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

Abstract

EphB4 is a member of the largest family of transmembrane receptor tyrosine kinases and plays critical roles in axonal pathfinding and blood vessel maturation. We wanted to determine the biological role of EphB4 in ovarian cancer. We studied the expression of EphB4 in seven normal ovarian specimens and 85 invasive ovarian carcinomas by immunohistochemistry. EphB4 expression was largely absent in normal ovarian surface epithelium, but was expressed in 86% of ovarian cancers. EphB4 expression was significantly associated with advanced stage of disease and the presence of ascites. Overexpression of EphB4 predicted poor survival in both univariate and multivariate analyses. We also studied the biological significance of EphB4 expression in ovarian tumour cells lines in vitro and in vivo. All five malignant ovarian tumour cell lines tested expressed higher levels of EphB4 compared with the two benign cell lines. Treatment of malignant, but not benign, ovarian tumour cell lines with progesterone, but not oestrogen, led to a 90% reduction in EphB4 levels that was associated with 50% reduction in cell survival. Inhibition of EphB4 expression by specific siRNA or antisense oligonucleotides significantly inhibited tumour cell viability by inducing apoptosis via activation of caspase-8, and also inhibited tumour cell invasion and migration. Furthermore, EphB4 antisense significantly inhibited growth of ovarian tumour xenografts and tumour microvasculature in vivo. Inhibition of EphB4 may hence have prognostic and therapeutic utility in ovarian carcinoma.

Liver Cancer: Ephrina2 Promotes Tumorigenicity Through Rac1/Akt/Nf-κB Signaling Pathway

“…29,30 In our study, we demonstrated that EphrinA2 could endow the HCC cells with resistance to both basal and cytokine-induced apoptosis, thus providing a growth advantage to cancer cells, which consequently enhanced the development and progression of HCC. Because the mechanism underlying the regulation of cell survival and apoptosis by Eph/Ephrins in cancer cells remains largely unknown, 31 our study provides novel insights into this mechanism.…”

Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

“…However, in recent years, Eph receptors and ephrins have been found to be integral players in cancer formation and progression (Wykosky and Debinski, 2008). Eph2A, as well as other members of the Eph receptor tyrosine kinase family, have been associated with advanced ovarian cancer and poor clinical outcome (Thaker et al, 2004;Wu et al, 2006;Kumar et al, 2007;Alam et al, 2008). On the basis of these data, we hypothesise that dasatinib, which targets SFKs as well as FAK and Eph2A, may show significant preclinical activity in ovarian cancer cells supporting its further clinical evaluation.…”

The Role of EphB4 and Ephrin-B2 Interactions in Prostate Cancer Models of Intravasation and Extravasation

“…Furthermore, down-regulation of EphB4 also resulted in a reduction in the microvessel density of tumours suggesting a negative effect on ephrin-B2 reverse signalling due to the absence of EphB4 [141]. The same findings were also concluded for studies in breast cancer cells [127], ovarian cancer cells [123,142], colorectal cancer cells [143] and bladder cancer cells [144]. These results were also demonstrated in murine mammary and ovarian xenograft models [15], and compared to models that over-expressed EphB4 which showed accelerated tumour progression and increased lung metastasis [145].…”

“…The sole, physiologically relevant ligand for EphB4 is ephrin-B2, a transmembrane protein expressed on the surface of certain cells, which interacts with EphB4 on adjacent cells during cell-to-cell contact. Data supports a role for EphB4-ephrin-B2 interaction in tumour angiogenesis and suggests that EphB4 positive tumour cells may preferentially attach to ephrin-B2 expressing endothelial cells during extravasation which is the process of translocation of circulating tumour cells out of blood vessels into surrounding tissues, thereby promoting metastatic spread [14][15][16][17][18][19].…”

“…EphB4 is a protein receptor expressed in increased amounts on the surface of cancer cells, including those from the prostate, and its function has been linked to several processes important for metastatic spread, including cell viability, migration, invasion and adhesion [14][15][16][17][18][19]. The sole, physiologically relevant ligand for EphB4 is ephrin-B2, a transmembrane protein expressed on the surface of certain cells, which interacts with EphB4 on adjacent cells during cell-to-cell contact.…”