Tumor growth and metastasis are critically dependent on the formation of new blood vessels (neovascularization). To date very little is understood about the process whereby tumors in vivo recruit various stromal elements for new blood vessel formation. The vascular endothelial growth factor (VEGF) gene appears to be pivotal in this process, but much more need to be learned about VEGF induction in the stroma surrounding the tumor and VEGF mediated recruitment of endothelial cells. The overall goals of this project are to develop transgenic murine models which will allow us to tract, through microPET imaging of PET reporter genes which will correlate with VEGF expression, the recruitment of stromal elements of tumor neovascularization. Because no good non- invasive and quantitative animal models exist for determining VEGF induction, the development and validation of such models will have wide- ranging implications both for better understanding for better understanding of tumor biology and for the in vivo evaluation of therapeutics aimed at inhibiting tumor-induced blood vessel formation. We will specifically study the recruitment of gene modified endothelial cells (GMEC) into tumors undergoing neovascularization as potential vehicles for gene delivery into tumors. GMEC are particularly suited for gene delivery because of their ability to have long-lasting transgene expression in vivo and some preliminary data that suggest that GMEC are incorporated into sites of active neovascularization. GMEC recruitment in tumors with varying levels of stromal VEGF induction will be directly evaluated while testing the hypothesis that stroma with increased VEGF production will lead to greater GMEC recruitment. This research should help to form a foundation for future investigati9ons leading to better understanding of neovascularization and stromal recruitment in living animals, and potentially lead to methods to methods for the evaluation of novel cell-based therapeutic strategies for inhibiting tumor growth MicroPET imaging will make possible the quantitative, non-invasive imaging of the dynamic interaction of tumor and stromal elements in a living animal which would otherwise not be feasible.
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