Carcinogenesis Advance Access originally published online on October 21, 2004
Carcinogenesis 2005 26(1):249-257; doi:10.1093/carcin/bgh300
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Carcinogenesis vol.26 no.1 © Oxford University Press 2005; all rights reserved.
ARTICLE |
UVB-induced apoptosis drives clonal expansion during skin tumor development
1 Department of Therapeutic Radiology and Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA, 2 Huntsman Cancer Institute and 3 Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA and 4 Department of Dermatology, University of Utah, Salt Lake City, UT 84132, USA
5 To whom correspondence should be addressed at: Huntsman Cancer Institute, Suite 5243, 2000 Circle of Hope, Salt Lake City, UT 84112, USA. Tel: +1 801 581 4682; Fax: +1 801 585 0900; Email: doug.grossman{at}hci.utah.edu or douglas.brash{at}yale.edu
The mechanism by which a single mutant cell clonally expands is usually assumed to involve an additional mutation in a cell cycle regulatory gene. An alternative mechanism for driving clonal expansion is apoptosis, which might create vacant stem cell compartments that can be repopulated by mutant cells. This model predicts that in a mouse with reduced apoptotic capacity (i) more mutated cells will appear initially but (ii) these cells will expand into clones more slowly than in wild-type animals. To test this hypothesis for ultraviolet B (UVB)-induced skin carcinogenesis, we examined UVB-induced p53 mutant clones and tumors in a transgenic (Tg) mouse (K14-Survivin) with skin-specific expression of the apoptosis inhibitor Survivin. To limit the effects of Survivin on apoptosis, without affecting epidermal proliferation or differentiation, we used Survivin expression levels and UVB doses that resulted in a 2-fold reduction in keratinocyte apoptosis. After 5 weeks of chronic UVB irradiation, newly created p53 mutant keratinocyte clones (indicative of initial mutation frequency) were 1.4-fold more frequent in K14-Survivin mice (P = 4 x 10–6). As predicted, this effect was reversed for clones growing by clonal expansion, which were rarer in Tg skin by 1.7-fold (P = 0.047). At 10 weeks large expanding Tg clones were rarer by a magnitude approaching the apoptosis differential (
2-fold, P = 4 x 10–5). Survivin expression also retarded clonal expansion at later stages of tumor development. By 20 weeks 95% of animals carried tumors (primarily papillomas), which were 1.6-fold rarer in apoptosis-defective Tg mice (P = 0.03). In contrast, the rate of tumors attaining large size (
3 mm, P = 0.048) and converting to carcinoma was increased 2-fold in Tg mice. Thus, Survivin-regulated apoptosis appears to suppress two stages that involve new mutations, initiation and malignant conversion, yet drives clonal expansion of existing p53 mutant cells.
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