Hyperplastic Transformation: The Response of the Skin to Irritation and Injury

  • Friedrich Marks
Part of the NATO ASI Series book series (NSSA, volume 181)


As the body’s most exposed organ, the epidermis fulfils its protective task by its capacity to respond very quickly and effectively to all kinds of harmful external influences and irritations. This response consists of a highly complex pattern of hyperproliferative, inflammatory and immunological reactions which have so far only been insufficiently investigated. One characteristic answer to irritation is epidermal hyperplasia, a thickening of the epithelium due to increased cellular proliferation which results in an increase of the number of epidermal cell layers and — after subsequent terminal differentiation -in a thickening of the protecting horny layer. Although hyperplastic development is the most common hyperproliferative response of the skin, it is not the only one.


Phorbol Ester Mouse Skin Epidermal Stem Cell Arachidonic Acid Cascade Horny Layer 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    S. Bertsch, K. Csontos, J. Schweizer, and F. Marks, Effect of mechanical stimulation on cell proliferation in mouse epidermis and on growth regulation by endogenous factors (chalones), Cell Tissue Kinet. 9:445 (1976)PubMedGoogle Scholar
  2. 2.
    G. Fürstenberger, H. Richter, T. S. Argyris, and F. Marks, Effects of the phorbol ester 4-O-methyl-TPA on mouse skin in vivo: evidence for its uselessness as a negative control compound in studies on the biological effects of phorbol ester tumor promoters, Cancer Res. 42:342 (1982)PubMedGoogle Scholar
  3. 3.
    L. Krieg, I. Kühlmann, and F. Marks, Effect of tumor-promoting phorbobl esters and of acetic acid on mechanisms controlling DNA synthesis and mitosis (chalones) and on the biosynthesis of histidine-rich protein in mouse epidermis, Cancer Res. 34:3135 (1974).PubMedGoogle Scholar
  4. 4.
    S. Rose-John, G. Fürstenberger, P. Krieg, E. Besemfelder, G. Rincke, and F. Marks, Differential effects of phorbol esters on c-fos and c-myc and ornithine decarboxylase gene expression in mouse skin in vivo, Carcinogenesis 9:831 (1988).PubMedCrossRefGoogle Scholar
  5. 5.
    F. Marks, S. Bertsch, and G. Fürstenberger, Ornithine decarboxylase activity, cell proliferation, and tumor promotion in mouse epidermis in vivo, Cancer Res. 39:4183 (1979).PubMedGoogle Scholar
  6. 6.
    A. K. Verma, D. Erickson, and B. J. Dolnick, Increased mouse epidermal ornithine decarboxylase activity by the tumor promoter TPA involves increased amounts of both enzyme protein and messenger RNA, Biochem. J. 237:297 (1986).PubMedGoogle Scholar
  7. 7.
    G. Fürstenberger and F. Marks, Eicosanoids in normal and neoplastic growth in mouse skin, in: “Eicosanoids and the Skin”, T. Ruzicka, ed., CRC Press, Boca Raton, Fa., in press.Google Scholar
  8. 8.
    F. Marks, G. Fürstenberger, and E. Kownatzki. Prostaglandin E-mediated mitogenic stimulation of mouse epidermis in vivo by divalent cation ionophore A23187 and by tumor promoter TPA, Cancer Res. 41:696 (1981).PubMedGoogle Scholar
  9. 9.
    F. Marks, Prostaglandins, cyclic nucleotides and the effect of phorbol ester tumor promoters on mouse skin in vivo, Carcinogenesis 4:1465 (1983).PubMedCrossRefGoogle Scholar
  10. 10.
    G. Fürstenberger, M. Gross, and F. Marks, Eicosanoids and multistage carcinogenesis in NMRI mouse skin: role of prostaglandins E and F in conversion (first stage of tumor promotion) and promotion (second stage of tumor promotion), Carcinogenesis 10:91 (1989).PubMedCrossRefGoogle Scholar
  11. 11.
    S. Hammarström, J. A. Lindgren, C. Marcelo, E. A. Duell, T. F. Anderson, and J.J. Voorhees, Arachidonic acid transformation in normal and psoriatic skin, J. Invest. Dermatol. 73: 180 (1979).PubMedCrossRefGoogle Scholar
  12. 12.
