Distinct Subpopulations of Head and Neck Cancer Cells with Different Levels of Intracellular Reactive Oxygen Species Exhibit Diverse Stemness, Proliferation, and Chemosensitivity

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 21; pp. 6291 - 6305
• Main Authors: Chang, Ching-Wen, Chen, Yu-Syuan, Chou, Shiu-Huey, Han, Chia-Li, Chen, Yu-Ju, Yang, Cheng-Chieh, Huang, Chih-Yang, Lo, Jeng-Fan
• Format: Journal Article
• Language: English
• Published: United States 01.11.2014
• Subjects: Animals; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Differentiation - drug effects; Cell Line, Tumor; Cell Proliferation - genetics; Cisplatin - administration & dosage; Cytoplasm - drug effects; Cytoplasm - metabolism; Drug Resistance, Neoplasm - genetics; Epithelial-Mesenchymal Transition - genetics; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Humans; Mice; Neoplastic Stem Cells - metabolism; Reactive Oxygen Species - metabolism; Signal Transduction - genetics; Squamous Cell Carcinoma of Head and Neck
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-14-0626

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 (ROSLow) is known to help sustain stemness properties. In this report, we evaluated the hypothesis that ROSLow character conferred CIC properties in HNSCC. Sphere cultures define CIC in HNSCC cell populations (HN-CIC). We found that ROSLow cells in HN-CIC defined in this manner were more numerous than in parental HNSCC cells. Further, ROSLow 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 ROSLow 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. Cancer Res; 74(21); 6291–305. ©2014 AACR.