Research Papers:
Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels
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Abstract
Hong Sun Kim1, Yu-Chih Chen2,6, Felipe Nör1,3, Kristy A. Warner1, April Andrews1, Vivian P. Wagner3,4, Zhaocheng Zhang1, Zhixiong Zhang2, Manoela D. Martins3,4, Alexander T. Pearson1,5,6, Euisik Yoon2,7 and Jacques E. Nör1,6,7,8
1Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA
2Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI, USA
3Department of Oral Pathology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
4Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA
5Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA
6Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA
7Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA
8Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, MI, USA
Correspondence to:
Jacques E. Nör, email: [email protected]
Keywords: cancer stem cells; epithelial-mesenchymal transition; migration; head and neck squamous cell carcinoma; metastasis
Received: August 11, 2017 Accepted: October 13, 2017 Published: November 01, 2017
ABSTRACT
Recent evidence suggests that the metastatic spread of head and neck squamous cell carcinomas (HNSCC) requires the function of cancer stem cells endowed with multipotency, self-renewal, and high tumorigenic potential. We demonstrated that cancer stem cells reside in perivascular niches and are characterized by high aldehyde dehydrogenase (ALDH) activity and high CD44 expression (ALDHhighCD44high) in HNSCC. Here, we hypothesize that endothelial cell-secreted interleukin-6 (IL-6) contributes to tumor progression by enhancing the migratory phenotype and survival of cancer stem cells. Analysis of tissue microarrays generated from the invasive fronts of 77 HNSCC patients followed-up for up to 11 years revealed that high expression of IL-6 receptor (IL-6R) (p=0.0217) or co-receptor gp130 (p=0.0422) correlates with low HNSCC patient survival. We observed that endothelial cell-secreted factors induce epithelial to mesenchymal transition (EMT) and enhance invasive capacity of HNSCC cancer stem cells. Conditioned medium from CRISPR/Cas9-mediated IL-6 knockout primary human endothelial cells is less chemotactic for cancer stem cells in a microfluidics-based system than medium from control endothelial cells (p<0.05). Blockade of the IL-6 pathway with a humanized anti-IL-6R antibody (tocilizumab) inhibited endothelial cell-induced motility in vitro and decreased the fraction of cancer stem cells in vivo. Notably, xenograft HNSCC tumors vascularized with IL-6-knockout endothelial cells exhibited slower tumor growth and smaller cancer stem cell fraction. These findings demonstrate that endothelial cell-secreted IL-6 enhances the motility and survival of highly tumorigenic cancer stem cells, suggesting that endothelial cells can create a chemotactic gradient that enables the movement of carcinoma cells towards blood vessels.
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