Endothelial Cell - Stem Cell Crosstalk in Head and Neck Cancer.

Abstract

Head and neck squamous cell carcinomas contain a sub-population of highly tumorigenic cells that exhibit self-renewal and multipotency. These cells can be isolated from primary head and neck squamous cell carcinomas using Aldehyde Dehydrogenase (ALDH) activity and CD44 expression, and have been named head and neck cancer stem cells (HNCSC). It has been proposed that the HNCSC are the “drivers” of head and neck tumor progression, and therefore have to be eliminated to achieve cancer cure. However, little is known about mechanisms underlying the survival and self-renewal of HNCSC. The hypothesis underlying this dissertation is that head and neck cancer stem cells (i.e. ALDH+CD44+) are localized in the perivascular niche and depend on endothelial cell-secreted factors for their survival and self-renewal. Here, we observed that HNCSC are found in close proximity to blood vessels in primary head and neck squamous cell carcinomas. Endothelial cell-secreted factors promoted the proliferation, self-renewal and survival of HNCSC in vitro, as evidenced by the increase in number of orospheres (i.e. non-adherent colonies of cells) formed in soft agar or ultra-low attachment plates. In vivo, selective ablation of tumor endothelial cells caused a marked decrease in the fraction of HNCSC suggesting that cancer stem cells depend on intact perivascular niches for their survival. In our search for a possible mechanism to explain the dependency of HNCSC on endothelial cells, we observed that cancer stem cells have a constitutively active IL-6R/STAT3 pathway, while tumor endothelial cells secrete high levels of IL-6. Inhibition of endothelial cell IL-6 caused a decrease in the self-renewal and tumorigenicity of the HNCSC. Notably, a humanized antibody to IL-6R delayed tumor initiation and decreased the survival of HNCSC in vivo. Collectively, these results unveil the endothelial cell-secreted factors as critical regulators of HNCSC survival and self-renewal, and suggest that patients with head and neck cancer might benefit from targeted therapies against cancer stem cells.