In the three stage model of carcinogenesis in mouse skin, to a certain compartment of normal cells new and adverse biological properties are imposed by the initiator DMBA yielding ‘potential tumor cells,’ or ‘initiated cells.’ These initiated cells exhibit a selective advantage of growth over surrounding normal cells if exposed to DTE promoters. The new properties may result from a genomic mutation associated with an increase of density, affinity or cooperativity of certain membrane receptors as compared to normal cells. Complete promoters, such as TPA, but not incomplete promoters such as RPA may impose a second additional genomic or epigenomic insult onto initiated cells (‘conversion'). As a consequence, initiated cells become ready to respond to unspecific mitogenic stimuli (‘propagation'), as provided by hyperplasiogenic agents. The initiation/promotion model of mouse skin presents new and attractive possibilities to apply the oncogene approach for further in-depth analysis of the molecular mechanisms of its stages. It remains to be seen to what extent molecular events demonstrated causative for the stages in the mouse skin model are applicable also to stages in multistage models of chemical carcinogenesis operational in other target tissues.
References
1.
1. Adolf W, Bigbee JW, Bigbee JW, and Bigbee JW (1982). Structure-activity relations of polyfunctional diterpenes of the daphnane type. I. Revised structure for resiniferatoxin and structure-activity relations of resiniferonol and some of its esters. J. Nat. Prod.45: 347–354.
2.
2. Amtmann E, Bigbee JW, and Bigbee JW (1984). Tumour induction in the rodent Mastomys natalensis by activation of endogenous papilloma virus genomes. Nature308: 291–292.
3.
3. Balmain A (1985). Transforming ras oncogenes and multistage carcinogenesis. Brit. J. Cancer51: 1–7.
4.
4. Balmain A, Bigbee JW, Bigbee JW, and Bigbee JW (1984). Activation of the mouse cellular Harvey ras gene in chemically induced benign skin papillomas. Nature307: 658–660.
5.
5. Berridge MJ, and Bigbee JW (1984). Inositol triphosphate, a novel second messenger in cellular single transduction. Nature312: 23–38.
6.
6. Boutwell RK (1964). Some biological aspects of skin carcinogenesis. Progr. Exp. Tumor Res.4: 207–250.
7.
7. Boveri T (1914). Zur Frage der Entstehung maligner Tumoren.Gustav Fischer, Jena; Bauer KH (1928). Mutationstheorie der Geschwulstentstehung. Springer, Berlin.
8.
8. Brown K, Bigbee JW, Bigbee JW, Bigbee JW, Bigbee JW, and Bigbee JW (1986). v-ras genes from Harvey and BALB murine sarcoma viruses can act as initiators of two-stage mouse skin carcinogenesis. Cell46: 447–456.
9.
9. Castagna M, Bigbee JW, Bigbee JW, Bigbee JW, Bigbee JW, and Bigbee JW (1982). Direct activation of calcium-activated, phospholipid dependent protein kinase by tumor-promoting phorbol esters. J. Biol. Chem.257: 7847–7851.
10.
10. Cerutti PA (1985). Prooxidant states and tumor promotion. Science227: 375–381.
11.
11. Chorazy M (1985). Sequence rearrangements and genome instability. A possible step in carcinogenesis. J. Cancer Res. Clin. Oncol.109: 159–172.
12.
12. Colburn N, Bigbee JW, Bigbee JW, Bigbee JW, and Bigbee JW (1984). Role of specific membrane and genetic changes in the mechanism of tumour promotion. Studies with promoter-resistant variants. In: Models, Mechanisms and Etiology of Tumour Promotion, M Börzsönyi, NE Day, K Lapis, and H Yamasaki (eds). IARC Scientific Publications No. 56, Lyon, pp. 205–215.
13.
13. Delclos KB, Bigbee JW, and Bigbee JW (1980). Specific binding of phorbol ester tumor promoters to mouse skin. Cell19: 1025–1032.
14.
