-containing glycolipids that are enriched in plasma membranes and are shed from tumor cells into the extracellular matrix. Gangliosides may influence brain tumor angiogenesis through multiple effects on the tumor cells and tumor associated host cells, e.g., endothelial cells and macrophages. Preliminary findings from this laboratory suggest that the simple monosialoganglioside GM3 is antiangiogenic and that more complex gangliosides (GM2, GM1, GDla and GTlb) are proangiogenic in experimental mouse brain tumors. We propose that altering tumor ganglioside composition will influence tumor growth and vascularity. We will test this hypothesis by manipulating the genes for GalNAc transferase (GalNac-T) and sialyltransferase 2 (SAT-2), two essential enzymes required for the synthesis of complex gangliosides. These genes will be up-regulated or down-regulated in stable transfectants of three well-established experimental brain tumors, i.e., the mouse EPEN and CT-2A tumors and the human glioma U87. These tumors are good models for the proposed studies because they differ in ganglioside composition, vascularity, and growth rate. Control untransfected or vector transfected tumors will be compared with their stable transfectants and will be studied as solid tumors grown in vivo and as cell lines grown in vitro. The degree of tumor angiogenesis in vivo will be assessed from analysis of microvessel density, tumor growth rate, vascular endothelial growth factor (VEGF) expression, and macrophage infiltration. The mechanisms by which gangliosides influence angiogenesis will be examined using cultured endothelial cells and the Matrigel plug model of angiogenesis. The proposed research will better define the relationship between gangliosides and tumor angiogenesis and can lead to new experimental strategies for managing brain tumors.