Carcinogenesis Advance Access published online on April 22, 2004
Carcinogenesis, doi:10.1093/carcin/bgh170
© 2004 by Oxford University Press
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1 Department of Biology, Clarkson University, Potsdam, NY 13699-5805
* To whom correspondence should be addressed. E-mail: woodworth{at}clarkson.edu.
The multistage evolution of squamous skin tumors induced by chemical or viral carcinogens on mice from different genetic backgrounds has been a valuable model to define low penetrance loci that determine cancer susceptibility or resistance. Susceptibility determinants are multigenic, stage specific, dependent on the carcinogenesis protocol, and in the case of initiating events, intrinsic properties of keratinocytes. In this study we examined the malignant conversion frequency of keratinocytes derived from FVB/N, inbred SENCARA/Pt, BALB/c, or C57BL/6 mouse strains that differ substantially in the frequency of progression from papilloma to carcinoma. Keratinocytes were cultured from newborn mice and tested in an in vitro malignant conversion assay induced by a chemical carcinogen or immortalized by infection with replication defective HPV-16 E6/E7 retroviruses and tested for malignancy by grafting immortalized cell lines to nude mice. In vitro, FVB/N keratinocytes were 10-fold more sensitive to chemically induced malignant conversion than keratinocytes from other strains, consistent with the known sensitivity of this strain to premalignant progression in vivo. The E6/E7 genes induced immortalization of keratinocytes from FVB/N, SENCARA/Pt, or C57BL/6 mice more efficiently than BALB/c, and HPV-16-immortalized FVB/N keratinocytes formed tumors more frequently (64%) than SENCARA/Pt (31%) BALB/c (1.9%) or C57BL/6 (2.5%). Furthermore, 78% of the tumors formed by FVB/N keratinocytes progressed to squamous carcinomas compared to 46% for SENCARA/Pt derived cells and less than 3% for the others. In F1 offspring of crosses from SENCARA/Pt and FVB/N mice, both the papilloma incidence and frequency of malignant conversion reflected the SENCARA/Pt parent indicating that predisposition to premalignant progression is not a dominant characteristic. This predisposition is an intrinsic property of the target keratinocytes and as such should be amenable to further study in isolated cells.
Revised April 8, 2004
Accepted April 9, 2004
CARCINOGENESIS
Strain dependent differences in malignant conversion of mouse skin tumors is an inherent property of the epidermal keratinocyte
2 Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892
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