14. Delclos KB, Bigbee JW, and Bigbee JW (1983). Specific labeling of mouse brain membrane phospholipids with [20-3H]phorbol-12-p-azidobenzoate-13-benzoate, a photolabile phorbol ester. Proc. Natl. Acad. Sci. USA80: 3054–3058.
15.
15. Dunphy WG, Bigbee JW, and Bigbee JW (1980). Kinetics and subcellular localization of specific [3H]phorbol-12,13-dibutyrate binding to mouse brain. Cancer Res.40: 3635–3641.
16.
16. Dzarlieva-Petrusevska RT, and Bigbee JW (1985). Tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced chromosome aberrations in mouse keratinocyte cell lines: A possible genetic mechanism of tumour promotion. Carcinogenesis6: 1447–1456.
17.
17. Dzarlieva-Petrusevska RT, Fürstenberger G, Bigbee JW, and Bigbee JW (1987). Different cytogenetic effects of first and second stage promoters on mouse keratinocytes in primary cultures and inhibition of clastogenic TPA effects by antipromoters. In: The Role of DNA Amplification in Tumor Initiation and Promotion, H zur Hausen and JR Schlehofer (eds). Accomplishments in Cancer Research 1986, J G Fortner and JE Rhoads (eds). J. B. Lippincott, Philadelphia (in press).
18.
18. Friesel H, Schöpe KB, and Bigbee JW (1983). ‘Bayregion’ versus ‘L-region’ activation of the tumor-initiator 7,12-dimethylbenz[a]anthracene. In: Polynuclear Aromatic Hydrocarbons: Formation, Metabolism and Measurement, M Cooke and AJ Dennis (eds). Batelle Press, Columbus, Ohio, pp. 517–530.
19.
19. Fürstenberger G, Bigbee JW, Bigbee JW, and Bigbee JW (1981). Skin tumor promotion by phorbol esters is a two-stage process. Proc. Natl. Acad. Sci. USA78: 7722–7726.
20.
20. Fürstenberger G, and Bigbee JW (1986). On the active principles of Euphorbiaceae, XII. Highly unsaturated irritant diterpene esters from Euphorbia tirucalli L. originating from Madagascar. J. Nat. Prod.49: 386–397.
21.
21. Fusenig NE, Dzarlieva-Petrusevska RT, and Bigbee JW (1985). Phenotypic and cytogenetic characteristics of different stages during spontaneous transformation of mouse keratinocytes in vitro. Carcinogenesis9: 293–326.
22.
22. Gschwendt M, Horn F, Kittstein W, Fürstenberger G, Bigbee JW, and Bigbee JW (1984). Calcium and phospholipid dependant protein kinase activity in mouse epidermis cytosol. Stimulation by complete and incomplete tumor promoters and inhibition by various compounds. Biochem. Biophys. Res. Comm.124: 63–68.
23.
23. Hecker E (1978). Structure-activity relationships in diterpene esters irritant and co-carcinogenic to mouse skin. In: Mechanisms of Tumor Promotion and Co-carcinogenesis. Vol. 2. [Carcinogenesis–A Comprehensive Survey], TJ Slaga, A Sivak, and RK Boutwell (eds). Raven Press, New York, pp. 11–48.
24.
24. Hecker E (1979). Diterpene ester type modulators of carcinogenesis–New findings in the mechanism of chemical carcinogenesis and the etiology of human tumors. In: Naturally Occurring Carcinogens–Mutagens and Modulators of Carcinogenesis, EC Miller, JA Miller, T Horono, E Sugimura, and S Takayama (eds). Japan Sci. Soc. Press, Tokyo, pp. 263–286.
25.
25. Hecker E (1981). Co-carcinogenesis and tumor promoters of the diterpene ester type as possible carcinogenic risk factors. J. Cancer Res. Clin. Oncol.99: 103–124.
26.
