1. ¹Department of Surgery, University of Southern California, Los Angeles, CA, USA
2. ²Department of Pathology, University of Southern California, Los Angeles, CA, USA
3. ³Department of Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
4. ⁴Department of Medicine, University of Southern California, Los Angeles, CA, USA
5. ⁵Department of Pathology and Laboratory Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
6. ⁶VasGene Therapeutics Inc., Los Angeles, CA, USA
7. ⁷Department of Cancer Biology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence: Dr PS Gill, USC/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, NOR 6330, Los Angeles, CA 90033, USA. E-mail: parkashg@usc.edu

⁸These authors contributed equally to the work.

Received 13 November 2006; Revised 22 January 2007; Accepted 24 January 2007; Published online 13 March 2007.

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.