    V. A. Ziboh, T. L. Casebolt, C. Marcelo, and J. J. Voorhees, Lipoxygenation of arachidonic acid by subcellular preparations from murine keratinocytes, J. Invest. Dermatol. 83:248 (1984).PubMedCrossRefGoogle Scholar
  13. 13.
    H. Hagedorn, Epidermaler Arachidonsäurestoffwechsel in normaler und in Tumorpromtor-behandelter Mäusehaut unter besonderer Berücksichtigung der 8-Lipoxygenase, Ph.D. Thesis, University of Heidelberg (1988).Google Scholar
  14. 14.
    M. Gschwendt, G. Fürstenberger, W. Kittstein, E. Besemfelder, W. E. Hull, H. Hagedorn, H.J. Opferkuch, and F. Marks, Generation of the arachidonic acid metabolite 8-HETE by extracts of mouse skin treated with phorbol ester in vivo; identification by 1H-n.m.r. and GC-MS spectroscopy, Carcinogenesis 7:449 (1986).PubMedCrossRefGoogle Scholar
  15. 15.
    M. Castagna, Y. Takai, K. Kaibuchi, K. Sano, V. Kikkawa, and Y. Nishizuka, Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters, J. Biol. Chem. 257:7847 (1982).PubMedGoogle Scholar
  16. 16.
    Y. Nishizuka, The role of proteinkinase C in cell surface signal transduction and tumor promotion, Nature 308:693 (1984).PubMedCrossRefGoogle Scholar
  17. 17.
    A. Fournier and A. W. Murray, Application of phorbol ester to mouse skin causes a rapid and sustained loss of protein kinase C., Nature 330:767 (1987).PubMedCrossRefGoogle Scholar
  18. 18.
    K. Chida, N. Kato, and T. Kuroki, Down regulation of phorbol diester receptors by proteolytic degradation of protein kinase C in a cultured cell line of fetal rat skin keratinocytes, J. Biol. Chem. 261:13013 (1986).PubMedGoogle Scholar
  19. 19.
    S. Inohara, Y. Tatsumi, Y. Tanaka, H. Tateishi, and S. Sagami, Immunohistological identification of protein kinase C isozymes in normal and psoriatic epidermis, Arch. Dermatol. Res. 280:454 (1988).PubMedCrossRefGoogle Scholar
  20. 20.
    G. J. Fisher, Y. A. Harris, C. J. Petersen, and J. J. Voorhees, Proteinkinase C isoforms alpha and beta are expressed in adult human epidermis, J. Invest. Dermatol. 92:428 (1989).CrossRefGoogle Scholar
  21. 21.
    J. R. Woodgett, T. Hunter, K. L. Gould, Protein kinase C and its role in cell growth, in: “Cell Membranes. Methods and Reviews”, Vol. 3, E. Elson, W. Frazier, and L. Glaser, eds., pp. 215, Plenum, New York (1988).Google Scholar
  22. 22.
    P. Angel, M. Imagawa, R. Chin, B. Stein, R. J. Imbra, H. J. Rahmsdorf, C. Jonat, P. Herrlich, and M. Karin, Phorbol ester-inducible genes contain a common ciselement recognized by a TPA-modulated trans-acting factor, Cell 49:729 (1987).PubMedCrossRefGoogle Scholar
  23. 23.
    R. Käst, Primäre und transformierte Mäusekeratinocyten als Zielzellen für Bradykinin, Diploma Thesis, University of Heidelberg (1989).Google Scholar
  24. 24.
    B. C. Tilly, P.A. van Paridon, I. Verlaan, and W.H. Moolenar, Inositolphosphate metabolism in bradykinin-stimulated human A431 carcinoma cells, Biochem. J. 244:129 (1987).PubMedGoogle Scholar
  25. 25.
    M. J. Berridge, Inositol trisphosphate and diacylglycerol as second messengers, Biochem. J. 220:345 (1984).PubMedGoogle Scholar
  26. 26.
