title: Endothelial interleukin-6 defines the tumorigenic potential of primary human cancer stem cells.
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.
authors: Angiogenesis Research Laboratory, Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA.
authors: Sudha
authors: S
authors: Krishnamurthy
authors: Kristy A
authors: KA
authors: Warner
authors: Zhihong
authors: Z
authors: Dong
authors: Atsushi
authors: A
authors: Imai
authors: Carolina
authors: C
authors: Nör
authors: Brent B
authors: BB
authors: Ward
authors: Joseph I
authors: JI
authors: Helman
authors: Russell S
authors: RS
authors: Taichman
authors: Emily L
authors: EL
authors: Bellile
authors: Laurie K
authors: LK
authors: McCauley
authors: Peter J
authors: PJ
authors: Polverini
authors: Mark E
authors: ME
authors: Prince
authors: Max S
authors: MS
authors: Wicha
authors: Jacques E
authors: JE
authors: Nör
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology*; D042783:Endothelial Cells / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000166:cytology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse
keywords: Angiogenesis; Perivascular niche; Self-renewal; Squamous cell carcinoma; Survival