Endothelial cells in tumor vessels express angiogenic markers that are not detectable in normal vessels. We have developed an in vivo selection system in which phage capable of homing into tumors are recovered from a phage display peptide library following intravenous administration. Using this strategy, we have isolated tumor-homing phage displaying the tripeptide asparagine-glycine-arginine (NGR). We have shown that CD13/Aminopeptidase N is the receptor for the NGR motif in tumor angiogenic vasculature. Based on our in vivo studies involving tumor targeting with NGR-phage and the blocking of angiogenesis with CD13 antagonists, we propose that CD13 is a key regulator in this process. Here we plan to study the induction and activity of CD13 during tumor progression. We will evaluate the expression of CD13 in tumor vasculature at different stages of tumor development by immunohistochemical staining and by in vivo phage targeting. A transgenic mouse model for pancreatic islet cell carcinoma (Rip-Tag) will be used. We will test whether CD13 expression is specific for a certain stage. We will study the nature of the angiogenic stimuli that lead to up- regulation and activation of CD13. The expression and function of CD13 will be investigated in vitro using endothelial cell lines, and in vivo using cornea and chorioalantoic membrane assays. We will examine the effects of inhibitors of CD13 on tumor growth using transgenic and xenograft models. Inhibitory antibodies and known chemical blockers will be tested. Finally, we will evaluate the phenotype of CD13 deficient mice in respect to angiogenesis. We will eliminate the CD13 gene by homologous recombination in embryonic stem cells and proceed to create CD13 null mice. The phenotype of the CD13 deficient mice will be evaluated in respect to angiogenesis by using cytokine-, oxygen- and tumor-induced angiogenesis models. These studies will clarify the role of CD13 in angiogenesis and may lead to the development of new anti-tumor therapeutic strategies.
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