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Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes

PNAS, 8 March 2011
Vol. 108, Issue 10, p. 4099-4104
DOI: 10.1073/pnas.1014489108

Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes

  1. Maria Kaspera,1,
  2. Viljar Jaksa,b,1,
  3. Alexandra Area,
  4. Åsa Bergströma,
  5. Anja Schwägera,
  6. Jessica Svärda,
  7. Stephan Teglunda,
  8. Nick Barkerc,2, and
  9. Rune Toftgårda,3
  1. aCenter for Biosciences and Department of Biosciences and Nutrition, Karolinska Institutet, Novum, 141 83 Huddinge, Sweden;
  2. bInstitute of Molecular and Cell Biology and Estonian Biocentre, University of Tartu, 51010 Tartu, Estonia; and
  3. cHubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, 3584CT Utrecht, The Netherlands
  1. 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.

  • Lgr5
  • stem cells
  • wound healing
  • carcinogenesis

Footnotes

  • 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.

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

  • 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.

Freely available online through the PNAS open access option.

Citation:

M. Kasper, V. Jaks, A. Are, Å. Bergström, A. Schwäger, J. Svärd, S. Teglund, N. Barker, and R. Toftgård, Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes. PNAS 108, 4099-4104 (2011).

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