Targeting Head and Neck Cancer Stem Cells and Endothelial Cell Interaction.

[摘要] Tumor recurrence and loco-regional metastases are the major clinical challenges in the management of patients with head and neck squamous cell carcinoma (HNSCC). A subpopulation of cells, called cancer stem cells, has been identified in HNSCC and characterized as cells with uniquely high tumor-forming ability and resistance to conventional chemotherapies. Multiple reports have shown that head and neck cancer stem cells drive the metastatic process. How tumorigenic cells are displaced from the tumor ;;island”, travel through connective tissues, and get into blood vessels is still not well understood. We hypothesized that endothelial cell-secreted factors generate a chemotactic gradient that attracts head and neck cancer stem cells towards blood vessels. Head and neck cancer stem cells reside in perivascular niches. Close proximity between cancer stem cells and blood vessels may facilitate cancer stem cells to invade into the bloodstream and initiate metastasis. Our group previously has shown that endothelial cell-secreted factors, specifically interleukin-6 (IL-6), potentiate the self-renewal and tumorigenicity of head and neck cancer stem cells. Here, we assessed the role of endothelial cell-initiated IL-6 pathway activation in head and neck cancer stem cell motility. Endothelial cell-secreted IL-6 induced the expression of the mesenchymal marker Vimentin and epithelial-mesenchymal transition-activating transcription factor Snail in head and neck cancer stem cells. When endothelial cell-secreted IL-6 was inhibited, we observed decreased motility in head and neck cancer stem cells. Xenograft HNSCC tumors vascularized with IL-6 knockout human endothelial cells grew slower than tumors vascularized with control endothelial cells. Notably, tumors grown with IL-6 knockout endothelial cells had smaller fraction of cancer stem cells than those with control endothelial cells. In addition, anti-IL-6 receptor (IL-6R) antibody, tocilizumab, also decreased cancer stem cell population. Tissue microarray analysis of 80 HNSCC patient samples revealed that high IL-6R or its co-receptor gp130 expressions correlated with low patient survival. Taken together, these results highlight the contribution of endothelial cell secreted factors on the migratory behavior of head and neck cancer stem cell that ultimately result in dissemination of tumor cells. Further, we show the therapeutic potential of tocilizumab targeting cancer stem cells in head and neck cancer.

[发布机构] University of Michigan

[效力级别] Science (General)

[关键词] head and neck cancer stem cell and endothelial cell interaction;Science (General);Science;Cancer Biology