Tumor Promotion: A Problem of Differential Responses of Normal and Neoplastic Cells to Trophic Stimuli

  • Stuart H. Yuspa
  • Henry Hennings
  • Takashi Sako
  • George R. Pettit
  • John Hartley
  • Peter M. Blumberg


Increased understanding of the tumor promotion phase of chemical carcinogenesis has resulted from the discovery of pure tumor promoting-agents and the development of animal models in which tumor promoters modify experimental carcinogenesis (1). Simultaneously, interest in this area of cancer research has been stimulated by epidemiological studies indicating that a promotion phase is important in the development of human cancer (2). Tumor promoters cause or allow the expression of the latent tumor phenotype induced in some cells by limited doses of carcinogens. Commonly, the model systems where tumor promotion plays an important role in neoplastic development are those involving epithelial tissues, in particular those composed of more than one cell type or cells in different states of maturation such as skin, breast and bronchus. As a classical model for carcinogenesis in a lining epithelium, mouse skin has provided most of the conceptual framework regarding the biology of tumor promotion (1,3).


Phorbol Ester Benzoyl Peroxide Tumor Promotion Mouse Skin Mouse Keratinocytes 
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  1. 1.
    T.J. Slaga, Mechanisms of Tumor Promotion, Vols. I, II, III, IV. CRC Press, Boca Raton, 1983.Google Scholar
  2. 2.
    S.H. Moolgavkar and A.G. Knudson, Mutation and cancer: A model for human carcinogenesis. J. Natl. Cancer Inst. 66, 1037–1052 (1981).PubMedGoogle Scholar
  3. 3.
    S.H. Yuspa, Cutaneous chemical carcinogenesis. J. Am. Acad. Dermatol. 15, 1031–1044 (1986).PubMedCrossRefGoogle Scholar
  4. 4.
    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 (London) 304, 67–69 (1983).CrossRefGoogle Scholar
  5. 5.
    T.L. Goldsworthy and H.C. Pitot, The quantitative analysis and stability of histochemical markers of altered hepatic foci in rat liver following initiation by diethyl nitrosamine administration and promotion with phenobarbital. Carcinogenesis 6, 1261–1269 (1985).PubMedCrossRefGoogle Scholar
  6. 6.
    W.K. Kaufman, S.A. Mackenzie, and D.G. Kaufman, Quantitative relationship between hepatocytic neoplasms and islands of cellular alteration during hepatocarcinogenesis in the male F344 rat. Am. J. Pathol. 119, 171–174 (1985).PubMedGoogle Scholar
  7. 7.
    P.M. Blumberg, In vitro studies on the mode of action of the phorbol esters, potent tumor promoters: part I. CRC Crit. Rev. Toxicol. 8, 153–197 (1980).CrossRefGoogle Scholar
  8. 8.
    K.L. Leach, M.L. James, and P.M. Blumberg, Characterization of a specific phorbol ester aporeceptor in mouse brain cytosol. Proc. Natl. Acad. Sci. USA 80, 4208–4212 (1983).PubMedCrossRefGoogle Scholar
  9. 9.
    C.L. Ashendel, The phorbol ester receptor: a phospholipid-regulated protein kinase. Biochim. Biophys. Acta. 822, 219–242 (1985).PubMedGoogle Scholar
  10. 10.
    Y. Nishizuka, Studies and perspectives of protein kinase C. Science 233, 305–312 (1986).PubMedCrossRefGoogle Scholar
  11. 11.
    S.H. Yuspa, H. Hennings, and U. Lichti, Initiator and promoter induced specific changes in epidermal function and biological potential. J. Cell Biochem. 17, 245–257 (1981).Google Scholar
  12. 12.
    S.H. Yuspa, T. Ben, H. Hennings, and U. Lichti, Divergent responses in epidermal basal cells exposed to the tumor promoter 12-0-tetradecanoyl phorbol-13-acetate. Cancer Res. 42, 2344–2349 (1982).PubMedGoogle Scholar
  13. 13.
    J.A. Dunn and P.B. Blumberg, Specific binding of [20–3H]12-deoxyphorbol 13-isobutyrate to phorbol ester receptor subclasses in mouse skin particulate preparations. Cancer Res. 43, 4632–4637 (1983).PubMedGoogle Scholar
  14. 14.
    J.A. Dunn, A.Y. Jeng, S.H., Yuspa, and P.B. Blumberg, Heterogeneity of [3H]phorbol 12,13 dibutyrate binding in primary mouse keratinocytes at different stages of maturation. Cancer Res. 5540–5546 (1985).Google Scholar
  15. 15.
    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
  16. 16.
    T.S. Argyris, Regeneration and the mechanism of epidermal tumor promotion. CRC Crit. Rev. Toxicol. 14, 211–258 (1985).CrossRefGoogle Scholar
