Research Papers:

Fractionation of a tumor-initiating UV dose introduces DNA damage-retaining cells in hairless mouse skin and renders subsequent TPA-promoted tumors non-regressing

Gerline van de Glind _, Heggert Rebel, Marika van Kempen, Kees Tensen and Frank de Gruijl

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:8067-8077. https://doi.org/10.18632/oncotarget.6932

Metrics: PDF 1144 views  |   HTML 2621 views  |   ?  


Gerline van de Glind1, Heggert Rebel1, Marika van Kempen1, Kees Tensen1, Frank de Gruijl1

1Department of Dermatology, LUMC, Leiden, 2333RC, The Netherlands

Correspondence to:

Gerline van de Glind, e-mail: [email protected]

Frank de Gruijl, e-mail: [email protected]

Keywords: UV carcinogenesis, dose fractionation, CPD retaining basal cells, hyperkeratotic tumors

Received: August 17, 2015    Accepted: January 07, 2016    Published: January 18, 2016


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 ≥4mm/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.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 6932