Biochemistry of Brain Tumor Microvessel Development

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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.