Pilot--Angiopoietins 1 & 2 in colon cancer angiogenesis

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Angiogenesis is driven by specific factors that lead to endothelial ce1l (EC) proliferation, invasion, survival, and differentiation. The activity of pro-angiogenic molecules must exceed that of anti-angiogenic molecules to induce neovascularization. In addition to the induction of angiogenesis, tumors must support the vasculature under adverse environmental conditions (hypoxia or low pH). For ECs to survive in these conditions, tumors must secrete EC "survival factors". Vascular endothelial growth factor (VEGF), an important angiogenic factor in colon cancer progression and metastases, has also been shown to be an EC survival factor. Recently, the angiopoietin (Ang) family of ligands has been found to be important in tumor angiogenesis. Ang- 1 and Ang-2 both bind to the specific EC receptor Tie-2; however, their biologic effects are antagonistic. Ang-l binds to the Tie-2 receptor, initiating activity of the tyrosine kinase activity of this transmembrane receptor. Activation of the Tie-2 receptor leads to EC stability, and inhibits EC apoptosis. Alternatively, Ang-2 binds to the Tie-2 receptor, but antagonizes the effect of Ang-1, leading to EC destabilization and apoptosis. The coordinated induction of Ang-1, Ang-2, and VEGF has been shown to be important in the induction of tumor angiogenesis. The overall goal of this proposal is to determine the function and regulation of the angiopoietins in colon cancer angiogenesis. Specifically, we will determine: 1) the relative expression of Ang-1 and Ang-2 in human colon cancer specimens and normal mucosa. 2) the effect of over expression of the Ang-1 or Ang-2 on tumor growth, angiogenesis, and metastases in a murine model of human colon cancer. 3) the effect of over expression of Ang-l and Ang-2 on tumor permeability . 4) the effect of conditioned medium from colon cancer cells, pericytes, and non-malignant ce1ls on Ang-l and Ang-2 expression in Ecs. The significance of this pilot project is that (1) a more thorough understanding of the role of the angiopoietins in "stabilizing" and "destabilizing" the tumor neovasculature may lead to new therapeutic strategies and/or (2) may identify targets for imaging the altered neovasculature when exposed to anti-angiogenic agents.