    R. M. Burch and J. Axelrod, Dissociation of bradykinin-in-duced prostaglandin formation from phosphatidylinositol turnover in Swiss 3T3 fibroblasts: Evidence for a G protein regulation of phospholipase A2, Proc. Natl. Acad. Sci. USA 84:6374 (1987).PubMedCrossRefGoogle Scholar
  27. 27.
    F. Hirata, Lipomodulin: A possible mediator of the action of glucocorticoids, in: “Advances in Prostaglandin, Thromboxane and Leukotriene Research”, Vol. 11, B. Samuelson, B. Paoletti, and P. Ramwell, eds., pp. 73, Raven Press, New York (1985).Google Scholar
  28. 28.
    A. C. Nairn and H.C. Palfrey, Identification of the major Mr 100.000 substrate for calmodulin-dependent protein kinase III in mammalian cells as elongation factor-2. J. Biol. Chem. 262:17299 (1987).PubMedGoogle Scholar
  29. 29.
    M. Gschwendt, W. Kittstein, and F. Marks. Ciclosporin inhibits phorbol ester-induced hyperplastic transformation and tumor promotion in mouse skin probably by suppression of Ca2+/calmodulin-dependent processes such as phosphorylation of elongation factor 2, Skin Pharmacol. 1:84 (1988).PubMedCrossRefGoogle Scholar
  30. 30.
    M. Gschwendt, W. Kittstein, and F. Marks. Didemnin B inhibits biological effects of tumor promoting phorbol esters on mouse skin, as well as phosphorylation of a 100 kD protein in mouse epidermis cytosol, Cancer Letters 34:187 (1987).PubMedCrossRefGoogle Scholar
  31. 31.
    M. Gschwendt, W. Kittstein, and F. Marks, The immunosuppressant FK-506, like cyclosporines and didemnin B, inhibits calmodulin-dependent phosphorylation of the elongation factor 2 in vitro and biological effects of the phorbol ester TPA on mouse skin in vivo, J. Immunol. 179:1 (1989).Google Scholar
  32. 32.
    M. Gschwendt, W. Kittstein, and F. Marks, Cyclosporin A suppresses an early process in phorbol ester activation, Cancer Letters, in press.Google Scholar
  33. 33.
    M. Gschwendt, W. Kittstein, and F. Marks, Effect of tumor promoting phorbol ester TPA on epidermal protein synthesis: stimulation of an elongation factor 2 phosphatase activity by TPA in vivo, Biochem. Biophys. Res. Comm. 153:1129 (1988).PubMedCrossRefGoogle Scholar
  34. 34.
    H. C. Palfrey, A.C. Nairn, L.L. Muldoon, and M. L. Villereal, Rapid activation of calmodulin-dependent protein kinase III in mitogen-stimulated human fibroblasts, J. Biol. Chem. 262:9785 (1987).PubMedGoogle Scholar
  35. 35.
    S. Cohen, Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal, J. Biol. Chem. 237:1555 (1962).PubMedGoogle Scholar
  36. 36.
    J. Schlessinger, A. B. Schreiber, A. Levi, I. Lax, T. Libermann, and Y. Yarden, Regulation of cell proliferation by epidermal growth factor, CRC Crit. Rev. Biochem. 14,2:93 (1983).Google Scholar
  37. 37.
    G. L. Brown, L. Curtsinger, J.R. Brightnell, D.M. Ackerman, G.R. Tobin, H.C. Polk, C.G. Nascimento, P. Valenzuela, and G. S. Schultz, Enhancement of epidermal regeneration by biosynthetic epidermal growth factor, J. Exp. Med. 163:1319 (1986).PubMedCrossRefGoogle Scholar
  38. 38.
    M. Laato, J. Ninikoshi, L. Lebel, and D. Gerdin. Ann. Surg. 203:379 (1986).PubMedCrossRefGoogle Scholar
  39. 39.
    G. S. Schultz, M. White, R. Mitchell, G. Brown, J. Lynch, D. R. Twardzik, and G. J. Todaro, Epithelial wound healing enhanced by transforming growth factor/α and vaccinia growth factor, Science 235:350 (1987).PubMedCrossRefGoogle Scholar
  40. 40.
