Endothelial Interleukin-6 Defines the Tumorigenic Potential of Primary Human Cancer Stem Cells

Authors

  • Sudha Krishnamurthy,

    1. Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
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  • Kristy A. Warner,

    1. Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
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  • Zhihong Dong,

    1. Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
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  • Atsushi Imai,

    1. Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
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  • Carolina Nör,

    1. Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
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  • Brent B. Ward,

    1. Department of Oral and Maxillofacial Surgery, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
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  • Joseph I. Helman,

    1. Department of Oral and Maxillofacial Surgery, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
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  • Russell S. Taichman,

    1. Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
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  • Emily L. Bellile,

    1. Biostatistic Unit, University of Michigan Comprehensive Cancer Center; University of Michigan School of Medicine, Ann Arbor, Michigan, USA
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  • Laurie K. McCauley,

    1. Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
    2. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
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  • Peter J. Polverini,

    1. Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
    2. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
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  • Mark E. Prince,

    1. Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
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  • Max S. Wicha,

    1. Department of Internal Medicine/Oncology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
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  • Jacques E. Nör

    Corresponding author
    1. Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
    2. Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
    3. Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, Michigan, USA
    • Correspondence: Jacques E. Nör, D.D.S., Ph.D., Professor of Dentistry, Biomedical Engineering, Otolaryngology, University of Michigan, 1011 N. University Rm. 2309, Ann Arbor, Michigan 48109-1078, USA. Telephone: 734-936-9300; Fax: 734-936-1597; e-mail: jenor@umich.edu

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Abstract

Head and neck squamous cell carcinomas (HNSCC) contain a small subpopulation of stem cells endowed with unique capacity to generate tumors. These cancer stem cells (CSC) are localized in perivascular niches and rely on crosstalk with endothelial cells for survival and self-renewal, but the mechanisms involved are unknown. Here, we report that stromal interleukin (IL)−6 defines the tumorigenic capacity of CSC sorted from primary human HNSCC and transplanted into mice. In search for the cellular source of Interleukin-6 (IL-6), we observed a direct correlation between IL-6 levels in tumor-associated endothelial cells and the tumorigenicity of CSC. In vitro, endothelial cell-IL-6 enhanced orosphere formation, p-STAT3 activation, survival, and self-renewal of human CSC. Notably, a humanized anti-IL-6R antibody (tocilizumab) inhibited primary human CSC-mediated tumor initiation. Collectively, these data demonstrate that endothelial cell-secreted IL-6 defines the tumorigenic potential of CSC, and suggest that HNSCC patients might benefit from therapeutic inhibition of IL-6/IL-6R signaling. Stem Cells 2014;32:2845–2857

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