Heparan sulfate proteoglycans as critical regulators of brain cancer malignancy

硫酸乙酰肝素蛋白多糖作为脑癌恶性肿瘤的关键调节因子

• 批准号: 8551786
• 负责人: Joanna Phillips
• 金额: $ 33.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8551786
• 关键词: Abnormal Cell; Anaplastic astrocytoma; Astrocytoma; Automobile Driving; Behavior; Binding; Biological Availability; Biology; Brain Neoplasms; Breast Carcinoma; CXCL12 gene; Cell membrane; Cell surface; Clinical; Diffuse; Disease; Drug Targeting; Environment; Enzymes; Extracellular Matrix; FGF2 gene; GDNF gene; Glioblastoma; Glucosamine; Goals; Growth Factor; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Human; Immune response; Immunocompetent; Inorganic Sulfates; Ligand Binding; Ligands; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Microglia; Modeling; Mus; Myelogenous; Neoplasm Metastasis; Oncogenic; Outcome; PDGFRB gene; Pathway interactions; Phase II Clinical Trials; Primary carcinoma of the liver cells; Proteins; Proteoglycan; Receptor Protein-Tyrosine Kinases; Regulation; Research; Role; Signal Pathway; Signal Transduction; Specimen; Sulfatases; Suppressor-Effector T-Lymphocytes; Testing; Translations; Treatment outcome; Tumor-Derived; Unspecified or Sulfate Ion Sulfates; Vascular Endothelial Growth Factors; Xenograft procedure; angiogenesis; base; carcinogenesis; chemokine; clinically relevant; extracellular; human disease; improved; innovation; lung Carcinoma; macrophage; malignant breast neoplasm; melanoma; mimetics; morphogens; mortality; neoplastic cell; new therapeutic target; novel; novel strategies; novel therapeutics; outcome forecast; pre-clinical; preclinical study; protein expression; proteoglycan core protein; response; sulfation; therapeutic target; tumor; tumor growth; tumor microenvironment; tumor progression; versican

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.

描述（由申请人提供）：胶质母细胞瘤 (GBM) 是一种均致死性脑癌，其特征是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)。尽管有目前的治疗方法，GBM 的预后很差，平均生存期仍不足 2 年。更好地了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，并确定临床相关的可药物治疗靶点。具体而言，我们重点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通路的活性 (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。 HSPG 存在于细胞表面和细胞外基质中，通过其结合和改变 多种配体的生物利用度，包括生长因子、形态发生素、趋化因子和酶。 SULF2 是一种细胞外硫酸乙酰肝素内硫酸酯酶，通过去除葡萄糖胺 (6OS) 6-O- 上的硫酸盐并从 HSPG 隔离中释放蛋白质配体，主动调节 HSPG 依赖性信号传导 (5)。 HSPG核心蛋白表达和SULF2表达的改变在多种癌症中很常见，该提案的PI表明SULF2可以通过调节RTK信号通路驱动恶性星形细胞瘤的癌变。作为既束缚在细胞膜上又分泌的细胞外酶，SULF 及其 HSPG 底物存在于细胞外环境中，具有作为新型治疗靶点的巨大潜力。我们的目标是： 目标 1：在人类浸润性星形细胞瘤中，确定与肿瘤恶性肿瘤相关的 HSPG 表达和硫酸化的变化。目标 2：确定驱动肿瘤生物学行为的 HSPG 变化，包括小胶质细胞/巨噬细胞对肿瘤的反应。目标 3：确定 HSPG 改变如何激活信号通路以促进 GBM 恶性行为。拟议的研究将确定 HSPG 的改变驱动恶性脑癌中致癌细胞信号通路的机制，并验证 HSPG 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以 HSPG 为靶标的药物作为恶性脑癌的新型治疗选择提供了临床前基础。