title: Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes.
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.
authors.affiliation: Center for Biosciences and Department of Biosciences and Nutrition, Karolinska Institutet, Novum, 141 83 Huddinge, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Kasper
authors.forename: Viljar
authors.initials: V
authors.lastname: Jaks
authors.forename: Alexandra
authors.initials: A
authors.lastname: Are
authors.forename: Åsa
authors.initials: Å
authors.lastname: Bergström
authors.forename: Anja
authors.initials: A
authors.lastname: Schwäger
authors.forename: Jessica
authors.initials: J
authors.lastname: Svärd
authors.forename: Stephan
authors.initials: S
authors.lastname: Teglund
authors.forename: Nick
authors.initials: N
authors.lastname: Barker
authors.forename: Rune
authors.initials: R
authors.lastname: Toftgård
mesh_terms: D000818:Animals; D002280:Basal Cell Carcinoma / Q000473:pathology*; D004195:Disease Models, Animal; D006197:Hair / Q000166:cytology*; D015603:Keratinocytes / Q000166:cytology*; D051379:Mice; D008822:Mice, Transgenic; D012878:Skin Neoplasms / Q000473:pathology*; D014947:Wounds and Injuries / Q000473:pathology*