title: Fractionation of a tumor-initiating UV dose introduces DNA damage-retaining cells in hairless mouse skin and renders subsequent TPA-promoted tumors non-regressing.
abstract: Sunburns and especially sub-sunburn chronic UV exposure are associated with increased risk of squamous cell carcinomas (SCCs). Here we focus on a possible difference in tumor initiation from a single severe-sunburn dose (on day 1, 21 hairless mice) and from an equal dose fractionated into very low sub-sunburn doses not causing any (growth-promoting) epidermal hyperplasia (40 days daily exposure, n=20). From day 47 all mice received 12-O-Tetradecanoylphorbol-13-acetate (TPA) applications (2x/wk) for 20 weeks to promote tumor development within the lifetime of the animals. After the sub-sunburn regimen sparse DNA damage-retaining basal cells (quiescent stem cells, QSCs) remained in the non-hyperplastic epidermis. These cells were forced to divide by TPA. After discontinuation of TPA tumors regressed and disappeared in the 'sunburn group' but persisted and grew in the 'sub-sunburn group' (0.06 vs 2.50 SCCs and precursors ≥4 mm/mouse after 280 days, p=0.03). As the tumors carried no mutations in p53, H/K/N-Ras and Notch1/2, these 'usual suspects' were not involved in the UV-driven tumor initiation. Although we could not selectively eliminate QSCs (unknown phenotype) to establish causality, our data suggest that forcing specifically DNA damage-retaining QSCs to divide--with high mutagenic risk--gives rise to persisting (mainly 'in situ') skin carcinomas.
authors.affiliation: Department of Dermatology, LUMC, Leiden, 2333RC, The Netherlands.
authors.forename: Gerline
authors.initials: G
authors.lastname: van de Glind
authors.affiliation: Department of Dermatology, LUMC, Leiden, 2333RC, The Netherlands.
authors.forename: Heggert
authors.initials: H
authors.lastname: Rebel
authors.affiliation: Department of Dermatology, LUMC, Leiden, 2333RC, The Netherlands.
authors.forename: Marika
authors.initials: M
authors.lastname: van Kempen
authors.affiliation: Department of Dermatology, LUMC, Leiden, 2333RC, The Netherlands.
authors.forename: Kees
authors.initials: K
authors.lastname: Tensen
authors.affiliation: Department of Dermatology, LUMC, Leiden, 2333RC, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: de Gruijl
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects*; D004817:Epidermis / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D005260:Female; D006965:Hyperplasia / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D009154:Mutation / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D002273:Carcinogens; D016159:Tumor Suppressor Protein p53; D013755:Tetradecanoylphorbol Acetate
keywords: CPD retaining basal cells; UV carcinogenesis; dose fractionation; hyperkeratotic tumors