The role of tumor angiogenesis in glioblastoma multiforme and implications for anticancer therapy

UnrestrictedGlioblastoma multiforme (GBM) is the most malignant form of brain tumor. GBM displays characteristics of rapid invasiveness and massive vascularization. Despite modern advances in surgery, radiation, and chemotherapy, GBM patients typically survive only 12 to 15 months after diagnosis. Therefore, there is still an urgent need to find alternative and more effective therapies. Tumor cells depend on the vasculature for nutrients and oxygen. In consideration of the highly vascularized environment of GBM, we hypothesized that antiangiogenic therapy, in combination with standard chemotherapy, would prove beneficial for curing or stabilizing this disease. The tumor-associated brain endothelial cells (TuBEC) display unique functional and phenotypic properties that are not shared by normal brain-associated endothelial cells (BEC). These distinct traits of the glioma vasculature should be exploited for developing antiangiogenic drugs. The overall aim of this investigation is to further characterize and understand the properties of TuBEC and the glioma vasculature, so that more effective antiangiogenic therapies can be developed.; Extensive research from our laboratory demonstrates that TuBEC display an inherent chemoresistant phenotype. In particular, TuBEC are unresponsive to temozolomide, which is currently the standard of care for GBM. The issue of endothelial cell chemoresistance is of great clinical importance because GBM are marked by increased angiogenesis. Through molecular and pharmacological approaches, we identified that the mechanism behind this chemoresistance is due to the overexpression of the inhibitor of apoptosis survivin and also to the overexpression of the endoplasmic reticulum chaperone glucose-regulated protein 78 (GRP78). Survivin and GRP78 are specifically elevated on the glioma vasculature and not expressed on normal blood vessels, making them prime targets for antiangiogenic therapy.; Our studies also indicate that the novel compound 2, 5-Dimethyl-celecoxib (DMC) exerts potent antiangiogenic activities. DMC is a structural analog of the selective Cox-2 inhibitor celecoxib, but lacks the ability to inhibit Cox-2. We previously reported that DMC mimics the antitumor effects of celecoxib. The studies presented here reveal that DMC also displays antivascular properties. DMC induces endothelial cell cytotoxicity, inhibits proliferation and migration in vitro, and suppresses angiogenesis in vivo. DMC dually targets glioma cells and TuBEC, making it an attractive candidate for GBM therapy