Critical Events in Skin Tumor Promotion and Progression

  • Thomas J. Slaga
Part of the Basic Life Sciences book series (BLSC, volume 57)


Carcinogenesis in skin as well as other target tissues in a number of species has been shown to be a multistage process which can be divided into at least three major stages, initiation, promotion and progression. An important aspect of the multistage skin carcinogenesis is that it has suggested that both genetic and epigenetic mechanisms are important. Altered growth control and differentiation leading to a more embryonic phenotype appear to be critical consequences of the genetic and epigenetic changes.


Benzoyl Peroxide Mouse Skin Skin Tumor Dark Cell Mouse Epidermis 
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  1. 1.
    T. J. Slaga, S. M. Fischer, C. E. Weeks, A. J. P. Klein-Szanto, and J. Reiners, Studies on the mechanisms involved in multistage carcinogenesis in mouse skin, J. Cellular Bioch. 18:99–119 (1982).CrossRefGoogle Scholar
  2. 2.
    A. J. P. Klein-Szanto and T. J. Slaga, Numerical variation of dark cells in normal and chemically induced hyperplastic epidermis with age of animal and efficiency of tumor promoter, Cancer Res. 41:4437–4440 (1981).PubMedGoogle Scholar
  3. 3.
    E. Christophers, Cellular architecture of the stratum corneum, J. Invest. Dermatol. 56:165–169 (1981).CrossRefGoogle Scholar
  4. 4.
    I. C. Mackenzie, Relationship between mitosis and the ordered structure of the stratum corneum in mouse epidermis, Nature 226:653–655 (1970).PubMedCrossRefGoogle Scholar
  5. 5.
    F. Marks, Epidermal growth control mechanisms, hyperplasia, and tumor promotion in the skin, Cancer Res. 36:2636–2643 (1976).PubMedGoogle Scholar
  6. 6.
    R. J. Morris, S. M. Fischer, and T. J. Slaga, Evidence that a slowly cycling subpopulation of adult murine epidermal cells retains carcinogen, Cancer Res. 46:3061–3066 (1986).PubMedGoogle Scholar
  7. 7.
    T. J. Slaga and A. J. P. Klein-Szanto, Initiation-promotion versus complete skin carcinogenesis in mice: Importance of dark basal keratinocytes (stem cells), Cancer Investigation 1:425–436 (1983).PubMedCrossRefGoogle Scholar
  8. 8.
    T. J. Slaga, S. M. Fischer, C. E. Weeks, and A. J. P. Klein-Szanto, Cellular and biochemical mechanism of mouse skin tumor promoters, in: “Reviews in Biochemical Toxicology,” E. Hodgson, J. Bend, R. M. Philpot, eds., Elsevier North-Holland, Inc., New York 3:231–281 (1981).Google Scholar
  9. 9.
    T. G. O’Brien, R. C. Simsiman, and R. K. Boutwell, Induction of the polyarnine biosynthetic enzymes in mouse epidermis by tumor promoting agents, Cancer Res. 35:1662–1670 (1975).PubMedGoogle Scholar
  10. 10.
    R. A. Mufson, S. M. Fischer, A. K. Verma, G. L. Gleason, T. J. Slaga, and R. K. Boutwell, Effects of 12-0-tetradecanoylphorbol-13-acetate and mezerein on epidermal ornithine decarboxylase acrivity, isoproterenol-stimulated levels of cyclic adenosine 3′,5′-monophosphate, and induction of mouse skin tumors, Cancer Res. 39:4791–4795 (1979).PubMedGoogle Scholar
  11. 11.
    A. N. Raick, Cell proliferation and promoting action in skin carcinoenesis, Cancer Res. 34:920–926 (1974).PubMedGoogle Scholar
  12. 12.
    A. J. P. Klein-Szanto, S. M. Major, and T. J. Slaga, Induction of dark keratinocytes by 12-0-tetradecanoylphorbol-13-acetate and mezerein as an indicator of tumor promoting efficiency, Carcinogenesis 1:399–406 (1980).PubMedCrossRefGoogle Scholar
  13. 13.
