EphB4 Expression and Biological Significance in Prostate Cancer

Abstract

Prostate cancer is the most common cancer in men. Advanced prostate cancer spreading beyond the gland is incurable. Identifying factors that regulate the spread of tumor into the regional nodes and distant sites would guide the development of novel diagnostic, prognostic, and therapeutic targets. The aim of our study was to examine the expression and biological role of EphB4 in prostate cancer. EphB4 mRNA is expressed in 64 of 72 (89%) prostate tumor tissues assessed. EphB4 protein expression is found in the majority (41 of 62, 66%) of tumors, and 3 of 20 (15%) normal prostate tissues. Little or no expression was observed in benign prostate epithelial cell line, but EphB4 was expressed in all prostate cancer cell lines to varying degrees. EphB4 protein levels are high in the PC3 prostate cancer cell line and several folds higher in a metastatic clone of PC3 (PC3M) where overexpression was accompanied by EphB4 gene amplification. EphB4 expression is induced by loss of PTEN, p53, and induced by epidermal growth factor/epidermal growth factor receptor and insulinlike growth factor-I/insulin-like growth factor-IR. Knockdown of the EphB4 protein using EphB4 short interfering RNA or antisense oligodeoxynucleotide significantly inhibits cell growth/viability, migration, and invasion, and induces apoptosis in prostate cancer cell lines. Antisense oligodeoxynucleotide targeting EphB4 in vivo showed antitumor activity in murine human tumor xenograft model. These data show a role for EphB4 in prostate cancer and provide a rationale to study EphB4 for diagnostic, prognostic, and therapeutic applications. (Cancer Res 2005; 65(11): 4623-32)

The receptor tyrosine kinase EphB4 is overexpressed in ovarian cancer, provides survival signals and predicts poor outcome

“…However, there is growing evidence that EphB4 may provide more direct survival cues to cancer cells. We have shown recently such a role of EphB4 in prostate (Xia et al, 2005), bladder , breast , and head and neck cancers (Masood et al, 2006). In this report, we extend those findings to ovarian cancer as well.…”

“…Similarly, treatment of HOC-7 cells with 25 nM EphB4 siRNA resulted in 75% reduction in cell numbers (data not shown). Treatment of EphB4-negative tumour cell lines with EphB4 siRNA does not affect tumour cell numbers (Xia et al, 2005 and data not shown).…”

“…The Eph receptors are the largest family of tyrosine kinases, comprising of 15 individual members, divided into EphA and EphB classes. Recently, several studies have documented high expression of the Eph family of receptor tyrosine kinases in tumours (Stephenson et al, 2001;Berclaz et al, 2003;Wu et al, 2004Wu et al, , 2006Lee et al, 2005;Xia et al, 2005Xia et al, , 2006Kumar et al, 2006;Masood et al, 2006). Although there is limited data on the protein levels of EphB4 in cancers, only recently, data on the biological significance of this protein in tumour biology is being accrued.…”

EphB4 receptor tyrosine kinase is expressed in bladder cancer and provides signals for cell survival

“…Overexpression of EphB4 has been documented in other epithelial cancer types, including breast cancer (Berclaz et al, 1996), uterine caner (Berclaz et al, 2003), prostate cancer (Xia et al, 2005b) and mesothelioma (Xia et al, 2005a). Ours is the first report of EphB4 overexpression in bladder cancer.…”

Tumor Suppressor Activity of the EphB2 Receptor in Prostate Cancer

“…Although Fc fusion proteins are quite stable when administered systemically in vivo, Eph receptor-and ephrin-based agents lack selectivity because of the promiscuity of Eph receptor-ephrin binding (section 1.3). More selective Eph receptor-targeting reagents that have been developed include antagonistic peptides that target the ephrin-binding site of individual Eph receptors (91,92), siRNAs and anti-sense oligodeoxynucleotides (93)(94)(95).…”