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

Craig D. Woodworth, Evan Michael, Laura Smith, Kinnimulki Vijayachandra, Adam Bleier Glick, Henry Hennings, Stuart H. Yuspa

Research output: Contribution to journalArticle

51 Citations (Scopus)

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 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 with 46% for SENCARA/Pt-derived cells and < 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 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.

Original languageEnglish (US)
Pages (from-to)1771-1778
Number of pages8
JournalCarcinogenesis
Volume25
Issue number9
DOIs
StatePublished - Sep 1 2004

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Keratinocytes
Skin
Neoplasms
Human papillomavirus 16
Papilloma
Inbred C57BL Mouse
Carcinogens
Penetrance
Retroviridae
Nude Mice
Squamous Cell Carcinoma
Carcinogenesis
Carcinoma
Cell Line
Incidence
Infection
Genes

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Woodworth, Craig D. ; Michael, Evan ; Smith, Laura ; Vijayachandra, Kinnimulki ; Glick, Adam Bleier ; Hennings, Henry ; Yuspa, Stuart H. / Strain-dependent differences in malignant conversion of mouse skin tumors is an inherent property of the epidermal keratinocyte. In: Carcinogenesis. 2004 ; Vol. 25, No. 9. pp. 1771-1778.
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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 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 with 46{\%} for SENCARA/Pt-derived cells and < 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 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.",
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Strain-dependent differences in malignant conversion of mouse skin tumors is an inherent property of the epidermal keratinocyte. / Woodworth, Craig D.; Michael, Evan; Smith, Laura; Vijayachandra, Kinnimulki; Glick, Adam Bleier; Hennings, Henry; Yuspa, Stuart H.

In: Carcinogenesis, Vol. 25, No. 9, 01.09.2004, p. 1771-1778.

Research output: Contribution to journalArticle

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