The formation of blood vessels is a crucial event during tumor progression, but we are only beginning to understand it at the molecular level. The Eph family of receptor tyrosine kinases and their ligands, which belong to the ephrin family, have been recently implicated in the formation of blood vessels during embryonic development and in in vivo and in vitro models of angiogenesis. Eph receptors and receptors presumably play a role in tumor vascularization. We propose here to investigate this pathological role. Binding of the membrane-anchored ephrin ligands to Eph receptors involves a cell-cell interaction and generates signals that affect cell adhesion, cell migration, and cytoskeletal organization. Spatially regulated Eph/ephrin signals likely play an important role in the organized migration and assembly of cells into tumor blood vessels. We will identify Eph receptors and ephrins expressed in tumor vasculature. Although Eph receptors have been found to be over- expressed in many types of tumors, their cellular localization in tumor tissue is not known. In vitro bioassays with human umbilical vein endothelial cells (HUVECs) will be used to dissect specific Eph/ephrin signal transduction pathways that are important during angiogenesis. The effects of inhibiting Eph/ephrin signaling on tumor growth and vascularization will be assessed by using a tumor xenograft in nude mice. Peptides that bind to Eph receptors or ephrins expressed in tumor blood vessels will be isolated by phage display. These peptides will be tested for their ability to selectively target tumor vasculature when injected intravenously and, therefore, as possible vectors for the delivery of anti- cancer drugs to tumors. The proposed work will elucidate whether Eph receptors and ephrins participate in tumor blood vessel morphogenesis and could be used as targets for anti-cancer therapies.
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