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PNAS 108 (10): 4099-4104

Copyright © 2011 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes

Maria Kaspera,1, Viljar Jaksa,b,1, Alexandra Area, Åsa Bergströma, Anja Schwägera, Jessica Svärda, Stephan Teglunda, Nick Barkerc,2, and Rune Toftgårda,3

aCenter for Biosciences and Department of Biosciences and Nutrition, Karolinska Institutet, Novum, 141 83 Huddinge, Sweden; bInstitute of Molecular and Cell Biology and Estonian Biocentre, University of Tartu, 51010 Tartu, Estonia; and c Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, 3584CT Utrecht, The Netherlands

Edited by Matthew P. Scott, Stanford University/Howard Hughes Medical Institute, Stanford, CA, and approved January 19, 2011 (received for review September 28, 2010)

Abstract: Chronic wounds and acute trauma constitute well-established risk factors for development of epithelial-derived skin tumors, although the underlying mechanisms are largely unknown. Basal cell carcinomas (BCCs) are the most common skin cancers displaying a number of features reminiscent of hair follicle (HF)-derived cells and are dependent on deregulated Hedgehog (Hh)/GLI signaling. Here we show, in a mouse model conditionally expressing GLI1 and in a model with homozygous inactivation of Ptch1, mimicking the situation in human BCCs, that the wound environment accelerates the initiation frequency and growth of BCC-like lesions. Lineage tracing reveals that both oncogene activation and wounding induce emigration of keratinocytes residing in the lower bulge and the nonpermanent part of the HFs toward the interfollicular epidermis (IFE). However, only oncogene activation in combination with a wound environment enables the participation of such cells in the initiation of BCC-like lesions at the HF openings and in the IFE. We conclude that, in addition to the direct enhancement of BCC growth, the tumor-promoting effect of the wound environment is due to recruitment of tumor-initiating cells originating from the neighboring HFs, establishing a link between epidermal wounds and skin cancer risk.

Key Words: Lgr5 • stem cells • wound healing • carcinogenesis


Freely available online through the PNAS open access option.

Author contributions: M.K., V.J., and R.T. designed research; M.K., V.J., A.A., Å.B., and A.S. performed research; J.S., S.T., and N.B. contributed new reagents/analytic tools; M.K., V.J., A.A., Å.B., A.S., and R.T. analyzed data; and M.K., V.J., and R.T. wrote the paper.

1M.K. and V.J. contributed equally to this work.

2Present address: Institute of Medical Biology, 8A Biomedical Grove, Immunos #06-06, Singapore 138648, Singapore.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1014489108/-/DCSupplemental.

3To whom correspondence should be addressed. E-mail: rune.toftgard{at}ki.se.


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