Endothelial Cell-Initiated Signaling Promotes the Survival and Self-Renewal of Cancer Stem Cells

Abstract

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 (ALDHþCD44þLinÀ) led to tumors in 13 (out of 15) mice, whereas 10,000 noncancer stem cells (ALDHÀCD44ÀLinÀ) 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 ALDHþCD44þLinÀ 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-mm 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 tumorassociated 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. Cancer Res; 70(23); 9969-78. Ó2010 AACR.

Akt-Activated Endothelium Constitutes the Niche for Residual Disease and Resistance to Bevacizumab in Ovarian Cancer

“…The concept that a physical niche protects tumor cells during drug treatment has also been suggested for the perivascular space within the tumors. Indeed, recent work has highlighted a tumor reinitiating cells along tumor vessels, suggesting that these locations have a predictive role in tumor sensitivity to treatment (43,44). Bissel group demonstrated that ECs and factors deposited within their surrounding basement membrane may be a prime player within the dormant niche and revealed that stable microvasculature constitutes a dormant niche, whereas sprouting neovasculature sparks micrometastatic outgrowth (45).…”

Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma: A Review

“…In head and neck tumors, the vast majority of the stem cells are found within a 100 microns radius of a blood vessel (Krishnamurthy et al, 2010). Using the SCID mouse model of human tumor angiogenesis (Nör et al, 2001), it was observed that specific ablation of tumor associated endothelial cells with an inducible Caspase-9 results in the decrease in the fraction of head and neck cancer stem cells (Krishnamurthy et al, 2010).…”

“…Using the SCID mouse model of human tumor angiogenesis (Nör et al, 2001), it was observed that specific ablation of tumor associated endothelial cells with an inducible Caspase-9 results in the decrease in the fraction of head and neck cancer stem cells (Krishnamurthy et al, 2010). It is becoming increasingly evident that the molecular crosstalk between HNSCC and endothelial cells is mutually relevant (Neiva et al, 2009;.…”

“…IL-6, CXCL8) enhance the migration of tumor cells and protect them against anoikis (Neiva et al, 2009). Notably, endothelial cell-secreted factors promote the survival and self-renewal of cancer stem cells in HNSCC via upregulation of Bmi-1 expression (Krishnamurthy et al, 2010).…”

“…Gene expression signatures in ALDH/CD44-sorted HNSCC cells demonstrated BMI-1, a known CSC marker, to be differentially overexpressed, and when knocked down, demonstrated reduced tumorigenesis (Krishnamurthy et al, 2010). Sun and Wang looked at CMET+ cells compared to CMET− and found increased tumorigenicity in a flank injections and found higher percentage of implantation in CMET+ cells compared to CD44+ cells and slightly lower than ALDH+ cells (Sun et al, 2011).…”