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Focal transgene expression associated with papilloma development in v‐Ha‐ ras –transgenic TG.AC mice
Author(s) -
Hansen Laura A.,
Tennant Raymond
Publication year - 1994
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.2940090306
Subject(s) - biology , transgene , papilloma , genetically modified mouse , epidermis (zoology) , microbiology and biotechnology , stratum spinosum , immunohistochemistry , in situ hybridization , cancer research , pathology , gene expression , immunology , gene , biochemistry , medicine , genetics , stratum corneum , anatomy
Abstract The homozygous transgenic mouse line TG.AC contains a v‐Ha‐ ras transgene and rapidly develops epidermal papillomas in response to either wounding or treatment with tumor promoters such as 12‐ O ‐tetradecanoylphorbol‐13‐acetate (TPA). The transgenic v‐Ha‐ ras protein product was detected in all papillomas removed from TPA‐treated TG.AC mice but not in vehicle‐or TPA‐treated TG.AC skin without tumors. In situ hybridization demonstrated that focal expression of the transgene was limited to regions of papilloma development and further localized the expression of the transgene message to the epidermal component of the papillomas, with the strongest signal in the basal epidermoid cells. Cellular proliferation, as indicated by immunohistochemical staining for proliferating‐cell nuclear antigen (PCNA), was similarly localized primarily to basal epidermoid cells and, to a lesser extent, stratum spinosum cells in all papillomas analyzed. Cells that stained positively for PCNA were much more common in the papillomas than in the surrounding, normal‐appearing skin. The focal nature of papilloma development was also evidenced by protein kinase C activity and hyperplasia after TPA treatment. As early as 18 d after the start of TPA treatment, focal hyperplasias associated with the follicular epidermis were observed in TG.AC but not nontransgenic FVB/N skin; these hyperplasias were assumed to be the precursors of the epidermal papillomas. To explain the development of transgene‐expressing tumors from apparently transgene‐negative, normal‐appearing skin, we hypothesize that the papillomas arise from the clonal expansion of focal areas of epidermal cells that overexpress the transgene. We also propose that the TG.AC line is an excellent model for studying very early events in papillomagenesis. © 1994 Wiley‐Liss, Inc.