    M. B. Sporn, A. B. Roberts, J. H. Shull, J. M. Smith, and J. M. Ward, Polypeptide transforming growth factors, isolated from bovine sources and used for wound healing in vivo, Science 219:1329 (1983).PubMedCrossRefGoogle Scholar
  41. 41.
    H. J. Ristow, A major factor contributing to epidermal proliferation in inflammatory skin diseases appears to be interleukin 1 or a related protein, Proc. Natl. Acad. Sci. USA 84:1940 (1987).PubMedCrossRefGoogle Scholar
  42. 42.
    G. H. Hancock, G. Kaplan, and Z. A. Cohen, Keratinocyte growth regulation by products of immune cells, J. Exp. Med. 168:1395 (1988).PubMedCrossRefGoogle Scholar
  43. 43.
    T. Tanaka, K. Danno, V. Ikai, and S. Imamura, Effects of substance P and substance K on the growth of cultured keratinocytes, J. Invest. Dermatol. 90:399 (1988).PubMedCrossRefGoogle Scholar
  44. 44.
    V. B. Morhenn, Keratinocyte proliferation in wound healing and skin diseases, Immunol. Today 9:104 (1988).PubMedCrossRefGoogle Scholar
  45. 45.
    M. Eisinger, S. Sadan, I.A. Silver, and R.B. Flick, Growth regulation of skin cells by epidermal cell-derived factors: implications for wound-healing, Proc. Natl. Acad. Sci. USA 85:1937 (1988).PubMedCrossRefGoogle Scholar
  46. 46.
    A.Y. Fourtanier, J. Courty, E. Muller, Y. Courtois, M. Prunieras, and D. Barritault, Eye-derived growth factor isolated from bovine retina and used for epidermal wound- healing in vivo, J. Invest. Dermatol. 87:76 (1986)PubMedCrossRefGoogle Scholar
  47. 47.
    T. S. Kupper, A. O. Chua, P. Flood, J. McGuire, and U. Gubler, Interleukin 1 gene expression in cultured keratinocytes is augmented by ultraviolet irradiation, J. Clin. Invest. 80:430 (1987).PubMedCrossRefGoogle Scholar
  48. 48.
    H. A. Hansson, R. Jonsson, and K. Petruson, Transiently increased insulin-like growth factor. I. Immuno reactivity in UVB-irradiated mouse skin, J. Invest. Dermatol. 91:328 (1988).PubMedCrossRefGoogle Scholar
  49. 49.
    R. Halaban, R. Langdon, N. Birchall, C. Cuono, A. Baird, G. Scott, G. Moellmann, and J. McGuire, Basic fibroblast growth factor from human keratinocytes is a natural mitogen for melanocytes, J. Cell Biol. 107:1611 (1988).PubMedCrossRefGoogle Scholar
  50. 50.
    D. Gospadorowicz, N. Ferrara, L. Schweigerer, and G. Neufeld, Structural characterization and biological function of fibroblast growth factor, Endocr. Rev. 8:95 (1987).CrossRefGoogle Scholar
  51. 51.
    M. R. Pittelkow and R.J. Coffey, Protein-kinase-C-mediated expression of transforming growth factor a in normal human keratinocytes, Ann. N. Y. Acad. Sci. 548 (1988).Google Scholar
  52. 52.
    R. J. Akhurst, F. Fee, and A. Balmain, Localized production of TGFß-mRNA in tumor promoter-stimulated mouse epidermis, Nature 331:363 (1988).PubMedCrossRefGoogle Scholar
  53. 53.
    M. J. Koury, A. Balmain, and J. B. Pragneil, Induction of granulocyte-macrophage colony-stimulating activity in mouse skin by inflammatory agents and tumor promoters, EMBO J. 2:1877 (1983).PubMedGoogle Scholar
  54. 54.
    R.J. Coffey, R. Derynck, J. N. Wilcox, T. S. Bringman, A. S. Goustin, H. L. Moses, and M. R. Pittelkow, Production and auto-induction of transforming growth factor a in human keratinocytes, Nature 328:817 (1987).PubMedCrossRefGoogle Scholar
  55. 55.
    T. S. Kupper, Interleukin 1 and other immunologically active keratinocyte cytokines: molecular and functional characterization, Adv. Dermatol. 3:293 (1988).PubMedGoogle Scholar
  56. 56.