26. Hecker E (1984). Cocarcinogens of the tumour-promoter type as potential risk factors of cancer in man–First complete analysis of an etiological model situation and some of its consequences. In: Models, Mechanisms and Etiology of Tumour Promotion, M Börzsönyi, NE Day, K Lapis, and H Yamasaki (eds). IARC Scientific Publication No. 56, Lyon, pp. 441–446.
27.
27. Hecker E (1984). Co-carcinogens of the initiation-(or tumor)promoter type as environmental risk factors of cancer in man–Experimental analysis of an etiological model situation of life style cancer and current problems of assessment of cancer risk in multifactorial carcinogenesis. In: Modifiers of Carcinogenesis, I Knudsen, H Pedersen, and EB Thorling (eds). Acta Pharmacol. Toxicol.55: (Suppl. 2)145–164.
28.
28. Hecker E (1984). Concluding remarks and future perspectives. In: Models, Mechanisms and Etiology of Tumour Promotion, M Börzsönyi, NE Day, K Lapis, and H Yamasaki (eds). IARC Scientific Publication No. 56, Lyon, pp. 509–521.
29.
29. Hecker E (1985). Multifaktorielle und Mehrstufenkarzinogenese–Ätiologische (epidemiologische) und experimentelle Modelle, sowie aktuelle Probleme der Bewertung von Krebsrisikofaktoren der Umwelt. In: “Tumor promotoren: Erkennung, Wirkungsmechanismen und Bedeutung.” bga-Schriften 6/1985, KE Appel and AG Hildebrandt (eds). MMV Medizin Verlag, München, pp. 14–42.
30.
30. Hecker E (1985). Cell membrane associated protein kinase C as receptor of diterpene ester co-carcinogens of the tumor promoter type and the phenotypic expression of tumors. In: Die Rezeptoren: Funktion und klinische Bedeutung, H Gillmann (ed). Arzneimittel-Forsch.35: 1890–1903.
31.
31. Hecker E, Bigbee JW, Bigbee JW, Bigbee JW, and Bigbee JW (1984). Keynote lecture: Irritant promoters of mouse skin–Contributions to etiologies of environmental cancer and to biochemical mechanisms of carcinogenesis by diterpene esters. In: Cellular Interactions of Environmental Promoters, H Fujiki, E Hecker, RE Moore, T Sugimura, and IB Weinstein (eds). Japan Sci. Press, Tokyo, Japan, VNU Science Press, Utrecht, The Netherlands, pp. 3–63.
32.
32. Hecker E, Bigbee JW, Bigbee JW, Bigbee JW, and Bigbee JW (1983). Multi-stage tumor development in the human esophagus–The first identification of co-carcinogens of the tumor promoter type as principal carcinogenic risk factors in a local life style cancer. In: Current Perspectives in Cancer, 13th International Cancer Congress, EA Mirand, WB Hutchinson, E Mihich (eds). Part B. Biology of Cancer, Progress in Clinical and Biological Research, Vol. 132. Alan R. Liss, New York, 219–238.
33.
33. Hecker E., Bigbee JW, Bigbee JW, Bigbee JW, Bigbee JW, and Bigbee JW (1984). Antineoplastische Mittel auf Basis von nicht oder nur geringfügig irritierenden und/oder promovierenden Diterpenal koholen und Derivaten daren und deren Herstellung. European Patent No. 0013983, and corresponding patents worldwide.
34.
34. Hecker E, and Bigbee JW (1968). Zum biochemischen Mechanismus der Tumorgenese der Mäusehaut I. Verteilung und Stoffwechsel intragastral verfütterten 9,10-Dimethyl-(1,2)-benzanthracens in der Maus. Z. Krebsforsch.71: 153–166.
35.
35. Hecker E, and Bigbee JW (1974). Phorbol esters–The irritants and co-carcinogens of Croton tiglium L. Progr. Chem. Org. Natur. Prod.31: 377–467.
36.
36. Hennings H, and Bigbee JW (1985). Two-stage tumor promotion in mouse skin. An alternative interpretation. J. Natl. Cancer Inst.74: 735–739.
