Identification and chemoresistance of cancer stem cells in HPV-negative oropharyngeal cancer

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Abstract

The underlying mechanisms of resistance to chemoradiotherapy of human papilloma virus (HPV)-negative patients with oropharyngeal cancer (OPC) remain unclear. The present study aimed to characterize cancer stem cells (CSC) of the HPV-negative OPC cell line in terms of chemotherapy resistance. CSCs were isolated through magnetic activated cell sorting using the CSC specific marker aldehyde dehydrogenase 1 antibody, and characterized by sphere formation capacity, immunofluorescence staining, and CSC marker expression. CSC response to cisplatin treatment was evaluated via XTT-assays. Spheres of CSCs of the HPV-negative UTSCC-60A cell line were highly dark holospheres. RNA expression levels of CSC markers OCT4, SOX2, Kruppel-like factor 4 and BMI1 were significantly higher in CSC. CSCs were significantly resistant to cisplatin treatment at various dosages compared with nonCSC. The present study suggested that the proportion of CSCs is very low in the tumor bulk, CSCs are resistant to cisplatin in HPV-negative OPC, which requires further investigation to define their mechanism.

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Drug Resistance Driven by Cancer Stem Cells and Their Niche

Marta Prieto-Vila, Ryou-u Takahashi, Wataru Usuba … (2017)

Drug resistance represents one of the greatest challenges in cancer treatment. Cancer stem cells (CSCs), a subset of cells within the tumor with the potential for self-renewal, differentiation and tumorigenicity, are thought to be the major cause of cancer therapy failure due to their considerable chemo- and radioresistance, resulting in tumor recurrence and eventually metastasis. CSCs are situated in a specialized microenvironment termed the niche, mainly composed of fibroblasts and endothelial, mesenchymal and immune cells, which also play pivotal roles in drug resistance. These neighboring cells promote the molecular signaling pathways required for CSC maintenance and survival and also trigger endogenous drug resistance in CSCs. In addition, tumor niche components such as the extracellular matrix also physically shelter CSCs from therapeutic agents. Interestingly, CSCs contribute directly to the niche in a bilateral feedback loop manner. Here, we review the recent advances in the study of CSCs, the niche and especially their collective contribution to resistance, since increasingly studies suggest that this interaction should be considered as a target for therapeutic strategies.

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Aldehyde dehydrogenase: its role as a cancer stem cell marker comes down to the specific isoform.

Paola Marcato, Cheryl Dean, Carman A. Giacomantonio … (2011)

Recent evidence suggests that enhanced aldehyde dehydrogenase (ALDH) activity is a hallmark of cancer stem cells (CSC) measurable by the aldefluor assay. ALDH1A1, one of 19 ALDH isoforms expressed in humans, was generally believed to be responsible for the ALDH activity of CSCs. More recently, experiments with murine hematopoietic stem cells, murine progenitor pancreatic cells, and human breast CSCs indicate that other ALDH isoforms, particularly ALDH1A3, significantly contribute to aldefluor positivity, which may be tissue and cancer specific. Therefore, potential prognostic application involving the use of CSC prevalence in tumor tissue to predict patient outcome requires the identification and quantification of specific ALDH isoforms. Herein we review the suggested roles of ALDH in CSC biology and the immunohistological studies testing the potential application of ALDH isoforms as novel cancer prognostic indicators.

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Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness.

Paul Szotek, Rafael Pieretti-Vanmarcke, Peter T Masiakos … (2006)

The recent identification of "side population" (SP) cells in a number of unrelated human cancers and their normal tissue sources has renewed interest in the hypothesis that cancers may arise from somatic stem/progenitor cells. The high incidence of recurrence attributable to multidrug resistance and the multiple histologic phenotypes indicative of multipotency suggests a stem cell-like etiology of ovarian cancer. Here we identify and characterize SP cells from two distinct genetically engineered mouse ovarian cancer cell lines. Differential efflux of the DNA-binding dye Hoechst 33342 from these cell lines defined a human breast cancer-resistance protein 1-expressing, verapamil-sensitive SP of candidate cancer stem cells. In vivo, mouse SP cells formed measurable tumors sooner than non-SP (NSP) cells when equal numbers were injected into the dorsal fat pad of nude mice. The presence of Mullerian Inhibiting Substance (MIS) signaling pathway transduction molecules in both SP and NSP mouse cells led us to investigate the efficacy of MIS against these populations in comparison with traditional chemotherapies. MIS inhibited the proliferation of both SP and NSP cells, whereas the lipophilic chemotherapeutic agent doxorubicin more significantly inhibited the NSP cells. Finally, we identified breast cancer-resistance protein 1-expressing verapamil-sensitive SPs in three of four human ovarian cancer cell lines and four of six patient primary ascites cells. In the future, individualized therapy must incorporate analysis of the stem cell-like subpopulation of ovarian cancer cells when designing therapeutic strategies for ovarian cancer patients.

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Author and article information

Journal

Journal ID (nlm-ta): Oncol Lett

Journal ID (iso-abbrev): Oncol Lett

Journal ID (publisher-id): OL

Title: Oncology Letters

Publisher: D.A. Spandidos

ISSN (Print): 1792-1074

ISSN (Electronic): 1792-1082

Publication date (Print): January 2020

Publication date (Electronic): 21 November 2019

Publication date PMC-release: 21 November 2019

Volume: 19

Issue: 1

Pages: 965-971

Affiliations

Department of Otorhinolaryngology-Head and Neck Surgery, Wakayama Medical University, Wakayama 641-8509, Japan

Author notes

Correspondence to: Professor Muneki Hotomi, Department of Otorhinolaryngology-Head and Neck Surgery, Wakayama Medical University, Kimiidera 811-1, Wakayama 641-8509, Japan, E-mail: mhotomi@ 123456wakayama-med.ac.jp

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Contributed equally

Article

Publisher ID: OL-0-0-11127

DOI: 10.3892/ol.2019.11127

PMC ID: 6924148

PubMed ID: 31897209

SO-VID: 2375dfea-7bb7-4a10-b1e8-3dba04431c9a

License:

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

History

Date received : 30 July 2019

Date accepted : 22 October 2019

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Identification and chemoresistance of cancer stem cells in HPV-negative oropharyngeal cancer

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Karger: Oncology

Most cited references 35

Drug Resistance Driven by Cancer Stem Cells and Their Niche

Aldehyde dehydrogenase: its role as a cancer stem cell marker comes down to the specific isoform.

Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness.

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