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）是一种均匀致死性脑癌，其特征是弥漫性侵袭和多受体酪氨酸激酶（RTK）信号通路异常激活(1)。尽管目前的治疗方法，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传导机制的理解对于改善治疗结果至关重要。这项创新提议的长期目标是确定肿瘤-微环境相互作用在脑癌中至关重要，并确定临床相关的可药物治疗靶点。具体来说，我们关注细胞外硫酸肝素蛋白多糖（HSPGs）的作用，因为它们调节多种配体介导的信号通路的活性(2)，在恶性脑肿瘤中发生改变（3,4），并且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。HSPGs存在于细胞表面和细胞外基质中，通过其结合和改变蛋白的能力来调节信号传导

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.