37.
37. Hergenhahn M, and Bigbee JW (1981). Specific binding of the tumor promoter TPA in various mouse organs as measured by a ‘cold acetone-filter assay’. Carcinogenesis2: 1277–1281.
38.
38. Hergenhahn M, and Bigbee JW (1983). Specific binding sites for the tumor promoter TPA–Studies on distribution, specificity and nature of the sites. Period. Biol. (Zagreb)85: (Suppl. 2)143–145.
39.
39. Hergenhahn M, and Bigbee JW (1984). Essential lipid components in membrane receptors of 12-O-tetradecanoylphorbol-13-acetate (TPA) as revealed by direct photoaffinity labeling. In: Models, Mechanisms and Etiology of Tumour Promotion, M Börzsönyi, NE Day, K Lapis, and MH Yamasaki (eds). IARC Scientific Publication No. 56, Lyon, pp. 165–175.
40.
40. Hergenhahn M, Bigbee JW, Bigbee JW, Bigbee JW, and Bigbee JW (1987). Evidence for two classes of diterpene ester receptors in mouse neutrophils–Receptor binding, photoaffinity labelling and chemoluminescence induction. Intl. J. Cancer (in preparation).
41.
41. Jeffrey AM, and Bigbee JW (1986). Computer-assisted molecular modeling of tumor promoters: Rationale for the activity of phorbol esters, teleocidin B, and aplysiatoxin. Proc. Natl. Acad. Sci. USA83: 241–245.
42.
42. Kubinyi H (1976). Quantitative structure-activity relationships. Drug Research26: 1991–1997.
43.
43. Lotter H, and Bigbee JW (1985). Wechselwirkung von Tumorpromotoren mit zellulären Rezeptoren–Feinstruktureller Vergleich der drei Prototypen irritierender und co-carcinogener Diterpenester aus Euphorbiaceen und Thymelaeaceen. Fresenius Z. Anal. Chem.321: 640–642.
44.
44. Lotter H, and Bigbee JW (1986). Analysis of the structure/activity relationships in diterpene ester irritants and promoters by computer graphic methods. Abstracts. XI. International Symposium on Medicinal Chemistry, Berlin.
45.
45. Marks F (1984). On the role of superoxide anion radicals in skin tumour promotion. Carcinogensis5: 1663–1670.
46.
46. Marks F (1987). Multistage carcinogenesis: The mouse skin model. Accomplishments in Oncology2: 18–30.
47.
47. Marks F, Berry DL, Bertsch S, Fürstenberger G, and Bigbee JW (1982). On the relationship between epidermal hyperproliferation and skin tumor promotion. In: Mechanisms of Tumor Promotion and Cocarcinogenesis. Carcinogenesis–A Comprehensive Survey, Vol. 7, E Hecker, NE Fusenig, W Kunz, F Marks, and HW Thielmann (eds). Raven Press, New York, pp. 331–346.
48.
48. Marks F and Fürstenberger G (1984). Stages of tumor promotion in skin. In: Models, Mechanisms and Etiology of Tumor Promotion, M Börzönyi, K Lapis, NE Day, and H Yamasaki (eds). IARC Scientific Publications No. 56, Lyon, pp. 13–22.
49.
49. Nishizuka Y (1983). Phospholipid degradation and signal translation for protein phosphorylation. Trends Biochem. Sciences4: 13–16.
50.
50. Oberender HA (1983). Zur Pharmakokinetik von peroral verabreichten 7,12-Dimethylbenz[a]anthracen in der Maus. University of Heidelberg, Thesis Dissertation.
51.
51. Oberender HA, Bigbee JW, Bigbee JW, and Bigbee JW (1980). Tierexperimentelle Daten zur Xenobiotico-Kinetik peroral aufgenommener carcinogener Kohlenwasserstoffe. Ernährungsumschau27: 317.
52.
