Characterizing tumor endothelial cell abnormalities to develop rational anti-angi

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DESCRIPTION (provided by applicant): The idea that tumors could be eradicated by destroying tumor-associated blood vessels was first proposed over 30 years ago. Today there are about 11 anti-angiogenic drugs in clinical trials. But the results of most clinical studies to date have so far been disappointing. The idea behind anti-angiogenesis (anti-endothelial) therapy is that the endothelial cells lining tumor blood vessels are homogeneous, normal, are not mutable, and will not develop dmg resistance in contrast to tumor cells. However, that basic assumption has been challenged by recent studies showing morphological and molecular changes (e.g. ectopic calcification) and striking heterogeneity in tumor-specific endothelial cells. Endothelial cells conscripted by a growing tumor may evade anti-angiogenic strategies through diverse, acquired mechanisms. For example, tumor-specific endothelial cells may be derived from multiple cell types, including sprouting endothelium, bone marrow- derived vascular progenitors, trans-differentiated myeloid cells, and multi-potent mesodermal stem cells. It is surprising, then, that most anti-angiogenic therapies today are routinely tested on normal endothelial cell lines in the laboratory. To address this problem, our goals are: 1) To use transgenic mouse models of breast and prostate carcinoma to isolate and characterize tumor-specific endothelial cells from breast and prostate tumors. 2) To determine the relationship between tumor blood vessel calcification and tumor progression and metastasis. 3) To determine the tumor-specific "homing" and vascular differentiation potential of adult mesenchymal stem cells in tumor-bearing mice. 4) And to use laser capture micro-dissection and micro- arrays to identify a molecular signature in tumor-specific endothelial cells as tumors progress from the earliest neoplasia to adenocarcinoma. It is not known why anti-angiogenic therapies, which hold great promise in the treatment of cancer, have not succeeded in the clinic. Our study seeks to better understand the biology of tumor-specific endothelial cells through rigorous characterization of freshly isolated cells and high-throughput gene analysis to identify novel genes and gene networks. The long-term goal is to use this new knowledge for the rational design of more effective anti-angiogenic strategies. RELEVANCE: Anti-angiogenesis is based on the principle that tumors can be shrunk by using drugs to target the blood vessels feeding them with blood, oxygen, and nutrients. But our basic knowledge of tumor blood vessels is severely limited. Our study will better characterize the biology of tumor-specific blood vessels with the long- term goal of using this new knowledge towards the rational design of anti-angiogenic therapies.