    T. J. Slaga, Cellular and molecular mechanisms of tumour promotion, Cancer Surveys 2:595–612 (1983).Google Scholar
  14. 14.
    J. J. Reiners and T. J. Slaga, Effects of tumor promoters on the rate and commitment to terminal differentiation of subpopulations of murine keratinocytes, Cell 32:247–255 (1983).PubMedCrossRefGoogle Scholar
  15. 15.
    S. H. Yuspa, H. Hennings, M. Kulsease-Martin, and U. Lichti, The study of tumor promotion in a cell culture model for mouse skin, in: “Cocarcinogenesis and Biological Effects of Tumor Promoters,” pp. 217–230. E. Hecker, ed., Raven Press, New York (1982).Google Scholar
  16. 16.
    S. H. Yuspa and D. L. Morgan, Mouse skin cells resistant to terminal differentiation associated with initiation of carcinogenesis, Nature 293:72–74 (1981).PubMedCrossRefGoogle Scholar
  17. 17.
    P. Cerutti, I. Emerit, and P. Amstad, Membrane-mediated chromosomal damage, in: “Proc. of P and S Biomedical Sciences Symposium,” I. B. Weinstein and H. Vogel, eds., Academic Press, New York (in press).Google Scholar
  18. 18.
    A. Varshavsky, Phorbol ester dramatically increases incidence of methotrexate-resistant mouse cells: Possible mechanisms and relevance to tumor promotion, Cell 25:561–572 (1981).PubMedCrossRefGoogle Scholar
  19. 19.
    J. M. Parry, E. M. Parry, and J. C. Barrett, Tumor promoters induce mitotic aneuploidy in yeast, Nature 294:263–265 (1981).PubMedCrossRefGoogle Scholar
  20. 20.
    P. B. Fischer and I. B. Weinstein, Chemical viral interactions and multistep aspects of cell transformation, in: “Molecular and Cellular Aspects of Carcinogen Screening Tests,” R. Montesano, H. Bartsh, and L. Tomatis, eds., IARC Scientific Publications, Lyon, France (1980).Google Scholar
  21. 21.
    N. H. Colburn, B. F. Former, K. A. Nelson, and S. H. Yuspa, Tumor promoter induces anchorage independence irreversibly, Nature 281:589–591 (1979).PubMedCrossRefGoogle Scholar
  22. 22.
    A. R. Kinsella and M. Radman, Tumor promoter induces sister chromatid exchanges: Relevance to mechanisms of carcinogenesis, Proc. Natl. Acad. Sci. USA 75:6149–6153 (1978).PubMedCrossRefGoogle Scholar
  23. 23.
    A. J. P. Klein-Szanto, R. G. Nelson, Y. Shah, and T. J. Slaga, Keratin modifications and GGT activity as indication of tumor progression in skin papillomas, J. Natl. Cancer Inst. 70:161–168 (1983).PubMedGoogle Scholar
  24. 24.
    K. G. Nelson, K. B. Stephenson, and T. J. Slaga, Protein modification induced in mouse epidermis by potent and weak tumor-promoting hyperplasiogenic agents, Cancer Res. 42:4164–4174 (1982).PubMedGoogle Scholar
  25. 25.
    A. Balmain, M. Ramsden, G. T. Bowden, and J. Smith, Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas, Nature 307:658–660 (1984).PubMedCrossRefGoogle Scholar
  26. 26.
    A. Balmain, and I. D. Pragnell, Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ras oncogene, Nature 303:72–74 (1983).PubMedCrossRefGoogle Scholar
  27. 27.
    J. C. Pelling, D. C. Hixson, R. S. Nairn, and T. J. Slaga, Altered gene expression during two-stage tumorigenesis in SENCAR mouse skin (abstract), Proc. Amer. Assoc. Cancer Res. 25:78 (1984).Google Scholar
  28. 28.
