Thapsigargin, a weak skin tumor promoter, alters the growth and differentiation of mouse keratinocytes in culture.
Thapsigargin (Tg), applied twice weekly to the backs of CD-1 mice initiated with 7,12-dimethylbenz[a]anthracene, promoted papillomas on the skin of approximately 50% of the mice. Tg alone induced papillomas in 10% of the mice. Although Tg and 12-O-tetradecanoylphorbol-13-acetate (TPA) are synergistic in a keratinocyte co-culture assay for promotion, skin tumor promotion by TPA was inhibited by co-treatment with Tg. Treatment of cultured keratinocytes with non-toxic doses of Tg increased the level of intracellular free Ca(2+)-induced stratification. Tg blocked expression of the spinous layer differentiation marker keratin 1 (K1), while inducing cornification, a marker of differentiation in the granular layer/stratum corneum. In medium with 1.4 mM Ca2+, Tg prolonged keratinocyte proliferation and selected foci of monolayer cells. A Tg-independent cell line, TK-1, was developed from a single dish in which foci continued to expand after Tg removal. Grafting TK-1 cells on to the backs of nude mice as part of a reconstituted skin resulted in the development of dysplastic papillomas with a high rate of progression to squamous cell carcinomas.
Lowry
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Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, MD 20892, USA.
Li
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Hennings
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D000818:Animals; D002118:Calcium / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D005260:Female; D006965:Hyperplasia; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D010641:Phenotype; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D013729:Terpenes / Q000633:toxicity*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D019284:Thapsigargin
D002273:Carcinogens; D013729:Terpenes; D019284:Thapsigargin; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium