期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 26, 页码 10544-10549出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1107807108
关键词
cancer stem cell signature; epithelial-mesenchymal interactions; skin cancer
资金
- New York State Department of Health [C023046]
- Bioimaging Resource Center
- Comparative Biology Center
- Emerald Foundation [R01-AR27883]
- National Institutes of Health [5K99-AR057260-02]
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[alpha] 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 CD34(Io) or CD34(hi), alpha 6(hi)beta 1(hi) populations can initiate secondary tumors by serial limitdilution transplantation assays, but alpha 6(io)beta 1(io) populations cannot. Moreover, secondary tumors generated from a single CSC of either subtype contain both CD34(Io) and CD34(hi) alpha 6(hi)beta 1(hi)CSCs, 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, alpha 6(hi)beta 1(hi)CD34(Io) and alpha 6(hi)beta 1(hi)CD34(hi) CSCs differ in cell-cycle gene expression and proliferation characteristics. Indeed, proliferation and expansion of alpha 6(hi)beta 1(hi)CD34(hi) CSCs is sensitive to whether they can initiate a TGF-beta 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.
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