Carcinogenesis Advance Access published online on October 21, 2004
Carcinogenesis, doi:10.1093/carcin/bgh300
© 2004 by Oxford University Press
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1 Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA
* To whom correspondence should be addressed. 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 mousse with reduced apoptosis 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 to 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 wks 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=4x10-6). As predicted, this effect was reversed for clones growing by clonal expansion, which were rarer in Tg skin by 1.7-fold (p=.047). At 10 wks, large expanding Tg clones were rarer by a magnitude approaching the apoptosis differential (
Revised September 23, 2004
Accepted September 27, 2004
CARCINOGENESIS
UVB-induced apoptosis drives clonal expansion during skin tumor development
2 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
3 Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
4 Department of Dermatology, University of Utah, Salt Lake City, UT 84132, USA
5 Department of Dermatology, University of Utah, Salt Lake City, UT 84132, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
6 Department of Dermatology, University of Utah, Salt Lake City, UT 84132, USA; Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
Douglas Grossman, E-mail: doug.grossman{at}hci.utah.edu
Abstract 
2-fold, p=4x10-5). Survivin expression also retarded clonal expansion at later stages of tumor development. By 20 wks, 95% of animals carried tumors (primarily papillomas), which were 1.6-fold rarer in apoptosis-defective Tg mice (p=.03). By contrast, the rate of tumors attaining large size (
3 mm, p=.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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