Biochemistry of Brain Tumor Microvessel Development

脑肿瘤微血管发育的生物化学

• 批准号: 6912657
• 负责人: John J Laterra
• 金额: $ 38.24万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6912657
• 关键词: angiogenesis; biological signal transduction; cell line; gene expression; genetic transcription; glioma; hepatocyte growth factor; human tissue; microarray technology; mitogen activated protein kinase; neoplasm /cancer blood supply; neoplasm /cancer genetics; northern blottings; phosphatidylinositol 3 kinase; polymerase chain reaction; xenotransplantation

DESCRIPTION (provided by applicant): Gliomas remain among the least curable of human tumors despite the most aggressive surgical, radio- and chemo-therapeutics. The identification of molecular pathways that contribute to glioma malignancy is vital to the development of more effective therapeutics. We and others established that expression of the multifunctional growth factor scatter factor/hepatocyte growth factor (SF/HGF) and its tyrosine kinase receptor c-Met in human gliomas significantly correlates with degree of malignancy. During the last funding period, we combined gain-of-function and loss-of-function approaches with in vivo and in vitro glioma model systems to establish that SF/HGF:c-Met signaling activates autocrine and paracrine events that stimulate glioma malignancy (i.e. tumor angiogenesis, blood-brain barrier dysfunction, glioma cell cycle dysregulation and cell migration, chemo/radioresistance). We have partially characterized the mechanisms by which gliomas respond to SF/HGF:c-Met signal activation. This competing renewal proposes to utilize experimental glioma models and clinical tumor specimens to further identify biochemical and transcriptional mechanisms by which SF/HGF stimulates the malignant phenotype in human gliomas. Aim #1 will identify novel genes and gene families that are differentially regulated by SF/HGF:c-Met activation in human glioblastoma cells. Aim #2 will utilize novel hypotheses generated in aim #1 to determine how specific SF/HGF-regulated genes contribute to the malignant glioma phenotype. Aim #3 will identify cell signaling pathways and transcriptional mechanisms by which glioma cells respond to SF/HGF. Aim #4 will use tissue arrays to quantify expression of the biologically-important SF/HGF-responsive genes in clinical human gliomas and determine their correlation with pathological grade and other features of malignancy. The successful completion of the proposed experiments will reveal novel mechanisms of growth factor-stimulated glioma malignancy and new therapeutic targets for clinical development.

描述（由申请人提供）：尽管采用了最积极的手术、放疗和化疗方法，胶质瘤仍然是人类肿瘤中最难以治愈的肿瘤之一。确定导致胶质瘤恶性肿瘤的分子途径对于开发更有效的治疗方法至关重要。我们和其他人建立了多功能生长因子分散因子/肝细胞生长因子（SF/HGF）及其酪氨酸激酶受体c-Met在人胶质瘤中的表达与恶性程度显著相关。在上一个资助期内，我们将功能获得和功能丧失方法与体内和体外胶质瘤模型系统相结合，以确定SF/HGF:c-Met信号激活刺激胶质瘤恶性肿瘤的自分泌和旁分泌事件（即肿瘤血管生成、血脑屏障功能障碍、胶质瘤细胞周期失调和细胞迁移、化疗/放射耐药）。我们已经部分描述了胶质瘤对SF/HGF的反应机制：c-Met信号激活。