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Journal of Cellular Biochemistry

Cisplatin treatment of primary and metastatic epithelial ovarian carcinomas generates residual cells with mesenchymal stem cell-like profile

Authors

  • Ardian Latifi,

    1. Women's Cancer Research Centre, Royal Women's Hospital, Victoria 3052, Australia
    2. University of Melbourne Department of Surgery, St Vincent Hospital, Victoria 3065, Australia
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  • Khalid Abubaker,

    1. Women's Cancer Research Centre, Royal Women's Hospital, Victoria 3052, Australia
    2. University of Melbourne Department of Surgery, St Vincent Hospital, Victoria 3065, Australia
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  • Natalie Castrechini,

    1. Women's Cancer Research Centre, Royal Women's Hospital, Victoria 3052, Australia
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  • Alister C. Ward,

    1. School of Medicine, Deakin University, Victoria 3217, Australia
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  • Clifford Liongue,

    1. School of Medicine, Deakin University, Victoria 3217, Australia
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  • Francoise Dobill,

    1. Women's Cancer Research Centre, Royal Women's Hospital, Victoria 3052, Australia
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  • Janani Kumar,

    1. School of Medicine, Deakin University, Victoria 3217, Australia
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  • Erik W. Thompson,

    1. University of Melbourne Department of Surgery, St Vincent Hospital, Victoria 3065, Australia
    2. St. Vincent's Institute, Victoria 3065, Australia
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  • Michael A. Quinn,

    1. Women's Cancer Research Centre, Royal Women's Hospital, Victoria 3052, Australia
    2. Department of Obstetrics and Gynaecology, University of Melbourne, Victoria 3052, Australia
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  • Jock K. Findlay,

    1. Women's Cancer Research Centre, Royal Women's Hospital, Victoria 3052, Australia
    2. Department of Obstetrics and Gynaecology, University of Melbourne, Victoria 3052, Australia
    3. Prince Henry's Institute of Medical Research, Victoria 3168, Australia
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  • Nuzhat Ahmed

    Corresponding author
    1. Women's Cancer Research Centre, Royal Women's Hospital, Victoria 3052, Australia
    2. University of Melbourne Department of Surgery, St Vincent Hospital, Victoria 3065, Australia
    3. Department of Obstetrics and Gynaecology, University of Melbourne, Victoria 3052, Australia
    4. Prince Henry's Institute of Medical Research, Victoria 3168, Australia
    • Women's Cancer Research Centre, Royal Women's Hospital, 20 Flemington Road, Parkville, VIC 3052, Australia.
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  • Ardian Latifi and Khalid Abubaker contributed equally to this work.

Abstract

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.

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