Ang/Tie2 Signaling in Tumor Vascular Normalization. Tumor vessels have structural and functional abnormalities that impair drug penetration and the delivery of oxygen, which is essential for radiation therapy. The focus of this research proposal- the normalization of tumor vasculature- is based on our laboratory's clinically relevant finding: anti-angiogenic treatment can """"""""normalize"""""""" the aberrant structure and function of tumor vessels, and improve the delivery of therapeutics. However, vascular normalization is transient and leads to the eventual regression of many vessels within a few days. Our studies show that vascular normalization is accompanied by a transient upregulation of Ang-1 expression and increased mural cell recruitment, both of which are known to enhance vessel stability. Furthermore, we find that Ang1/Tie2 signaling is required for vascular normalization. I postulate that enhanced and sustained Ang/Tie2 signaling will increase mural cell recruitment and vessel stability, thus prolonging the period of normalization induced by anti-VEGFR2 treatment. To monitor mural cells in vivo, I will employ transgenic mice that express EGFP under the control of the alpha-smooth muscle actin promoter. By improving and prolonging vessel normalization, I aim to improve tumor oxygenation and hence the efficacy of radiation therapy in preclinical models, and ultimately to translate these findings into the clinic.