    A. B. Schreiber, M. E. Winkler, and R. Derynck, Transforming growth factor a: a more potent angiogenic mediator than epidermal growth factor, Science 232:1250 (1986).PubMedCrossRefGoogle Scholar
  57. 57.
    P. Weiss and J. L. Kavanau, A model of growth and growthcontrol in mathematical terms, J. Gen. Physiol. 41:1 (1957).PubMedCrossRefGoogle Scholar
  58. 58.
    D. Mazia, Mitosis and the physiology of cell division, in: “The Cell”, Vol. III, chapter 2, J. Brächet and A. Mirsky, eds., Academic Press, New York (1961).Google Scholar
  59. 59.
    O. H. Iversen, The regulation of cell numbers in epidermis. A cybernetic point of view, Acta Pathol. Microbiol. Scand. Suppl. 148:91 (1961).Google Scholar
  60. 60.
    W. S. Bullough, The control of mitotic activity in adult mammalian tissues, Biol. Rev. 37:307 (1962).Google Scholar
  61. 61.
    K. M. Halprin, J. R. Taylor, V. Levine, C. Woodgard, K. Adachi, and M. Comerford, Agents that activate cyclic AMP-dependent protein kinase inhibit expiant culture growth and mitotic activity, J. Invest. Dermatol. 81:553 (1983).PubMedCrossRefGoogle Scholar
  62. 62.
    J. E. Birnbaum, T. M. Sapp, and J. B. Moore, Effects of reserpine, epidermal growth factor, and cyclic nucleotide modulators on epidermal mitosis, J. Invest. Dermatol. 66:313 (1976).PubMedCrossRefGoogle Scholar
  63. 63.
    C. Delescluse, N. H. Colburn, E. A. Duell, and J. J. Voorhees, Cyclic AMP-elevating agents inhibit proliferation of keratinizing guinea pig epidermal cells. Differentiation 2:343 (1974).PubMedCrossRefGoogle Scholar
  64. 64.
    F. Marks and W. Rebien, Cyclic 3`,5`-AMP and theophylline inhibit epidermal mitosis in G2 phase, Naturwiss. 59:41 (1972).PubMedCrossRefGoogle Scholar
  65. 65.
    R. Link and F. Marks, Histone phosphorylation in phorbol ester-stimulated and β-adrenergically stimulated mouse epidermis in vivo and characterization of an epidermal protein phosphorylation system, Biochim. Biophys. Acta 675:265 (1981).CrossRefGoogle Scholar
  66. 66.
    K. Yoshikawa, J. Takeda, O. Nemoto, T. Ito, K. M. Halprin, and K. Adachi, Phosphorylation of pig epidermal soluble protein by endogeneous cAMP-dependent protein kinase, J. Invest. Dermatol. 80:108 (1983).PubMedCrossRefGoogle Scholar
  67. 67.
    F. Marks, M. Ganss, and W. Grimm, Agonist- and mitogen-in-duced desensitization of isoproterenol-stimulated cyclic AMP-formation in mouse epidermis in vivo. Biochim. Biophys. Acta 678:122 (1981).PubMedCrossRefGoogle Scholar
  68. 68.
    H. Iizuka and A. Ohkawara, Effects of glucocorticoids on the beta-adrenergic adenylate cyclase system of pig skin. J. Invest. Dermatol. 80:524 (1983).PubMedCrossRefGoogle Scholar
  69. 69.
    D. I. Wilkinson and E. K. Orenberg, Retinoids increase the response of guinea pig but not human keratinocytes to agonists of adenylate cyclase in vitro, Arch. Dermatol. Res. 275:147 (1983).PubMedCrossRefGoogle Scholar
  70. 70.
    H. Iizuka, N. Ohkuma, and A. Ohkawara, Effects of retinoids on the cyclic AMP system of pig skin epidermis, J. Invest. Dermatol. 85:324,(1985)PubMedCrossRefGoogle Scholar
  71. 71.
    H. Green, Cyclic AMP in relation to proliferation of the epidermal cell: a new view, Cell 15:801 (1978).PubMedCrossRefGoogle Scholar
  72. 72.
