Cisplatin induces stemness in ovarian cancer

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.

Stem Cell Factor-Based Identification and Functional Properties of In Vitro-Selected Subpopulations of Malignant Mesothelioma Cells

“…In the sorted murine RN5-SO high cells, besides Sox2 and Oct4 , the stem cell marker Nanog was also significantly increased (Figure S1F). A hallmark for putative MM and other tumor type-derived CSCs is their increased resistance toward chemotherapeutic drugs including cis-Pt, as also reported previously for ovarian cancer-derived CSCs (Wiechert et al., 2016). ZL55-SO and ZL55-SO-P2 cells were treated with cis-Pt concentrations ranging from 0.625 to 10 μM, and cell survival was assessed 5 days later (Figure 2A, left panel).…”

Platinum sensitivity of ovarian cancer cells does not influence their ability to induce M2‐type macrophage polarization

“…43 Continuous drug treatment caused not only the morphology shift from rounded epithelial-like to spindle-shaped mesenchymal-like cells, but also significant changes in gene expression profile. 11,50 The transcriptional adjustment may be a sign of chemotherapy adaptation, 54 These alterations may promote the early development of potentially less sensitive cancer cell sub-clones, which can be accountable for therapy failure. Consistently, A2780Cis and A2780Dox cells retained increased migratory capacity.…”

“…Therefore, even a single dose of the drug may cause a significant change toward activating EMT, CSC, MDR profile, as previously reported. 11,50 The transcriptional adjustment may be a sign of chemotherapy adaptation, 54 as seen in resistant and coresistant cells upon treatment with cisplatin. Together, the evidence for drug-induced cell plasticity and proliferation in A2780-derived cell lines provides a rationale for studying their role in tumor-stroma interplay and shaping of the tumor microenvironment.…”

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

“…Wnt signaling is tightly regulated by the stability, subcellular localization, and transcriptional activity of bcatenin supporting cancer stem cell (CSC) survival and chemoresistance (Condello, Morgan et al, 2015, Nagaraj, Joseph et al, 2015. Platinum treatment can, paradoxically, also enhance ovarian cancer 'stemness' (Wiechert, Saygin et al, 2016). Increased aldehyde dehydrogenase (ALDH) activity, arising from elevated expression of a family of cellular detoxifying enzymes, is a hallmark of ovarian CSCs (Raha, Wilson et al, 2014, Silva, Bai et al, 2011.…”