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Mechanisms Underlying Glioblastoma Progression

We investigate mechanisms of progression to glioblastoma (GBM), the highest grade astrocytoma, including genetics, hypoxia, glioma stem cells and angiogenesis. In all instances, progression is characterized by the development of tumor necrosis, severe hypoxia and microvascular hyperplasia, a type of angiogenesis. Based on prior work, we have proposed that vaso-occlusion and intravascular thrombosis within a high-grade glioma results in hypoxia, necrosis and hypoxia-induced microvascular hyperplasia in the tumor’s periphery, leading to neoplastic expansion outward. We have initiated a xenograft mouse model in which a fluorescently labeled human glioma is implanted under a skull window and these events can be viewed directly. We induce thrombosis in the tumor by photo-activating Rose Bengal within the blood stream, which causes focal thrombosis and can track subsequent events, including the influx and activation of macrophages, the enrichment of stem cells and the development of angiogenesis. We are also using samples from patients with GBM to determine if regions from distinct tumor micro-environments that arise from these events have differing transcriptional profiles, signaling networks, and therapeutic targets.