Cisplatin induces stemness in ovarian cancer.

Andrew Wiechert,Nikhil Gupta,Justin D Lathia,Analisa Difeo,James S Hale,Praveena S Thiagarajan,Caner Saygin,Masahiro Hitomi,Anil Belur Nagaraj,Vinay S Rao,Ofer Reizes

doi:10.18632/oncotarget.8852

Andrew Wiechert, Nikhil Gupta + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.8852

Copy DOI

Abstract

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.

Highlights

Ovarian cancer is the most lethal gynecological malignancy in the United States [1]
Leveraging our previous success in the enrichment of cancer stem cells (CSCs) in triple-negative breast cancer using a NANOG promoter-driven green fluorescence protein (GFP) reporter system [25], we applied this to ovarian cancer cell lines
We introduced the reporter into cisplatin-naïve high-grade serous ovarian cancer (HGSOC) patient-derived xenograft (PDX), OV81

Summary

Introduction

Ovarian cancer is the most lethal gynecological malignancy in the United States [1]. Over the past three decades, advances in cytotoxic chemotherapy have allowed a subset of patients to survive for 3–5 years [1]. While initial treatment with taxane-platinum combination chemotherapy and debulking surgery allows eighty percent of patients to achieve clinical remission, the vast majority of these patients recur with a median time to recurrence of 12–24 months [2, 3]. The remaining twenty percent of patients fail initial treatment, with progression of disease either during or within the first six months following chemotherapy. Relapsed ovarian cancer is universally incurable and current standard of care is cytotoxic chemotherapy with symptomatic management [4]. Data from large genetic analyses, including The Cancer Genome Atlas, has demonstrated that epithelial ovarian cancer is a genetically heterogeneous disease, and has failed to identify targetable driver gene mutations for www.impactjournals.com/oncotarget the majority of patients [5]. An alternative strategy must be employed to define signaling pathways which may be targeted to either enhance chemotherapeutic response by synthetic lethality, or render otherwise chemo-resistant cells susceptible to currently used drugs such as platinum or taxanes

Methods

Results

Conclusion