    C. L. Marcelo and J. Tomick, Cyclic AMP, glucocorticoid and retinoid modulation of in vitro keratinocyte growth, J. Invest. Dermatol. 81:64s (1983).CrossRefGoogle Scholar
  73. 73.
    N. Okada, Y. Kitano, and K. Ichihara, Effects of cholera toxin on proliferation of cultured human keratinocytes in relation to intracellular cyclic AMP levels, J. Invest. Dermatol. 79:42 (1982).PubMedCrossRefGoogle Scholar
  74. 74.
    W. S. Bullough and E. B. Laurence, The role of glucocorticoid hormones in the control of epidermal mitosis, Cell Tissue Kinet. 1:5 (1968).Google Scholar
  75. 75.
    W. Hondius-Boldingh and E. B. Laurence, Extraction, purification, and preliminary characterization of the epidermal chalone. A tissue-specific inhibitor obtained from vertebrate skin. Europ. J. Biochem. 5:191 (1968).CrossRefGoogle Scholar
  76. 76.
    G. Isaksson-Forsen, K. Elgjo, D. Burton, and O. H. Iversen, Partial purification of the epidermal G2 chalone based on an in vivo assay system, Cell Biol. Internat. Rep. 5:195 (1981).Google Scholar
  77. 77.
    K. L. Reichelt, K. Elgjo, and P. D. Edminson, Isolation and structure of an epidermal mitosis inhibiting pentapeptide, Biochem. Biophys. Res. Commun. 146:1493 (1987).CrossRefGoogle Scholar
  78. 78.
    A. Tiegel, K. H. Richter, and F. Marks, Cell cycle specificity and reversibility of the inhibitory effect of epidermal Gl chalone on DNA synthesis in partially synchronized RTE-2 keratinocytes in vitro, Exp. Cell Res., in press (1989).Google Scholar
  79. 79.
    K. H. Richter, M. Clauss, W. Höfle, R. Schnapke, and F. Marks, The epidermal Gl chalone: an endogeneous tissue-specific inhibitor of epidermal cell proliferation. Ann. N. Y. Acad. Sei. 548:204 (1988).CrossRefGoogle Scholar
  80. 80.
    F. Marks and K. H. Richter, A request for a more serious approach to the chalone concept, Brit. J. Dermatol. Ill, Suppl. 27:58 (1984).CrossRefGoogle Scholar
  81. 81.
    G. D. Shipley, M. R. Pittelkow, J. J. Willie, R. E. Scott, and H. L. Moses, Reversible inhibition of normal human prokeratinocyte proliferation by type β transforming growth factor inhibitor in serum-free medium, Cancer Res. 46:2068 (1986).PubMedGoogle Scholar
  82. 82.
    G. Fürstenberger, M. Rogers, R. Schnapke, G. Bauer, P. Höfler, and F. Marks, Stimulatory role of transforming growth factors in multistage skin carcinogenesis: possible explanation of the tumor-inducing effect of wounding in initiated NMRI mouse skin, Int. J. Cancer 43, in press (1989).Google Scholar
  83. 83.
    M. B. Sporn, A. B. Roberts, L. M. Wakefield, and R. K. Assoian, Transforming growth factor-beta: biological function and chemical structure, Science 233:532 (1986).PubMedCrossRefGoogle Scholar
  84. 84.
    F. Marks, M. Clauss, A. Tiegel, and K.H. Richter, The epidermal Gl chalone: a tissue-specific, species non-specific “negative growth factor” in skin, in: “Biological Regulation of Cell Proliferation”, R. Baserga, P. Foa, D. Metcalf, and E. E. Polli, eds., pp. 267, Raven Press, New York (1986).Google Scholar
  85. 85.
    A. B. Roberts, M. B. Sporn, R. K. Assoian, J. M. Smith, N. S. Roche, L. M. Wakefield, V. I. Heine, L. A. Liotta, U. Falanger, J. H. Keteri, and A. Fauci, Transforming growth factor type ß: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro, Proc. Natl. Acad. Sci. USA 83:4167 (1986).PubMedCrossRefGoogle Scholar
  86. 86.
