Ardian Latifi and Khalid Abubaker contributed equally to this work.
Cisplatin treatment of primary and metastatic epithelial ovarian carcinomas generates residual cells with mesenchymal stem cell-like profile†
Article first published online: 19 SEP 2011
Copyright © 2011 Wiley-Liss, Inc.
Journal of Cellular Biochemistry
Volume 112, Issue 10, pages 2850–2864, October 2011
How to Cite
Latifi, A., Abubaker, K., Castrechini, N., Ward, A. C., Liongue, C., Dobill, F., Kumar, J., Thompson, E. W., Quinn, M. A., Findlay, J. K. and Ahmed, N. (2011), Cisplatin treatment of primary and metastatic epithelial ovarian carcinomas generates residual cells with mesenchymal stem cell-like profile. J. Cell. Biochem., 112: 2850–2864. doi: 10.1002/jcb.23199
- Issue published online: 19 SEP 2011
- Article first published online: 19 SEP 2011
- Accepted manuscript online: 26 MAY 2011 07:36AM EST
- Manuscript Accepted: 16 MAY 2011
- Manuscript Received: 13 MAY 2011
- Royal Women's Hospital Foundation
- Women's Cancer Foundation
- National Health and Medical Research Council of Australia. Grant Number: RegKey#441101
- Victorian Breast Cancer Research Consortium
- Ovarian Carcinoma;
- Cisplatin Resistance;
- Cancer Stem Cell;
- Epithelial Mesenchymal Transition;
Epithelial mesenchymal transition (EMT) and cancer stem cells (CSC) have been associated with resistance to chemotherapy. Eighty percent of ovarian cancer patients initially respond to platinum-based combination therapy but most return with recurrence and ultimate demise. To better understand such chemoresistance we have assessed the potential role of EMT in tumor cells collected from advanced-stage ovarian cancer patients and the ovarian cancer cell line OVCA 433 in response to cisplatin in vitro. We demonstrate that cisplatin-induced transition from epithelial to mesenchymal morphology in residual cancer cells correlated with reduced E-cadherin, and increased N-cadherin and vimentin expression. The mRNA expression of Snail, Slug, Twist, and MMP-2 were significantly enhanced in response to cisplatin and correlated with increased migration. This coincided with increased cell surface expression of CSC-like markers such as CD44, α2 integrin subunit, CD117, CD133, EpCAM, and the expression of stem cell factors Nanog and Oct-4. EMT and CSC-like changes in response to cisplatin correlated with enhanced activation of extracellular signal-regulated kinase (ERK)1/2. The selective MEK inhibitor U0126 inhibited ERK2 activation and partially suppressed cisplatin-induced EMT and CSC markers. In vivo xenotransplantation of cisplatin-treated OVCA 433 cells in zebrafish embryos demonstrated significantly enhanced migration of cells compared to control untreated cells. U0126 inhibited cisplatin-induced migration of cells in vivo, suggesting that ERK2 signaling is critical to cisplatin-induced EMT and CSC phenotypes, and that targeting ERK2 in the presence of cisplatin may reduce the burden of residual tumor, the ultimate cause of recurrence in ovarian cancer patients. J. Cell. Biochem. 112: 2850–2864, 2011. © 2011 Wiley-Liss, Inc.