  17. 17.
    S.H. Yuspa, D. Morgan, U. Lichti, E.F. Spangler, D. Michael, A. Kilkenny, and H. Hennings, Cultivation and characterization of cells derived from mouse skin papillomas induced by an initiation promotion protocol. Carcinogenesis 7, 949–958 (1986).PubMedCrossRefGoogle Scholar
  18. 18.
    H. Hennings, D. Michael, U. Lichti, and S.H. Yuspa, Response of carcinogen-altered mouse epidermal cells to phorbol ester tumor promoters and calcium. J. Invest. Dermatol. 88, 60–65 (1987).PubMedCrossRefGoogle Scholar
  19. 19.
    S.H. Yuspa and U. Lichti, Retinoids and skin carcinogenesis: a mechanism of anticarcinogenesis by the modulation of epidermal differentiation. In, Retinoids: New Trends in Research and Therapy (J.H. Saurat, Ed.), pp. 56–64. S. Karger AG, Basel, 1985.Google Scholar
  20. 20.
    T.J. Slaga, U. Lichti, H. Hennings, K. Elgjo, and S.H. Yuspa, Effects of tumor promoters and steroidal anti-inflammatory agents on skin of newborn mice in vivo and in vitro. J. Natl. Cancer Inst. 60, 425–431 (1978).PubMedGoogle Scholar
  21. 21.
    G.R. Pettit, C.L. Herald, D.L. Doubek, E. Arnold, and J. Clardy, Isolation and structure of bryostatin 1. J. Am. Chem. Soc. 104, 6846–6848 (1982).CrossRefGoogle Scholar
  22. 22.
    J.A. Smith, L. Smith, and G.R. Pettit, Bryostatins: potent, new mitogens that mimic phorbol ester tumor promoters. Biochem. Biophys, Res. Commun. 132, 939–945 (1985).CrossRefGoogle Scholar
  23. 23.
    A.S. Kraft, J.B. Smith, and R.L. Berkow, Bryostatin, an activator of the calcium phospholipid-dependent protein kinase, blocks phorbol ester-induced differentiation of human promyelocytic leukemia cells HL-60. Proc. Natl. Acad. Sci. USA 83, 1334–1338 (1986).PubMedCrossRefGoogle Scholar
  24. M.L. Dell’Aquila, H.T. Nguyen, C.L. Herald, G.R. Pettit and P.M. Blumberg, Bryostatin 1 inhibits phorbol ester-induced blockage of differentiation in hexamethylene bisacetamide-treated Friend erythroleukemia cells. Submitted.Google Scholar
  25. T. Sako, S.H. Yuspa, C.L. Herald, G.R. Pettit, and P.M. Blumberg, Bryostatin 1 both mimics and blocks effects of phorbol ester tumor promoters on primary mouse epidermal cells. Cancer Res., in press.Google Scholar
  26. H. Hennings, P.M. Blumberg, G.R. Pettit, C.L. Herald, R. Shores, and S.H. Yuspa, Bryostatin 1, an activator of protein kinase C, inhibits tumor promotion by phorbol esters in Senear mouse skin. Carcinogenesis, in press.Google Scholar
  27. 27.
    T.J. Slaga, A.J.P. Klein-Szanto, L.L. Triplett, and L.P. Yotti, Skin tumor-promoting activity of benzoyl peroxide, a widely used free radical-generating compound. Science 213, 1023–1025 (1981).PubMedCrossRefGoogle Scholar
  28. 28.
    A.J.P. Klein-Szanto and T.J. Slaga, Effects of peroxides on rodent skin: epidermal hyperplasia and tumor promotion. J. Invest. Dermatol. 79, 30–34 (1982).PubMedCrossRefGoogle Scholar
  29. 29.
    J.F. O’Connell, A.J.P. Klein-Szanto, D.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. 2863–2865 (1986).Google Scholar
  30. 30.
    J.A. Hartley, N.W. Gibson, L.A. Zwelling, and S.H. Yuspa, The association of DNA strand breaks with accelerated terminal differentiation in mouse epidermal cells exposed to tumor promoters. Cancer Res. 45, 4864–4870 (1985).PubMedGoogle Scholar
  31. J.A. Hartley, N.W. Gibson, A. Kilkenny, and S.H. Yuspa, Mouse keratinocytes derived from initiated skin or papillomas are resistant to DNA strand breakage by benzoyl peroxide: a possible mechanism for tumor promotion mediated by benzoyl peroxide. Submitted.Google Scholar
  32. 32.
    S.H. Yuspa, Tumor promotion. In, Accomplishments in Cancer Research 1986 (J.G. Fortner and J.E. Rhoads, Eds.) pp. 169–182. Lippincott Co., Philadelphia, 1987.Google Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • Stuart H. Yuspa
    • 1
  • Henry Hennings
    • 1
  • Takashi Sako
    • 1
  • George R. Pettit
    • 2
  • John Hartley
    • 3
  • Peter M. Blumberg
    • 1
  1. 1.Laboratory of Cellular Carcinogenesis and Tumor PromotionNational Cancer InstituteBethesdaUSA
  2. 2.Cancer Research Institute and Department of ChemistryArizona State UniversityTempeUSA
  3. 3.Department of ChemistryUniversity of Alberta EdmontonAlbertaCanada

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