Heparan sulfate proteoglycans as critical regulators of brain cancer malignancy

描述(申请人提供)：胶质母细胞瘤(GBM)是一种统一致命的脑癌，其特征是弥漫性侵袭和多受体酪氨酸激酶(RTK)信号通路的异常激活(1)。尽管有目前的治疗方法，但GBM的预后很差，平均生存期仍不到2年。提高对驱动异常细胞信号转导机制的理解对于改善治疗结果至关重要。这项创新建议的长期目标是定义脑癌关键的肿瘤-微环境相互作用，并确定临床相关的、可用药的治疗靶点。具体地说，我们专注于细胞外硫酸乙酰肝素蛋白多糖(HSPGs)的作用，因为它们调节多配体介导的信号通路的活性(2)，在恶性脑瘤中改变(3，4)，并有可能影响肿瘤细胞和关键的肿瘤-微环境相互作用，包括肿瘤相关的小胶质细胞/巨噬细胞反应。存在于细胞表面和细胞外基质中的HSPG通过结合和改变细胞外基质的能力来调节信号转导。 不同配体的生物利用度，包括生长因子、形态因子、趋化因子和酶。SULF2是一种胞外硫酸乙酰肝素内切酶，通过从氨基葡萄糖(6os)的6-O-中去除硫酸盐和从HSPG中释放蛋白质配体来主动调节HSPG依赖的信号转导(5)。HSPG核心蛋白表达的改变和SULF2表达的改变在多种癌症中都是常见的，这一提议的PI表明SULF2可以通过调节RTK信号通路来推动恶性星形细胞瘤的发生。作为胞外酶，SULF及其HSPG底物存在于细胞外环境中，具有作为新的治疗靶点的巨大潜力。我们的目标是：目标1：在人类浸润性星形细胞瘤中，确定与肿瘤恶性相关的HSPG表达和硫酸盐化的变化。目的：研究HSPG对肿瘤生物学行为的影响，包括小胶质细胞/巨噬细胞对肿瘤的反应。目的3：确定HSPG改变如何激活信号通路促进GBM恶性行为。这项拟议的研究将确定HSPGs的改变在恶性脑癌中驱动致癌细胞信号通路的机制，并验证HSPGs作为临床相关的新治疗靶点。这些研究的成功完成为研究以热休克蛋白为靶点的药物作为治疗恶性脑癌的一种新的治疗选择提供了临床前基础。

DESCRIPTION (provided by applicant): Glioblastoma (GBM), a uniformly lethal brain cancer, is characterized by diffuse invasion and abnormal activation of multiple receptor tyrosine kinase (RTK) signaling pathways (1). Despite current therapies, the prognosis for GBM is poor and mean survival remains less than 2 years. An improved understanding of the mechanisms driving abnormal cell signaling is essential for improving treatment outcomes. The long-term goal of this innovative proposal is to define tumor-microenvironment interactions critical in brain cancer and identify clinically relevant, druggable therapeutic targets. Specifically, we focus on the role of extracellular heparan sulfate proteoglycans (HSPGs) as they regulate the activity of multiple ligand-mediated signaling pathways (2), are altered in malignant brain tumors (3, 4), and have the potential to influence both tumor cells and critical tumor-microenvironment interactions, including the tumor-associated microglia/macrophage response. HSPGs, present on the cell surface and in the extracellular matrix, regulate signaling via their ability to bind and alter the bioavailability of diverse ligands, including growth factors, morphogens, chemokines, and enzymes. SULF2, an extracellular heparan sulfate endosulfatase, actively regulates HSPG-dependent signaling by removing the sulfate from 6-O- of glucosamine (6OS) and liberating protein ligands from HSPG sequestration (5). Alterations in HSPG core protein expression and SULF2 expression are common in diverse cancers and the PI of this proposal has shown SULF2 can drive carcinogenesis in malignant astrocytoma through regulation of RTK signaling pathways. As extracellular enzymes that are both tethered to the cell membrane and secreted, the SULFs and their HSPG substrates are present in the extracellular environment and have great potential as novel therapeutic targets. Our Aims are: Aim 1: In human infiltrating astrocytomas, identify the alterations in HSPG expression and sulfation associated with tumor malignancy. Aim 2: Determine HSPG changes driving tumor biologic behavior, including microglia/macrophage response to tumor. Aim 3: Identify how HSPG alterations activate signaling pathways to promote GBM malignant behaviors. The proposed research will determine the mechanisms by which alterations in HSPGs drive oncogenic cell signaling pathways in malignant brain cancer and validate HSPGs as clinically relevant, novel therapeutic targets. Successful completion of these studies provides a preclinical basis to study agents that target HSPGs as a novel therapeutic option in malignant brain cancer.