52. Oberender HA, Bigbee JW, Bigbee JW, and Bigbee JW (1982). In-vivo Untersuchungen zur Bestimmung der absorbierten Menge des peroral verabreichten carcinogene Kohlenwasserstoffs 7,12-Dimethylbenz[a]anthracen. Ernährungsumschau29: 237.
53.
53. Parker PJ, and Bigbee JW (1986). Protein Kinase C. In: Oncogenes and Growth Control, P Kahn and T Graf (eds). Springer-Verlag, Heidelberg, pp. 154–162.
54.
54. Parkinson EK (1985). Defective responses of transformed keratinocytes to terminal differentiation stimuli. Their role in epidermal tumor promotion by phorbol esters and by deep skin wounding. Brit. J. Cancer52: 479–493.
55.
55. Paul D, and Bigbee JW (1969). Zum biochemischen Mechanismus der Tumorgenese der Mäusehaut. II. Early effects on the biosynthesis of nucleic acids induced by initiating doses of DMBA and promoting doses of phorbol-12,13-diester TPA. Z. Krebsforsch.73: 149–163.
56.
56. Pyerin WG, and Bigbee JW (1979). On the biochemical mechanism of tumorigenesis in mouse skin. IX. Interrelation between tumor-initiation by 7,12-dimethylbenz[a]anthracene and the activities of epidermal arylhydrocarbon monooxygenase and epoxide hydratase. J. Cancer Res. Clin. Oncol.93: 7–30.
57.
57. Pyerin WG, and Bigbee JW (1980). Tumour initiation in mouse skin by 7,12-dimethylbenz(a)anthracene: Irrelevance of systemic activation. Cancer Lett.8: 317–321.
58.
58. Pyerin W, and Bigbee JW (1983). Monooxygenase activity of human epithelial cells (HeLa): Comparison of the response to treatment by arylhydrocarbons and diterpene esters. J. Cancer Res. Clin. Oncol.106: 71–73.
59.
59. Pyerin W, Bigbee JW, and Bigbee JW (1980). Extent of skin tumor initiation in mice by 7,12-dimethylbenz[a]anthracene and induction of arylhydrocarbon monooxygenase are not causally related. Cancer Lett.10: 155–162.
60.
60. Quintanilla M, Bigbee JW, Bigbee JW, and Bigbee JW (1986). Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature322: 78–80.
61.
61. Randerath K, Bigbee JW, and Bigbee JW (1981). 32P-labeling test for DNA damage. Proc. Natl. Acad. Sci. USA78: 6126–6129.
62.
62. Schmidt R, Bigbee JW, Bigbee JW, Bigbee JW, Bigbee JW, Bigbee JW, Bigbee JW, Bigbee JW, and Bigbee JW (1983). Inhibition of specific binding of (3H)phorbol-12,13-dipropionate to an epidermal fraction by certain irritants and irritant promoters of mouse skin. Carcinogenesis4: 77–81.
63.
63. Schmidt R, Bigbee JW, Bigbee JW, and Bigbee JW (1985). Phospholipids involved in specific binding of 12-O-(5-azido-2-nitrobenzoyl)phorbol-13-acetate to epidermal microsomes, a photolabeling study. Cancer Lett.26: 97–111.
64.
64. Schmidt R, and Bigbee JW (1982). Simple phorbol esters as inhibitors of tumor promotion by TPA in mouse skin. In: Cocarcinogenesis and Biological Effects of Tumor Promoters, Carcinogenesis–A Comprehensive Survey, Vol. 7, E Hecker, NE Fusenig, W Kunz, F Marks, and HW Thielmann (eds). Raven Press, New York, pp. 57–63.
65.
65. Schmidt R, and Bigbee JW (1983). Characterization of particulate and solubilized binding sites for 3H-phorbol-12,13-dipropionate of mouse skin epidermis. Period. Biol. (Zagreb)85: (Suppl. 2)155–157.
66.
