Biochemistry of Brain Tumor Microvessel Development

描述(申请人提供)：胶质瘤仍然是最难治愈的人类肿瘤之一，尽管手术、放疗和化疗是最具侵略性的。识别导致胶质瘤恶性的分子途径对于开发更有效的治疗方法至关重要。我们和其他人发现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在人脑胶质瘤中的表达与恶性程度显著相关。在上一个资助期，我们将功能获得和功能丧失的方法与体内和体外胶质瘤模型系统相结合，建立了SF/HGF：C-Met信号激活自分泌和旁分泌事件，刺激胶质瘤恶性(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/放射抵抗)。我们已经部分描述了胶质瘤对SF/HGF：C-Met信号激活的反应机制。 这一竞争性更新建议利用实验胶质瘤模型和临床肿瘤标本来进一步确定SF/HGF刺激人脑胶质瘤恶性表型的生化和转录机制。目的：1.寻找在人脑胶质母细胞瘤细胞中受SF/HGF：C-Met激活差异调控的新基因和新基因家族。AIM#2将利用在AIM#1中产生的新假设来确定特定的SF/HGF调节基因如何影响恶性胶质瘤的表型。目的#3将确定胶质瘤细胞对SF/HGF反应的细胞信号通路和转录机制。目的#4将使用组织阵列来量化临床人脑胶质瘤中具有生物学意义的SF/HGF反应基因的表达，并确定它们与病理分级和其他恶性特征的相关性。这些实验的成功完成将揭示生长因子刺激胶质瘤恶性的新机制，并为临床开发新的治疗靶点。

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.