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      Generation and Characterisation of Cisplatin-Resistant Non-Small Cell Lung Cancer Cell Lines Displaying a Stem-Like Signature

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          Abstract

          Introduction

          Inherent and acquired cisplatin resistance reduces the effectiveness of this agent in the management of non-small cell lung cancer (NSCLC). Understanding the molecular mechanisms underlying this process may result in the development of novel agents to enhance the sensitivity of cisplatin.

          Methods

          An isogenic model of cisplatin resistance was generated in a panel of NSCLC cell lines (A549, SKMES-1, MOR, H460). Over a period of twelve months, cisplatin resistant (CisR) cell lines were derived from original, age-matched parent cells (PT) and subsequently characterized. Proliferation (MTT) and clonogenic survival assays (crystal violet) were carried out between PT and CisR cells. Cellular response to cisplatin-induced apoptosis and cell cycle distribution were examined by FACS analysis. A panel of cancer stem cell and pluripotent markers was examined in addition to the EMT proteins, c-Met and β-catenin. Cisplatin-DNA adduct formation, DNA damage (γH2AX) and cellular platinum uptake (ICP-MS) was also assessed.

          Results

          Characterisation studies demonstrated a decreased proliferative capacity of lung tumour cells in response to cisplatin, increased resistance to cisplatin-induced cell death, accumulation of resistant cells in the G0/G1 phase of the cell cycle and enhanced clonogenic survival ability. Moreover, resistant cells displayed a putative stem-like signature with increased expression of CD133+/CD44+cells and increased ALDH activity relative to their corresponding parental cells. The stem cell markers, Nanog, Oct-4 and SOX-2, were significantly upregulated as were the EMT markers, c-Met and β-catenin. While resistant sublines demonstrated decreased uptake of cisplatin in response to treatment, reduced cisplatin-GpG DNA adduct formation and significantly decreased γH2AX foci were observed compared to parental cell lines.

          Conclusion

          Our results identified cisplatin resistant subpopulations of NSCLC cells with a putative stem-like signature, providing a further understanding of the cellular events associated with the cisplatin resistance phenotype in lung cancer.

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          Most cited references34

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          Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells.

          Shinji Masui, Yuhki Nakatake, Yayoi Toyooka … (2007)
          The pluripotency of embryonic stem (ES) cells is thought to be maintained by a few key transcription factors, including Oct3/4 and Sox2. The function of Oct3/4 in ES cells has been extensively characterized, but that of Sox2 has yet to be determined. Sox2 can act synergistically with Oct3/4 in vitro to activate Oct-Sox enhancers, which regulate the expression of pluripotent stem cell-specific genes, including Nanog, Oct3/4 and Sox2 itself. These findings suggest that Sox2 is required by ES cells for its Oct-Sox enhancer activity. Using inducible Sox2-null mouse ES cells, we show that Sox2 is dispensable for the activation of these Oct-Sox enhancers. In contrast, we demonstrate that Sox2 is necessary for regulating multiple transcription factors that affect Oct3/4 expression and that the forced expression of Oct3/4 rescues the pluripotency of Sox2-null ES cells. These results indicate that the essential function of Sox2 is to stabilize ES cells in a pluripotent state by maintaining the requisite level of Oct3/4 expression.
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            Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment.

            Giulia Bertolini, Luca Roz, Paola Perego … (2009)
            The identification of lung tumor-initiating cells and associated markers may be useful for optimization of therapeutic approaches and for predictive and prognostic information in lung cancer patients. CD133, a surface glycoprotein linked to organ-specific stem cells, was described as a marker of cancer-initiating cells in different tumor types. Here, we report that a CD133+, epithelial-specific antigen-positive (CD133+ESA+) population is increased in primary nonsmall cell lung cancer (NSCLC) compared with normal lung tissue and has higher tumorigenic potential in SCID mice and expression of genes involved in stemness, adhesion, motility, and drug efflux than the CD133(-) counterpart. Cisplatin treatment of lung cancer cells in vitro resulted in enrichment of CD133+ fraction both after acute cytotoxic exposure and in cells with stable cisplatin-resistant phenotype. Subpopulations of CD133+ABCG2+ and CD133+CXCR4+ cells were spared by in vivo cisplatin treatment of lung tumor xenografts established from primary tumors. A tendency toward shorter progression-free survival was observed in CD133+ NSCLC patients treated with platinum-containing regimens. Our results indicate that chemoresistant populations with highly tumorigenic and stem-like features are present in lung tumors. The molecular features of these cells may provide the rationale for more specific therapeutic targeting and the definition of predictive factors in clinical management of this lethal disease.
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              Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer.

