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

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 a...

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Bibliographic Details
Published in:British journal of cancer 2007-04, Vol.96 (7), p.1083-1091
Main Authors: KUMAR, S. R, MASOOD, R, WEAVER, F. A, SOOD, A. K, GILL, P. S, SPANNUTH, W. A, SINGH, J, SCEHNET, J, KLEIBER, G, JENNINGS, N, DEAVERS, M, KRASNOPEROV, V, DUBEAU, L
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Animals
Apoptosis
Biological and medical sciences
Caspases - metabolism
Cell Line, Tumor
Cell Movement
Cystadenocarcinoma, Serous - metabolism
Cystadenocarcinoma, Serous - pathology
Female
Female genital diseases
Gene Expression Regulation, Neoplastic
Gynecology. Andrology. Obstetrics
Humans
Medical sciences
Mice
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Neoplasm Invasiveness
Ovarian cancer
Ovarian Neoplasms - metabolism
Ovarian Neoplasms - pathology
Progesterone - pharmacology
Progestins - pharmacology
Receptor, EphB4 - antagonists & inhibitors
Receptor, EphB4 - metabolism
RNA, Small Interfering - therapeutic use
Survival Rate
Translational Therapeutics
Tumors
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Summary: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.
ISSN:0007-0920
1532-1827
DOI:10.1038/sj.bjc.6603642