Over-expression of EphB4 by cancer cells provides survival advantage by interrupting death receptor-mediated apoptotic pathways

UnrestrictedAn increasing body of evidence suggests overexpression of Eph receptor tyrosine kinases in tumors. However, their function in tumor biology is unknown. This thesis proposal evaluates the expression and biological significance of EphB4 in eight different epithelial cancers. Consistently, membranous expression of EphB4 was observed at much higher levels in tumor tissue compared to adjacent normal tissue, with a trend towards increased expression in higher grade, stage and proliferative front of tumors. EphB4 expression was upregulated by oncogenes such as EGFR, HER-2/neu and Akt, and downregulated by tumor suppressors such as PTEN, p53 and APC. EphB4 provides direct survival signals to tumor cells both in vitro and in vivo by interrupting extrinsic apoptotic pathways. Expression of the extracellular domain of EphB4 is sufficient for tumor cells to overcome apoptotic signals from the TRAIL-death receptor pathway. These results confirm that targeted overexpression of EphB4 on epithelial tumor cells provides a survival advantage to tumors by interrupting death-receptor-mediated apoptosis