The tumour microenvironment plays a significant role in regulating tumour growth, metabolism, DNA repair, metastasis and response to therapy including radiation treatment. In particular, the oxygenation of a tumour greatly affects the response to ionizing radiation as hypoxic cells are more resistant to radiation then normoxic cells. Conversely radiation influences the microenvironment of the tumour by alterations in the tumour vasculature. With high single doses of radiation (>15Gy), vascular destruction is seen. At lower single doses or with daily fractionated doses (multiple smaller doses), there is little evidence of vascular destruction. Under some conditions tumour hypoxia is reduced after irradiation, potentially attributable to decreased interstitial pressure, increased perfusion and decreased oxygen consumption. Furthermore, apoptosis of the endothelial cells has been reported after tumour or intestinal irradiation. Attempts to enhance the efficacy of radiation therapy by using anti-angiogenic or anti-vascular agents however; have been limited by their transient nature. As this summary indicates, the effects of radiation on the tumour vasculature are still incompletely understood, but of substantial clinical importance. Therefore the aim of the proposed project is to delineate the vascular response in tumours to radiation. Direct observation of the vasculature during and after radiation with state of the art microscopic techniques should resolve many of these outstanding issues. Therefore we will a) develop experimental approaches to observe angiogenesis in murine tumours with video microscopy, b) determine the underlying mechanisms for vascular normalization and c) determine the nature of vascular response to radiation. These studies will help characterize the processes accounting for the vascular response to radiation and allow the development of strategies to enhance radiation therapy through this understanding.
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