Glioblastoma multiforme (GBM) is the most common and aggressive type of brain tumor in adults. Despite the use of neuroimaging, neurosurgery, chemotherapy and radiation; the median survival time of patients with GBM remains 12-15 months. Endothelial proliferation, extensive angiogenesis and intrinsic resistance to radiation are prominent characteristics of GBMs. Interesting, studies have shown that, the glioma endothelium expresses high levels of Tie 2 and its ligands, angiopoietins-1 and -2 (Ang-1, -2). Tie 2 is an endothelium-specific receptor that mediates vascular formation, stability and survival. Our observation, that Ang1 expression level correlates to glioma vascular radioresistance and; Ang1 expression is up regulated after IR treatment, supports a role of Ang-1/Tie2 signaling in glioma vascular radioresistance. We hypothesize that a paracrine regulation between glioma cells and endothelial cells (EC) via Ang/Tie2 signaling pathway mediates endothelium survival and counteracts radiation-induced cell death, contributing to the radioresistance of glioma vasculature. This hypothesis is supported by our data illustrating that blocking Tie2 by a soluble Tie 2 receptor enhanced glioma vascular response to radiation treatment in vivo. To better understand the mechanism of the Ang/Tie2 signaling pathway in EC survival and vascular stability in response to radiation, human umbilical vein endothelial cells (HUVEC) expressing either dominant negative soluble Tie2 receptor or Ang-1 were exposed to a single, low dose of radiation. TUNEL assay and the clonogenic cell survival assay were employed for detection of apoptosis. We have determined that blocking Tie2 sensitized ECs to radiation-induced apoptosis and clonogenic cell death, thus supporting the role of Ang/Tie2 in mediating endothelial cell survival in response to radiation.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA