Ifat Sher and Sirin A. Adham contributed equally to this work.
Cancer Cell Biology
Autocrine VEGF-A/KDR loop protects epithelial ovarian carcinoma cells from anoikis
Article first published online: 2 SEP 2008
Copyright © 2008 Wiley-Liss, Inc.
International Journal of Cancer
Volume 124, Issue 3, pages 553–561, 1 February 2009
How to Cite
Sher, I., Adham, S. A., Petrik, J. and Coomber, B. L. (2009), Autocrine VEGF-A/KDR loop protects epithelial ovarian carcinoma cells from anoikis. Int. J. Cancer, 124: 553–561. doi: 10.1002/ijc.23963
- Issue published online: 18 NOV 2008
- Article first published online: 2 SEP 2008
- Accepted manuscript online: 2 SEP 2008 12:00AM EST
- Manuscript Accepted: 30 JUL 2008
- Manuscript Received: 19 MAR 2008
- The Canadian Cancer Society
- National Cancer Institute of Canada. Grant Number: #016117
- The Ontario Institute for Cancer Research
- epithelial ovarian cancer
Epithelial ovarian carcinoma (EOC) patients are usually diagnosed at an advanced stage, characterized by interperitoneal carcinomatosis and production of large volumes of ascites. Vascular endothelial growth factor-A (VEGF-A) and its main signaling receptor VEGFR2 (KDR) are coexpressed in primary ovarian tumors, ascitic cells and metastases, suggesting the existence of an autocrine VEGF-A/KDR loop in EOC cells. In the present study, we examined this possibility and explored the role of this autocrine loop in protecting EOC cells from apoptosis under anchorage free growth conditions (anoikis). We found that 3 different EOC cell lines (Caov3, OVCAR3, SKOV3) express both VEGF-A and its receptors, including KDR. In these cells, KDR is constitutively phosphorylated and is detected both in the cell plasma membrane and in the nucleus. Treating EOC cells with specific internal inhibitors of KDR kinase activity or a VEGF-A neutralizing antibody abolished KDR autophosphorylation and resulted in significant increase in apoptosis when cells were grown in single-cell, anchorage-free conditions. By contrast, these blocking reagents had no effect on cell viability when EOC cells were grown in adhesive monolayers. In summary, our results indicate that an autocrine VEGF-A/KDR loop exists in EOC cells and that it plays a role in protecting the cells from anoikis. Our results imply that treating EOC patients with VEGF blocking agents may potentially reduce peritoneal dissemination by decreasing vascular permeability as well as inducing apoptosis of shed ovarian cancer cells in ascites. © 2008 Wiley-Liss, Inc.