Cisplatin induces stemness in ovarian cancer
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Andrew Wiechert1,2,*, Caner Saygin1,*, Praveena S. Thiagarajan1, Vinay S. Rao1, James S. Hale1, Nikhil Gupta3, Masahiro Hitomi1,3,4, Anil Belur Nagaraj5, Analisa DiFeo5, Justin D. Lathia1,3,4,5, Ofer Reizes1,3,4,5
1Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
2Division of Gynecological Oncology, Women’s Health Institute, Cleveland Clinic, Cleveland, OH 44195, USA
3Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195
4Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH 44195, USA
5Department of Case Comprehensive Cancer Center, Cleveland, OH 44106, USA
*These authors contributed equally to this work
Ofer Reizes, e-mail: [email protected]
Justin D. Lathia, e-mail: [email protected]
Keywords: cancer stem cell, ovarian cancer, cisplatin, NANOG
Received: December 01, 2015 Accepted: March 31, 2016 Published: April 20, 2016
The mainstay of treatment for ovarian cancer is platinum-based cytotoxic chemotherapy. However, therapeutic resistance and recurrence is a common eventuality for nearly all ovarian cancer patients, resulting in poor median survival. Recurrence is postulated to be driven by a population of self-renewing, therapeutically resistant cancer stem cells (CSCs). A current limitation in CSC studies is the inability to interrogate their dynamic changes in real time. Here we utilized a GFP reporter driven by the NANOG-promoter to enrich and track ovarian CSCs. Using this approach, we identified a population of cells with CSC properties including enhanced expression of stem cell transcription factors, self-renewal, and tumor initiation. We also observed elevations in CSC properties in cisplatin-resistant ovarian cancer cells as compared to cisplatin-naïve ovarian cancer cells. CD49f, a marker for CSCs in other solid tumors, enriched CSCs in cisplatin-resistant and -naïve cells. NANOG-GFP enriched CSCs (GFP+ cells) were more resistant to cisplatin as compared to GFP-negative cells. Moreover, upon cisplatin treatment, the GFP signal intensity and NANOG expression increased in GFP-negative cells, indicating that cisplatin was able to induce the CSC state. Taken together, we describe a reporter-based strategy that allows for determination of the CSC state in real time and can be used to detect the induction of the CSC state upon cisplatin treatment. As cisplatin may provide an inductive stress for the stem cell state, future efforts should focus on combining cytotoxic chemotherapy with a CSC targeted therapy for greater clinical utility.
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