Heparan Sulfate Proteoglycans in Glioma Angiogenesis

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DESCRIPTION (provided by applicant): The induction of blood vessel growth (angiogenesis) is a crucial step during tumor development. In gliomas, active angiogenesis and pathologic endothelial cell proliferation are an important hallmark of progression. Therapeutic options are very limited in this disease and targeting of glioma blood vessels is an attractive new treatment approach. Fibroblast growth factors (FGF) are among the most potent angiogenic stimulators. They signal via FGF receptors (FGFR), but require heparan sulfate proteoglycans (HSPG) as co-stimulators. HSPGs are hybrid molecules composed of core proteins and covalently attached heparin-like heparan sulfate polysaccharide chains. We have preliminary data indicating a specific regulation of FGF activity by endothelial cell HSPGs at the level of heparan sulfate and core protein. A unique role was identified for the cell surface HSPG glypican-1, which is overexpressed in glioma vessels. Based on these observations we hypothesize that a) HSPGs regulate endothelial cell responses to FGFs by limiting FGF/FGFR signaling in normal brain endothelial cells and permitting cross-talk between different FGF/FGFR pathways in gliomas b) Glypican-1 specifically regulates endothelial cell growth by its association with lipid rafts. These hypotheses will be tested in the context of three specific aims: Aim 1 will investigate the role of endothelial cell-derived heparan sulfate in restricting or permitting signaling of angiogenic FGFs via individual FGFRs. Down-stream events dependent on these signaling pathways will be determined. In Aim 2, we will focus on the glypican-1 core protein and dissect the contribution of its respective molecular domains to FGF signaling. Aim 3 is dealing with the role of lipid raft membrane microdomains in angiogenic FGF signaling. We will investigate potential targeting of FGFRs and glypican-1 to lipid rafts and determine whether colocalization of these molecules in intact rafts is required for FGF signaling. A better understanding of the biology underlying angiogenesis regulation by HSPGs may lead to the development of therapeutic agents (carbohydrate or peptide-based) designed to disrupt pathologic angiogenesis in gliomas and other malignancies.