Despite aggressive multimodality therapy, glioblastoma multiforme (GBM) is most often fatal. GBM is very radiation resistant. We observed that glioblastoma blood vessels in both syngeneic and xenograft models did not respond to doses of radiation used in clinical settings using the vascular window model and Power Doppler and analysis of tumor blood flow. In contrast, non-glioma tumors showed vascular regression in response to clinical doses of radiotherapy. Interestingly, glioblastoma expresses high levels of Tie2 and its ligands, angiopoietins (Ang1, 2). Tie2 is an endothelium-specific receptor that mediates vascular formation, endothelium survival and recruitment of endothelial progenitors (vasculogenesis). Our observation that Ang1 expression level correlates to glioma vascular radioresistance and Ang1 expression is up regulated after IR treatment supports a role of Ang1/Tie2 signaling in glioma vascular radioresistance. We hypothesize that the tumor microenvironment predetermines the response of tumor blood vessels to ionizing radiation (IR), and that Tie2 receptor tyrosine kinase signaling mediates endothelium survival and counteracts radiation-induced cell death, contributing to radioresistance of glioma vasculature. Our preliminary data show that blocking Tie2 by a soluble Tie2 receptor enhanced endothelial cell (EC) death in response to radiation. Conversely, activating Tie2 by Ang1 rendered ECs radioresistance. Furthermore, we observed that blocking Tie2 action sensitized glioma tumor vessels to radiation in three complementary tumor models and also inhibited tumor growth. Based on these findings, we believe that the anti-tumor effects of radiotherapy can be enhanced by inhibition of Tie2 signaling within glioma vasculature. The proposed study will include the following three Specific Aims. ? ? Specific Aim 1. Study the role of Ang1 and Ang2 for the survival of endothelial cells and vascular tubes in vitro in response to IR. ? Specific Aim 2. Define the mechanism of Ang/Tie2 signaling in glioma vascular radioresistance in vivo. ? Specific Aim 3. Compare and analyze the Tie2 and VEGF pathways in glioma vascular radioresistance. ? ?
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