              Feng Jiang, Qi Qiu, Abha Khanna … (2009)
              Tumor contains small population of cancer stem cells (CSC) that are responsible for its maintenance and relapse. Analysis of these CSCs may lead to effective prognostic and therapeutic strategies for the treatment of cancer patients. We report here the identification of CSCs from human lung cancer cells using Aldefluor assay followed by fluorescence-activated cell sorting analysis. Isolated cancer cells with relatively high aldehyde dehydrogenase 1 (ALDH1) activity display in vitro features of CSCs, including capacities for proliferation, self-renewal, and differentiation, resistance to chemotherapy, and expressing CSC surface marker CD133. In vivo experiments show that the ALDH1-positive cells could generate tumors that recapitulate the heterogeneity of the parental cancer cells. Immunohistochemical analysis of 303 clinical specimens from three independent cohorts of lung cancer patients and controls show that expression of ALDH1 is positively correlated with the stage and grade of lung tumors and related to a poor prognosis for the patients with early-stage lung cancer. ALDH1 is therefore a lung tumor stem cell-associated marker. These findings offer an important new tool for the study of lung CSCs and provide a potential prognostic factor and therapeutic target for treatment of the patients with lung cancer.
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                Author and article information

                Contributors
                Pan-Chyr Yang: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2013
                Publication date (Electronic): 17 January 2013
                Volume: 8
                Issue: 1
                Electronic Location Identifier: e54193
                Affiliations
                [1 ]Thoracic Oncology, Institute of Molecular Medicine, Trinity Centre for Health Sciences St. James’s Hospital & Trinity College Dublin, Dublin, Ireland
                [2 ]Molecular Oncology Risk-Profile Evaluation (M.O.R.E.), Department of Medical Oncology, West German Cancer Centre, University Hospital Essen, Essen, Germany
                [3 ]Department of Cell Biology (Cancer Research), University Duisburg-Essen, Essen, Germany
                [4 ]Thoracic Medical Oncology, University of Leicester & Leicester University Hospitals, Leicester, United Kingdom
                [5 ]Institute of Health & Biomedical Innovation, Queensland University of Technology, Brisbane, Australia
                [6 ]Department of Histopathology, St. James’s Hospital & Trinity College Dublin, Dublin, Ireland
                National Taiwan University Hospital, Taiwan
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Provision of support and advice on cisplatin resistance: DR DF JJO. Reading of the Manuscript: JDO. Conceived and designed the experiments: MPB KJO. Performed the experiments: MPB. Analyzed the data: MPB ACH JT RAH JJO. Contributed reagents/materials/analysis tools: MPB SGG DF DR. Wrote the paper: MPB.

                Article
                Publisher ID: PONE-D-12-03628
                DOI: 10.1371/journal.pone.0054193
                PMC ID: 3547914
                PubMed ID: 23349823
                SO-VID: 4b8dd664-8832-4ded-8491-7dd8e9bc1c85
                Copyright statement: Copyright @ 2013
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 7 February 2012
                Date accepted : 10 December 2012
                Page count
                Pages: 20
                Funding
                The authors have no support or funding to report.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Genetics
                Subject: Cancer Genetics
                Subject: Molecular Cell Biology
                Subject: Cell Death
                Subject: Cell Division
                Subject: Medicine
                Subject: Oncology
                Subject: Cancer Treatment
                Subject: Chemotherapy and Drug Treatment
                Subject: Cancers and Neoplasms
                Subject: Lung and Intrathoracic Tumors
                Subject: Non-Small Cell Lung Cancer
                Subject: Basic Cancer Research

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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