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.
Highlights
Emerging evidence supports the hierarchical model of cancer-initiating cells [CIC; referred to as cancer stemNote: Supplementary data for this article are available at Cancer Research Online.C.-W
Compared with parental Head and neck squamous cell carcinoma (HNSCC), we observed that a subpopulation of cells with low intracellular level of Reactive oxygen species (ROS) was significantly increased in head and neck CICs (HN-CIC)
Patients with HNSCC are still very likely to relapse within months after therapy [37] that may be because conventional treatments cannot efficiently eliminate CICs, which are involved in the tumor progression, metastasis, and chemo/ radio resistance [2]
Summary
Emerging evidence supports the hierarchical model of cancer-initiating cells [CIC; referred to as cancer stemNote: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).C.-W. Emerging evidence supports the hierarchical model of cancer-initiating cells [CIC; referred to as cancer stem. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Cells (CSC)], in that, each tumor formation is generated from a distinct subset of cells with characteristics of self-renewal and differentiation capacity [1]. Conventional chemotherapeutics generally affect proliferative cells, potentially eliminate proliferating cancer cells but do not target slow dividing cells [2]. Like normal tissue stem cells, CICs exhibit quiescent slow-cycling phenotype [3]. CICs have been shown to be involved in tumor progression, cancer recurrence, and metastasis because of their therapeutic resistance [4, 5]. To uncover the regulatory physiologic mechanisms that sustain the slowgrowing CICs warrants an important study for future therapy development
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