title: Distinct subpopulations of head and neck cancer cells with different levels of intracellular reactive oxygen species exhibit diverse stemness, proliferation, and chemosensitivity.
abstract: Head and neck squamous cell carcinoma (HNSCC) is driven by cancer-initiating cells (CIC), but their maintenance mechanisms are obscure. For hematopoietic stem cells, low levels of intracellular reactive oxygen species (ROS(Low)) is known to help sustain stemness properties. In this report, we evaluated the hypothesis that ROS(Low) character conferred CIC properties in HNSCC. Sphere cultures define CIC in HNSCC cell populations (HN-CIC). We found that ROS(Low) cells in HN-CIC defined in this manner were more numerous than in parental HNSCC cells. Further, ROS(Low) cells frequently coexpressed CIC surface markers such as memGrp78 and Glut3. Exploiting flow cytometry to sort cells on the basis of their ROS level, we found that isolated ROS(Low) cells displayed relatively more CIC properties, including quiescence, chemoresistance, in vitro malignant properties, and tumorigenicity. Pharmacological depletion of ROS modulators in cisplatin-treated HN-CIC reduced CIC properties, enhancing cell differentiation and enhancing cisplatin-induced cell death. Overall, our work defined cell subpopulations in HNSCC on the basis of differential intracellular ROS levels, which associated with stemness and chemoresistance properties. On the basis of our findings, we suggest that strategies to promote intracellular ROS levels may heighten the efficacy of conventional chemotherapy used for HNSCC treatment.
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ching-Wen
authors.initials: CW
authors.lastname: Chang
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yu-Syuan
authors.initials: YS
authors.lastname: Chen
authors.affiliation: Department of Life Science, Fu-Jen University, New Taipei City, Taiwan.
authors.forename: Shiu-Huey
authors.initials: SH
authors.lastname: Chou
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Chia-Li
authors.initials: CL
authors.lastname: Han
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Yang
authors.affiliation: Graduate Institute of Chinese Medical Science and Institute of Medical Science, China Medical University, Taichung, Taiwan. Institute of Basic Medical Science, China Medical University, Taichung, Taiwan. Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan. jflo@ym.edu.tw cyhuang@mail.cmu.edu.tw.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan. Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan. Graduate Institute of Chinese Medical Science and Institute of Medical Science, China Medical University, Taichung, Taiwan. Genome Research Center, National Yang-Ming University, Taipei, Taiwan. Department of Dentistry, Taipei Veterans General Hospital, Taipei, Taiwan. National Yang-Ming University VGH Genome Research Center, Taipei, Taiwan. jflo@ym.edu.tw cyhuang@mail.cmu.edu.tw.
authors.forename: Jeng-Fan
authors.initials: JF
authors.lastname: Lo
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002945:Cisplatin / Q000008:administration & dosage; D003593:Cytoplasm / Q000187:drug effects* / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D017382:Reactive Oxygen Species; D002945:Cisplatin