Malignant gliomas are aggressive brain tumors with an increasing incidence. Their poor prognosis is due to the ability of glioma cells to proliferate rapidly, invade surrounding brain, induce angiogenesis, and disrupt blood-brain barrier (BBB) function. We have substantial evidence that the multifunctional cytokine and angiogenic factor scatter factor/hepatocyte growth factor (SF/HGF) and its receptor c-met in human gliomas and glioblastoma cells (ii) a correlation between glioma grade and SF/HGF content in clinical glioma specimens, (iii) SF/HGF induction of glioblastoma cell migration, and (iv) enhanced in vivo glioma growth and tumor-associated angiogenesis following SF/HGF gene transfer. This application proposes in vitro and in vivo experiments to determine how SF/HGF and c-met contribute to glioblastoma malignancy, and if inhibiting SF/HGF:c-met signaling can be used to reverse glioma malignancy, angiogenesis, and BBB dysfunction.
Aim #1 will determine how purified and glioma cell-derived SF/HGF alters BBB function in vivo. The effects of SF/HGF on BBB permeability and endothelial cell expression of BBB-specific proteins will be quantified.
Aims #2 and #3 will determine if inhibiting endogenous SF/HGF:c-met signaling by genetically altering glioblastoma cell lines reduces their malignancy in vitro and in vivo.
Aim #2 will examine the effects of inhibiting glioblastoma cell SF/HGF expression/function using gene transfer of antisense SF/HGF and NK2, a naturally occurring SF/HGF receptor antagonist.
Aim #3 will determine the effects of inhibiting c-met expression function by gene transfer of antisense c-met and dominant-negative mutant c-met receptors. The effects of these genetic manipulations on glioblastoma cell anchorage-dependent and - independent proliferation, migration , and invasion in vitro, and on tumor growth, angiogenesis, and BBB dysfunction in vivo will be quantified.
Aim #4 will determine if tumor malignancy can be reversed in established SF/HGF-producing gliomas by using the most promising approaches of Aims #2 and #3 with adenoviral- and cell-based gene transfer. These studies will produce new information on mechanisms of glioblastoma malignancy and BBB dysfunction and will establish the feasibility of altering SF/HGF:c-met signaling within gliomas for therapeutic intervention.
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