Reference SummaryWoodworth CD, Carcinogenesis 2004 Sep;25(9):1771-8

Title

Strain-dependent differences in malignant conversion of mouse skin tumors is an inherent property of the epidermal keratinocyte.

Authors

Woodworth CD; Michael E; Smith L; Vijayachandra K; Glick A; Hennings H; Yuspa SH

Journal

Carcinogenesis

Volume

25

Issue

9

Year

2004

Pages

1771-8

Abstract

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 human papillomavirus type 16 (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 pre-malignant 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 with 46% for SENCARA/Pt-derived cells and <3% for the others. In F(1) 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 pre-malignant 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.

Links

J:91957 – MGI References
15105299 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
SENCAR Skin carcinoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
Skin

observed

BALB/c Skin carcinoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
Skin

observed

C57BL/6 Skin carcinoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
Skin

0

FVB/N Skin carcinoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
Skin

observed

SENCARA/PtJ Skin carcinoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
Skin

observed

(SENCARA/PtJ x FVB/N)F1 Skin carcinoma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
Skin

observed

SENCAR Skin papilloma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
Skin

observed

BALB/c Skin papilloma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
Skin

observed

C57BL/6 Skin papilloma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
Skin

observed

FVB/N Skin papilloma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
Skin

observed

SENCARA/PtJ Skin papilloma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
Skin

observed

(SENCARA/PtJ x FVB/N)F1 Skin papilloma
  • 12-O-tetradecanoylphorbol-13-acetate (TPA)
  • 7,12-dimethylbenz[a]anthracene (DMBA)
Skin

observed