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

TLDR

Epithelial‑to‑mesenchymal transition drives tumor invasion and metastasis, and while cancer stem cells are linked to these processes, it is unclear whether EMT contributes to CSC function. The study aimed to determine whether squamous cell carcinoma contains both EMT‑positive and non‑EMT cancer stem cell populations. The authors identified two distinct CSC phenotypes in SCC—proliferative epithelial CD44highESAhigh cells and migratory mesenchymal CD44highESAlow cells—that can interconvert, but only ALDH1+ EMT cells can revert to epithelial form and seed new tumors, underscoring the need to target both variants. Published in Cancer Research, vol.

Abstract

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 CD44highESAhigh, was proliferative and retained epithelial characteristics (non-EMT CSCs), whereas the other phenotype, termed CD44highESAlow, 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+, implying that only ALDH1+ 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. ©2011 AACR.