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Short-term single treatment of chemotherapy results in the enrichment of ovarian cancer stem cell-like cells leading to an increased tumor burden

Khalid Abubaker12, Ardian Latifi12, Rod Luwor3, Simon Nazaretian4, Hongjian Zhu3, Michael A Quinn15, Erik W Thompson26, Jock K Findlay157 and Nuzhat Ahmed1257*

Author Affiliations

1 Women’s Cancer Research Centre, Royal Women’s Hospital, Victoria 3052, Australia

2 Department of Surgery, University of Melbourne, St Vincent Hospital, Victoria, Australia

3 Department of Surgery, University of Melbourne, Royal Melbourne Hospital, Victoria, 3052, Australia

4 Department of Anatomical Pathology, Royal Women’s Hospital, Victoria 3052, Australia

5 Department of Obstetrics and Gynaecology, University of Melbourne, Victoria 3052, Australia

6 St Vincent’s Institute, Victoria, 3065, Australia

7 Prince Henry’s Institute of Medical Research, Victoria 3168, Australia

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Molecular Cancer 2013, 12:24  doi:10.1186/1476-4598-12-24

Published: 27 March 2013

Abstract

Over 80% of women diagnosed with advanced-stage ovarian cancer die as a result of disease recurrence due to failure of chemotherapy treatment. In this study, using two distinct ovarian cancer cell lines (epithelial OVCA 433 and mesenchymal HEY) we demonstrate enrichment in a population of cells with high expression of CSC markers at the protein and mRNA levels in response to cisplatin, paclitaxel and the combination of both. We also demonstrate a significant enhancement in the sphere forming abilities of ovarian cancer cells in response to chemotherapy drugs. The results of these in vitro findings are supported by in vivo mouse xenograft models in which intraperitoneal transplantation of cisplatin or paclitaxel-treated residual HEY cells generated significantly higher tumor burden compared to control untreated cells. Both the treated and untreated cells infiltrated the organs of the abdominal cavity. In addition, immunohistochemical studies on mouse tumors injected with cisplatin or paclitaxel treated residual cells displayed higher staining for the proliferative antigen Ki67, oncogeneic CA125, epithelial E-cadherin as well as cancer stem cell markers such as Oct4 and CD117, compared to mice injected with control untreated cells. These results suggest that a short-term single treatment of chemotherapy leaves residual cells that are enriched in CSC-like traits, resulting in an increased metastatic potential. The novel findings in this study are important in understanding the early molecular mechanisms by which chemoresistance and subsequent relapse may be triggered after the first line of chemotherapy treatment.

Keywords:
Ovarian carcinoma; Cancer stem cell; Metastasis; Ascites; Chemoresistance; Recurrence