Recent studies have demonstrated that cancer stem cells play an important role in the pathobiology of
head and neck squamous cell carcinomas (
HNSCC). However, little is known about functional interactions between
head and neck cancer stem-like cells (CSC) and surrounding stromal cells. Here, we used
aldehyde dehydrogenase activity and CD44 expression to sort putative stem cells from primary human
HNSCC. Implantation of 1,000 CSC (ALDH+CD44+Lin-) led to
tumors in 13 (out of 15) mice, whereas 10,000 noncancer stem cells (ALDH-CD44-Lin-) resulted in 2
tumors in 15 mice. These data demonstrated that ALDH and CD44 select a subpopulation of cells that are highly tumorigenic. The ability to self-renew was confirmed by the observation that ALDH+CD44+Lin- cells sorted from human
HNSCC formed more spheroids (orospheres) in 3-D
agarose matrices or ultra-low attachment plates than controls and were serially passaged in vivo. We observed that approximately 80% of the CSC were located in close proximity (within 100-μm radius) of blood vessels in human
tumors, suggesting the existence of perivascular niches in
HNSCC. In vitro studies demonstrated that endothelial cell-secreted factors promoted self-renewal of CSC, as demonstrated by the upregulation of Bmi-1 expression and the increase in the number of orospheres as compared with controls. Notably, selective ablation of
tumor-associated endothelial cells stably transduced with a
caspase-based artificial death switch (iCaspase-9) caused a marked reduction in the fraction of CSC in xenograft
tumors. Collectively, these findings indicate that endothelial cell-initiated signaling can enhance the survival and self-renewal of head and neck CSC.