    S. Bertsch and F. Marks, Lack of an effect of tumorpromoting phorbol esters and of epidermal Gl chalone on DNA synthesis in the epidermis of newborn mice, Cancer Res. 34:3283 (1974).PubMedGoogle Scholar
  87. 87.
    S. Bertsch and F. Marks, Removal of the horny layer does not stimulate cell proliferation in neonatal mouse epidermis, Cell Tissue Kinet. 11: 651 (1978).PubMedGoogle Scholar
  88. 88.
    G. Fürstenberger, J. Schweizer, and F. Marks, Development of phorbol ester responsiveness in neonatal mouse epidermis: correlation between hyperplastic response and sensitivity to first-stage tumor promotion, Carcinogenesis 6:289 (1985).PubMedCrossRefGoogle Scholar
  89. 89.
    A. W. Murray, V. Solanki, and A. K. Verma, Accumulation of cyclic adenosine-3`,5`-monophosphate in adult and new-born mouse skin: responses to ischemia and isoproterenol, J. Invest. Dermatol. 68:125 (1977).PubMedCrossRefGoogle Scholar
  90. 90.
    S. Bertsch and F. Marks, A comparative study on woundhealing in neonatal and adult mouse epidermis in vivo, Cell Tissue Kinet. 15:81 (1982).PubMedGoogle Scholar
  91. 91.
    A. K. Gupta, G. J. Fisher, J. T. Elder, B. J. Nickoloff, and J. J. Voorhees, Sphingosine inhibits phorbol ester-induced inflammation, ornithine decarboxylase activity, and activation of protein kinase C in mouse skin, J. Invest. Dermatol. 91:486 (1988).PubMedCrossRefGoogle Scholar
  92. 92.
    S. Yamada, K. Hirota, K. Chida, and T. Kuroki, Inhibition of phorbol ester-caused induction of ornithine decarboxylase and tumor promotion in mouse skin by staurosporine, a potent inhibitor of protein kinase C., Biochem. Biophys. Res. Commun. 157:9 (1988).PubMedCrossRefGoogle Scholar
  93. 93.
    J. A. Schwarz, A. Viaje, and T. J. Slaga, Fluocinolone acetonide: a potent inhibitor of mouse skin tumor promotion and epidermal DNA synthesis, Chem. Biol. Interact. 17:331 (1977).PubMedCrossRefGoogle Scholar
  94. 94.
    T. J. Slaga, S. M. Fischer, C. E. Weeks, and A. J. P. Klein-Szanto, Cellular and biochemical mechanisms of mouse skin tumor promoters, Rev. Biochem. Toxicol. 3:231 (1980).Google Scholar
  95. 95.
    A. K. Verma, Biochemical mechanism of modulation of skin carcinogenesis by retinoids, in: “Retinoids”, C. E. Orfanos, ed., pp. 117–131, Springer-Verlag, Berlin (1981).CrossRefGoogle Scholar
  96. 96.
    K. Chida, H. Hashiba, T. Suda, and T. Kuroki, Inhibition by 1α, 25-dihydroxyvitamin D3 of induction of epidermal ornithine decarboxylase caused by 12–0-tetradecanoylphorbol-13-acetate and teleocidin B, Cancer Res. 44:1387 (1984).PubMedGoogle Scholar
  97. 97.
    H. H. Wolff, E. Christophers, and O. Braun-Falco, Beeinflussung durch Vitamin A-säure. Eine elektronenmikroskopische Untersuchung, Arch. klin. exp. Dermatol. 237:774 (1980).CrossRefGoogle Scholar
  98. 98.
    C. L. Peck, Synthetic retinoids in dermatology, in: “The Retinoids”, M. B. Sporn, A. B. Roberts, and D. S. Goodman, eds., Vol. 2, pp. 391, Academic Press, New York (1984).Google Scholar
  99. 99.
    S. Hammarström, M. Hamberg, B. Samuelsson, E. A. Duell, M. Stawishi, and J. J. Voorhees, Increased concentrations of nonésterified arachidonic acid, 12L-hydroxy-5,8,10,14-eicosatetraeonoic acid, prostaglandin E2 and prostaglandin F in epidermis of psoriasis, Proc. Natl. Acad. Sci. USA 72:5130 (1975).PubMedCrossRefGoogle Scholar
  100. 100.
