Heparan sulfate proteoglycans as critical regulators of brain cancer malignancy

描述（由申请人提供）：胶质母细胞瘤（GBM）是一种均匀致死的脑癌，其特征为弥漫性侵袭和多种受体酪氨酸激酶（RTK）信号通路的异常激活（1）。尽管目前的治疗，GBM的预后是差的，平均生存期仍然不到2年。更好地理解驱动异常细胞信号传导的机制对于改善治疗结果至关重要。这项创新提案的长期目标是定义脑癌中至关重要的肿瘤微环境相互作用，并确定临床相关的药物治疗靶点。具体而言，我们关注细胞外硫酸乙酰肝素蛋白聚糖（HSPG）的作用，因为它们调节多种配体介导的信号传导途径的活性（2），在恶性脑肿瘤中发生改变（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通过其结合和改变细胞内基质的能力来调节信号传导。 不同配体的生物利用度，包括生长因子、形态发生素、趋化因子和酶。SULF 2是一种细胞外硫酸乙酰肝素内切硫酸酯酶，通过从葡萄糖胺（6 OS）的6-O-中去除硫酸根并从HSPG螯合中释放蛋白质配体来积极调节HSPG依赖性信号传导（5）。HSPG核心蛋白表达和SULF 2表达的改变在不同的癌症中是常见的，并且该提议的PI已经显示SULF 2可以通过调节RTK信号传导途径来驱动恶性星形细胞瘤中的致癌作用。SULF及其HSPG底物作为既与细胞膜相连又分泌的胞外酶存在于细胞外环境中，具有作为新型治疗靶点的巨大潜力。我们的目的是：目的1：在人类浸润性星形细胞瘤中，鉴定与肿瘤恶性程度相关的HSPG表达和硫酸化的改变。目的2：确定HSPG改变驱动肿瘤生物学行为，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。拟议的研究将确定HSPGs改变驱动恶性脑癌致癌细胞信号通路的机制，并验证HSPGs作为临床相关的新型治疗靶点。这些研究的成功完成为研究靶向HSPG的药物作为恶性脑癌的新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.