Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels

Hong Sun Kim, Yu Chih Chen, Felipe Nör, Kristy A. Warner, April Andrews, Vivian P. Wagner, Zhaocheng Zhang, Zhixiong Zhang, Manoela D. Martins, Alexander T. Pearson, Euisik Yoon, Jacques E. Nör

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)100339-100352
Number of pages14
Issue number59
Publication statusPublished - 2017

Bibliographical note

Funding Information:
This work was funded by grant P50-CA-97248 (University of Michigan Head and Neck SPORE), and grants R01-DE23220 and R01-DE21139 from the NIH/ NIDCR (JEN).

Publisher Copyright:
© Kim et al.

All Science Journal Classification (ASJC) codes

  • Oncology


Dive into the research topics of 'Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels'. Together they form a unique fingerprint.

Cite this