Primary brain tumors cause over 12,000 deaths each year in the United States alone. Existing therapies are largely ineffective. Vessel- targeted therapies have substantial therapeutic potential since angiogenesis is required for solid tumor growth. In addition, blood- brain barrier dysfunction is a major cause of morbidity in patients with brain tumors. Because of the relationship between perivascular glia and microvessels within normal brain and gliomas, we have developed in vivo and in vitro methodologies to determine mechanisms by which these cells influence endothelial behavior. We have established that perivascular plasminogen activation regulates glioma angiogenesis and growth, and survival of glioma-bearing animals. The objectives of this application are to determine mechanisms by which glioma cells alter CNS microvessel growth and differentiation and to develop strategies for improving patient survival by targeting the plasminogen activation pathway. In vitro and in vivo experimental rat and human glioma models will be used to determine mechanisms by which glioma cells influence angiogenesis and endothelial differentiation.
In aim #1 we will determine how astrocytes and glioma cells alter periendothelial plasminogen activation and microvessel morphogenesis. Plasminogen activators (PA) and PA inhibitors will be quantitated and localized in endothelial, glioma, and mixed glioma endothelial cultures. The effects of purified components of the P6 pathway will be determined. Findings will reveal mechanisms by which PAs regulate glioma-induced microvessel formation.
In aim #2 we will establish roles of other glioma cell products during angiogenic cell interactions in vitro. Immunocytological and biochemical methods will be used to determine the functions of cell adhesion and de-adhesion molecules, collagen, collagenases, and proteoglycans during angiogenic glioma-endothelial interactions.
In aim #3 we will use immunohistochemical and biochemical techniques to determine if specific PAs, PAIs, adhesion molecules, and extracellular matrix regulate microvessel growth and differentiation in normal brain and brain tumors in vivo.
In aim #4 we will use systemic and interstitial drug delivery strategies to optimize the therapeutic response of intracranial gliomas to plasminogen activation inhibitors and to determine if responses are due to effects on tumor microvessel growth and endothelial barrier expression. Our findings will identify mechanisms by which glioma cells induce pathological microvessel responses and test novel vessel-targeted approaches to treating primary brain tumors.
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