Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF-β and integrin/focal adhesion kinase (FAK) signaling
- 13 June 2011
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 108 (26), 10544-10549
- https://doi.org/10.1073/pnas.1107807108
Abstract
Cancer stem cells (CSCs) sustain tumor growth through their ability to self-renew and to generate differentiated progeny. These functions endow CSCs with the potential to initiate secondary tumors bearing characteristics similar to those of the parent. Recently the hair follicle stem cell marker CD34 was used to purify a CSC-like cell population from early skin tumors arising from treatment with 7,12-dimethylbenz[α]anthracene/12-o-tetradecanoylphorbol-13-acetate, which typically generates benign papillomas that occasionally progress to squamous cell carcinomas (SCCs). In the present study, we identify and characterize CSCs purified from malignant SCCs. We show that SCCs contain two highly tumorigenic CSC populations that differ in CD34 levels but are enriched for integrins and coexist at the SCC–stroma interface. Intriguingly, whether CD34lo or CD34hi, α6hiβ1hi populations can initiate secondary tumors by serial limit-dilution transplantation assays, but α6loβ1lo populations cannot. Moreover, secondary tumors generated from a single CSC of either subtype contain both CD34lo and CD34hi α6hiβ1hiCSCs, indicating their nonhierarchical organization. Genomic profiling and hierarchical cluster analysis show that these two CSC subtypes share a molecular signature distinct from either the CD34− epidermal or the CD34hi hair follicle stem cell signature. Although closely related, α6hiβ1hiCD34lo and α6hiβ1hiCD34hi CSCs differ in cell-cycle gene expression and proliferation characteristics. Indeed, proliferation and expansion of α6hiβ1hiCD34hi CSCs is sensitive to whether they can initiate a TGF-β receptor II–mediated response to counterbalance elevated focal adhesion kinase-mediated integrin signaling within the tumor. Overall, the coexistence and interconvertibility of CSCs with differing sensitivities to their microenvironment pose challenges and opportunities for SCC cancer therapies.Keywords
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