    G. J. Patskan, J. C. Pelling, R. S. Nairn, and T. J. Slaga, Altered oncogene expression in mouse skin squamous cell carcinomas, presented at the Pennsylvania State University Fourth Summer Symposium in Molecular Biology (1985).Google Scholar
  29. 29.
    H. Hennings, R. Shores, M. L. Wenk, E. F. Spangler, R. Tarone, and S. H. Yuspa, Malignant conversion of mouse skin tumours is increased by tumour initiators and unaffected by tumour promoters, Nature 304:67–69 (1983).PubMedCrossRefGoogle Scholar
  30. 30.
    J. F. O’Connell, A. J. P. Klein-Szanto, D. M. DiGiovanni, J. W. Fries, and T. J. Slaga, Malignant progression of mouse skin papillomas treatd with ethylnitrosourea, N-methyl-N′-nitrosoguanidine or 12-0-tetradecanoylphorbol-13-acetate, Cancer Letters 30:269 (1986).PubMedCrossRefGoogle Scholar
  31. 31.
    J. F. O’Connell, A. J. P. Klein-Szanto, J. M. DiGiovanni, J. W. Fries, and T. J. Slaga, Enhanced malignant progression of mouse skin tumors by the free-radical generator benzoyl peroxide, Cancer Res. 46:2863–2865 (1986).PubMedGoogle Scholar
  32. 32.
    J. B. Rotstein, J. F. O’Connell, and T. J. Slaga, The enhanced progression of papillomas to carcinomas by peroxides in the 2-stage mouse skin model, Proc. Am. Assoc. Cancer Res. 27:143 (1986).Google Scholar
  33. 33.
    J. B. Rotstein and T. J. Slaga, Effect of exogenous glutathione on tumor progression in the murine skin multistage carcinogenesis model, Carcinogenesis 9:1547–1551 (1988).PubMedCrossRefGoogle Scholar
  34. 34.
    J. B. Rotstein, J. F. O’Connell, and T. J. Slaga, A possible role for free radicals in tumor progression, in: “Anticarcinogenesis and Radiation Protection,” pp. 211–219. P. A. Cerrutti, O. F. Nygaard, and M. G. Simic, Plenum Publishing Corp, New York (1987).Google Scholar
  35. 35.
    C. M. Aldaz, C. J. Conti, A. J. P. Klein-Szanto, and T. J. Slaga, Progressive dysplasia and aneuploidy are hallmarks of mouse skin papillomas: Relevance to malignancy, Proc. Natl. Acad. Sci. USA 84:2029–2032 (1987).PubMedCrossRefGoogle Scholar
  36. 36.
    C. M. Aldaz, D. Trono, F. Larcher, T. J. Slaga, and C. Conti, Sequential trisomization of chromosomes 6 and 7 in mouse skin premalignant lesions, Molecular Carcinogenesis (in press) (1989).Google Scholar
  37. 37.
    C. J. Conti, C. M. Aldaz, J. O’Connell, A. J. P. Klein-Szanto, and T. J. Slaga, Aneuploidy, an early event in mouse skin tumor development, Carcinogenesis 7:1845–1848 (1986).PubMedCrossRefGoogle Scholar
  38. 38.
    A. J. P. Klein-Szanto, Morphological evaluation of tumor promoter effects on mammalian skin, in: “Mechanisms of Tumor Promotion,” Vol. II, T. J. Slaga, ed., CRC Press, Boca Raton (1984).Google Scholar
  39. 39.
    M. D. Mamrack, A. J. P. Klein-Szanto, J. J. Reiners, Jr., and T. J. Slaga, Alteration in the distribution of the epidermal protein filaggrin during two stage chemical carcinogenesis in the SENCAR mouse skin, Cancer Res. 44:2634–2641 (1984).PubMedGoogle Scholar
  40. 40.
    V. L. Wilson, and P. A. Jones, Inhibition of DNA methylation by chemical carcinogens in vitro, Cell 32:239–246 (1983).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Thomas J. Slaga
    • 1
  1. 1.M. D. Anderson Cancer Center, Science Park-Research Division, Department of CarcinogenesisThe University of TexasSmithvilleUSA

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