Vaso-occlusive Mechanisms that Intiate Hypoxia and Necrosis in Glioblastoma: The Role of Thrombosis and Tissue Factor

Abstract

AbstractGlioblastoma (GBM) is a highly malignant, rapidly progressive astrocytoma that is distinguished from lower grade tumors by necrosis, severe hypoxia and microvascular hyperplasia. While the development of hypoxia and necrosis are known to be ominous prognostic features, precise mechanisms that underlie their development have not been elucidated. Pathologic observations and experimental evidence now suggest that vaso-occlusion and intravascular thrombosis may initiate or propagate hypoxia and necrosis. This emerging model suggests that thrombosis arises within the vasculature of high grade gliomas secondary to the overexpression of the highly pro-thrombotic protein tissue factor. This protein is dramatically upregulated in response to EGFR activation, PTEN loss and hypoxia, which occur at the transition from grade III to grade IV astrocytoma. A pro-thrombotic enviroment also activates the family of protease-activated receptors (PARs) on tumor cells, which are G-protein coupled and enhance invasive and pro-angiogenic properties. Vaso-occlusive and pro-thrombotic mechanisms in GBM could readily explain the rapid peripheral expansion seen on neuroimaging and the dramatic shift to an acceleration in clinical progression due to hypoxia-induced angiogenesis.KeywordsVascular Endothelial Growth FactorTissue FactorTissue Factor ExpressionPTEN LossIntravascular ThrombosisThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.