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Induction of Ephs/Ephrins-Mediated Tumor Cells-Endothelial Cells Repulsion as an Anti-Cancer Therapeutic Approach

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Annual rept. 16 Aug 2004-15 Aug 2005

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Eph receptors constitute the largest family of receptor tyrosine kinases. They comprise 8 type A receptors and 6 type B receptors. Originally identified as neuronal path finding molecules, where they guide the migrating cells to specific tissue targets, they are an essential component in vascular assembly regulation, including during angiogenesis, and in embryonic development. Ephs interact with membrane-bound ligands, the Ephrins, of which 8 have been found to date Ephrin-AI to 5 and Ephrin-BI to 3. We hypothesize that manipulating EphEphrin interactions could prevent attraction andor induce repulsion between tumor cells and endothelial cells. The goal is to take advantage of EphsEphrins interactions to turn endothelial cells into a barrier to metastatic tumor cells entering the blood flow through vascular endothelial cells, or exiting the flow through bone marrow endothelial cells in the direction of their specific metastatic sites. To test our hypothesis, we first performed a profiling of breast cancer cells with regard to the expression and activation levels of various EphsEphrins. We found that the EphB2 receptor is overexpressed in almost 50 of the cancer cell lines. Similarly, the Ephrin-B2, which is a ligand to EphB2, is also strongly expressed in over 50 of the cancer cell lines while not found in benign cell lines. Another EphB2 ligand, Ephrin-BI, is present in all normal cells but lost in 4 out of II cancer cell lines. We also found that EphB2 could be subject to defects in phosphorylation and response to the ligand. We are investigating attractiverepulsive behavior of tumor cells, with different expression levels of EphB2 and EphrinBs, towards endothelial cells and vice-versa. Next, we will study the invasive and metastatic potential of tumor cells with different expression levels of EphsEphrins in vivo.

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  • Medicine and Medical Research

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