Heparan Sulfate Proteoglycans in Glioma Angiogenesis

描述（由申请人提供）：诱导血管生长（血管生成）是肿瘤发展过程中的关键步骤。在神经胶质瘤中，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因子之一。它们通过FGF受体（FGFR）发出信号，但需要硫酸乙酰肝素蛋白聚糖（HSPG）作为共刺激物。HSPG是由核心蛋白和共价连接的肝素样硫酸乙酰肝素多糖链组成的杂合分子。我们有初步的数据表明，在硫酸乙酰肝素和核心蛋白的水平上，内皮细胞HSPGs对FGF活性有特异性的调节。一个独特的作用被确定为细胞表面HSPG磷脂酰肌醇蛋白聚糖-1，这是在神经胶质瘤血管过表达。基于这些观察结果，我们假设a）HSPG通过限制正常脑内皮细胞中的FGF/FGFR信号传导并允许神经胶质瘤中不同FGF/FGFR途径之间的串扰来调节内皮细胞对FGF的反应，B）磷脂酰肌醇蛋白聚糖-1通过其与脂筏的结合来特异性调节内皮细胞生长。这些假设将在三个特定目标的背景下进行测试：目标1将研究内皮细胞衍生的硫酸乙酰肝素在限制或允许血管生成FGF通过单个FGFR的信号传导中的作用。将确定依赖于这些信号通路的下游事件。在目标2中，我们将专注于磷脂酰肌醇蛋白聚糖-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是研究脂筏膜微区在血管生成FGF信号转导中的作用。我们将研究潜在的FGFR和磷脂酰肌醇蛋白聚糖-1脂筏靶向，并确定是否共定位这些分子在完整的筏是必需的FGF信号。更好地了解HSPGs的血管生成调控的生物学基础可能会导致开发旨在破坏神经胶质瘤和其他恶性肿瘤中病理性血管生成的治疗剂（基于碳水化合物或肽）。

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.