Heparan Sulfate Proteoglycans in Glioma Angiogenesis

描述（申请人提供）：诱导血管生长（血管生成）是肿瘤发展的关键步骤。在胶质瘤中，活跃的血管生成和病理性内皮细胞增殖是进展的重要标志。这种疾病的治疗选择非常有限，靶向胶质瘤血管是一种有吸引力的新治疗方法。成纤维细胞生长因子（FGF）是最有效的血管生成刺激剂之一。它们通过FGF受体（FGFR）发出信号，但需要硫酸肝素蛋白聚糖（HSPG）作为共刺激剂。hspg是由核心蛋白和共价连接的类肝素硫酸肝素多糖链组成的杂化分子。我们有初步数据表明内皮细胞HSPGs在硫酸肝素和核心蛋白水平上对FGF活性有特异性调节。在胶质瘤血管中过度表达的细胞表面HSPG glypican-1具有独特的作用。基于这些观察结果，我们假设a) HSPGs通过限制正常脑内皮细胞中的FGF/FGFR信号传导并允许胶质瘤中不同FGF/FGFR通路之间的交叉对话来调节内皮细胞对FGFs的反应；b) Glypican-1通过其与脂质筏的关联特异性调节内皮细胞的生长。这些假设将在三个特定目的的背景下进行验证：目的1将研究内皮细胞来源的硫酸肝素在通过单个fgfr限制或允许血管生成的FGFs信号传导中的作用。依赖于这些信号通路的下游事件将被确定。在Aim 2中，我们将重点关注glypican-1核心蛋白，并剖析其各自的分子结构域对FGF信号传导的贡献。目的3是处理脂筏膜微域在血管生成FGF信号传导中的作用。我们将研究fgfr和glypican-1对脂质筏的潜在靶向作用，并确定这些分子在完整脂质筏中的共定位是否需要FGF信号传导。更好地了解HSPGs调节血管生成的生物学原理可能会导致治疗药物（碳水化合物或肽基）的发展，旨在破坏胶质瘤和其他恶性肿瘤的病理性血管生成。

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.