    D. H. Russell, W. L. Combest, E. A. Duell, M. A. Stawiski, T.F. Anderson, and J.J. Voorhees, Glucocorticoid inhibits elevated polyamine biosynthesis in psoriasis, J. Invest. Dermatol. 71:177 (1978).PubMedCrossRefGoogle Scholar
  101. 101.
    H. Iizuka, K. Adachi, K. M. Halprin, and V. Levine, Cyclic AMP accumulation in psoriatic skin: differential responses to histamine, AMP, and epinephrine by the uninvolved and involved epidermis, J. Invest. Dermatol. 70:250 (1978).PubMedCrossRefGoogle Scholar
  102. 102.
    F. Horn, F. Marks, G. J. Fisher, C. L. Marcelo, and J. J. Voorhees, Decreased protein kinase C activity in psoriatic versus normal epidermis, J. Invest. Dermatol. 88:220 (1987).PubMedCrossRefGoogle Scholar
  103. 103.
    J. T. Elder, G. J. Fisher, P. B. Lindquist, G. L. Bennett, M. R. Pittelkow, R. J. Coffey, L. Ellings-worth, R. Derynck, and J. J. Voorhees, Overexpression of transforming growth factor a in psoriatic epidermis, Science 243:811 (1989).PubMedCrossRefGoogle Scholar
  104. 104.
    F. Marks and G. Fürstenberger, Experimental evidence that skin carcinogenesis is a multistep phenomenon, Brit. J. Dermatol. 115, Suppl. 31:1 (1986).CrossRefGoogle Scholar
  105. 105.
    F. Marks and G. Fürstenberger, From the normal cell to cancer: the multistep process of experimental skin carcinogenesis, in: “Concepts and Theories in Carcinogenesis”, A. P. Maskens, P. Ebbesen, and A. Burny, eds., pp. 169, Excerpta Medica, Amsterdam (1987).Google Scholar
  106. 106.
    F. Marks, Skin cancer (excluding melanomas), in: “Handbook of Experimental Pharmacology”, Vol. 87/11, chapter 15, Springer-Verlag, Berlin etc. (1989), in press.Google Scholar
  107. 107.
    F. Marks, and G. Fürstenberger, Stadi della carcinogenesi cutanea, Rassegna Clin. Scient. 63/I-II:2 (1987).Google Scholar
  108. 108.
    F. Marks, G. Fürstenberger, M. Gschwendt, M. Rogers, B. Schurich, B. Kaina, and G. Bauer, The wound response as a key element for an understanding of multistage skin carcinogenesis, in: “Chemical Carcinogenesis”, F. Feo, P. Pani, A. Columbano and R. Garcea, eds., pp. 217, Plenum, New York (1988).Google Scholar
  109. 109.
    G. Fürstenberger, M. Gschwendt, H. Hagedorn, and F. Marks, Modulation of the conversion stage of multistep carcinogenesis in mouse skin by eicosanoids, in: “Prostaglandins in Cancer Research”, E. Garaci, R. Paoletti, and M. G. Santoro, eds., Springer-Verlag, Berlin etc. (1987).Google Scholar
  110. 110.
    F. Marks, G. Fürstenberger, M. Ganss, and D. Seemann, Biological effects of phorbol ester tumor promoters in mouse skin, in: “Cell Function and Differentiation, Part A”, G. Akoyunoglou, A. E. Evangelopoulos, J. Georgatsos, G. Palaiologos, A. Trakatellis, and C. P. Tsiganos, eds., pp. 243, Liss, New York (1982).Google Scholar
  111. 111.
    F. Marks, S. Bertsch, G. Fürstenberger, and H. Richter, Growth control in mouse epidermis — facts and speculations, in: “Psoriasis: Cell Proliferation”, N. A. Wright, and R. S. Camplejohn, eds., pp. 173, Chruchill-Livingstone, Edinburgh (1983).Google Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • Friedrich Marks
    • 1
  1. 1.German Cancer Research CenterInstitute of BiochemistryHeidelbergGermany

Personalised recommendations