Cancer Stem Cells in Squamous Cell Carcinoma Switch between Two Distinct Phenotypes That Are Preferentially Migratory or Proliferative

Abstract

Epithelial-to-mesenchymal transition (EMT) is an important driver of tumor invasion and metastasis, which causes many cancer deaths. Cancer stem cells (CSC) that maintain and initiate tumors have also been implicated in invasion and metastasis, but whether EMT is an important contributor to CSC function is unclear. In this study, we investigated whether a population of CSCs that have undergone EMT (EMT CSCs) exists in squamous cell carcinoma (SCC). We also determined whether a separate population of CSCs that retain epithelial characteristics (non-EMT CSCs) is also present. Our studies revealed that self-renewing CSCs in SCC include two biologically-distinct phenotypes. One phenotype, termed CD44 high ESA high , was proliferative and retained epithelial characteristics (non-EMT CSCs), whereas the other phenotype, termed CD44 high ESA low , was migratory and had mesenchymal traits characteristic of EMT CSCs. We found that non-EMT and EMT CSCs could switch their epithelial or mesenchymal traits to reconstitute the cellular heterogeneity which was characteristic of CSCs. However, the ability of EMT CSCs to switch to non-EMT character was restricted to cells that were also ALDH1 þ , implying that only ALDH1 þ EMT cells had the ability to seed a new epithelial tumor. Taken together, our findings highlight the identification of two distinct CSC phenotypes and suggest a need to define therapeutic targets that can eradicate both of these variants to achieve effective SCC treatment. Cancer Res; 71(15); 5317-26. Ó2011 AACR.

Excessive Hyaluronan Production Promotes Acquisition of Cancer Stem Cell Signatures through the Coordinated Regulation of Twist and the Transforming Growth Factor β (TGF-β)-Snail Signaling Axis

“…Biddle et al (39) demonstrated that self-renewing CSCs in squamous cell carcinoma contained two biologically distinct phenotypes as follows: a population of CSCs that had undergone EMT (EMT CSCs), and a separate population of CSCs that had retained their epithelial characteristics (non-EMT CSCs). Their experiments revealed that the EMT and non-EMT CSCs are switchable (39). We observed in this study that SP fractions of both Has2 ϩNeo and Has2 ⌬Neo cells contained a significant number of CD44 high /CD24 low cells.…”

Towards elucidating the connection between epithelial–mesenchymal transitions and stemness

“…Furthermore, recent studies show that the bipotent CSCs in breast and squamous cell carcinoma often co-express both epithelial and mesenchymal markers [54,55] (see detailed discussion in the electronic supplementary material, §5). These results support our prediction that hybrid E/M cells can gain stemness.…”

Effects of irradiation on radioresistance, HOTAIR and epithelial-mesenchymal transition/cancer stem cell marker expression in esophageal squamous cell carcinoma

“…Several studies have identified an association between CSCs and the EMT, with evidence suggesting that cells undergoing the EMT acquire stem cell-like traits (32)(33)(34). Furthermore, CSCs exhibit a mesenchymal-like appearance in immortalized, non-tumorigenic mammary epithelial cells and breast cancer (33).…”