66. Schmidt R, and Bigbee JW (1984). Characterization of phorbol ester receptors (PER) and Protein kinase C (PKC) in mouse epidermis. Hoppe-Seylor's Z. Physiol. Chem.365: 1057–1058.
67.
67. Schöpe KB (1984). Stoffwechsel und Bindung an DNA von 7,12-Dimethylbenz(a)anthracen als typischem Tumorinitiator der Rückenhaut der Maus. University of Heidelberg, Thesis Dissertation.
68.
68. Schöpe K-B, Bigbee JW, and Bigbee JW (1987). DNA-binding and initiating activity of solitary carcinogens of the PAH-type. In: The Role of DNA Amplification in Tumor Initiation and Promotion, H zur Hausen and JR Schlehofer (eds). Accomplishments in Cancer Research, 1986, JG Fortner and JE Rhoads (eds). J. B. Lippincott, Philadelphia (in press).
69.
69. Schöpe KB, Bigbee JW, Bigbee JW, Bigbee JW, and Bigbee JW (1986). Comparative DNA-binding of 7,12-dimethylbenz[a]anthracene and some of its metabolites in mouse epidermis in vivo as revealed by the 32P-postlabeling technique. Carcinogenesis7: 535–540.
70.
70. Shoyab M, Bigbee JW, and Bigbee JW (1981). Tissue and species distribution and developmental variation of specific receptors for biologically active phorbol and ingenol esters. Carcinogenesis2: 1273–1276.
71.
71. Siebert D, Bigbee JW, Bigbee JW, and Bigbee JW (1981). Polycyclic aromatic hydrocarbons and possible metabolites: Convertogenic activity in yeast and tumor initiating activity in mouse skin. J. Cancer Res. Clin. Oncol.102: 127–139.
72.
72. Slaga TJ, Bigbee JW, Bigbee JW, and Bigbee JW (1980). Studies on the mechanism of skin tumor promotion: Evidence for several stages in promotion. Proc. Natl. Acad. Sci. USA77: 3659–3663.
73.
73. Sorg B, Fürstenberger G, Bigbee JW, Bigbee JW, and Bigbee JW (1982). Preparation of retinoic acid esters of phorbol derivatives. J. Lipid. Res.23: 443–447.
74.
74. Sorg B, and Bigbee JW (1982). Zur Chemie des Ingenols II. Ester des Ingenols und des Δ7,8Ingenols. Z. Naturforsch.37b: 748–756.
75.
75. Sorg B, Pećar S, Bigbee JW, Bigbee JW, and Bigbee JW (1987). Spin labeled phorbol esters and their interactions with cellular membranes, III. Irritant and tumor promoting activities of spin labeled phorbol-12,13-diesters. Carcinogenesis (in press).
76.
76. Sorg B, Bigbee JW, and Bigbee JW (1987). Structure-activity relationships of polyfunctional diterpenes of the ingenane type I. Tumor promoting activity of homologous, aliphatic 3-esters of ingenol and Δ7,8-isoingenol-3-tetradecanoate. Carcinogenesis8: 1–4.
77.
77. Tremp GL, and Bigbee JW (1985). Stability of the “second stage” promoter 12-O-Retinoylphorbol-13-acetate (RPA). Cancer Res.45: 2390–2391.
78.
78. Weinberg RA (1985). The action of oncogenes in the cytoplasm and nucleus. Science230: 770–776.
79.
79. Wislocki PG, Bigbee JW, Bigbee JW, Bigbee JW, and Bigbee JW (1980). Carcinogenicity and mutagenicity of the 3,4-dihydrodiols and other metabolites of 7,12-dimethylbenz[a]anthracene and its hydroxymethyl derivatives. Cancer Res.40: 3661–3664.
80.
80. Wislocki PG, Bigbee JW, Bigbee JW, Bigbee JW, Bigbee JW, and Bigbee JW (1981). Tumorigenecity of 7,12-dimethylbenz[a]anthracene its hydroxymethylated derivatives and selected dihydrodiols in the newborn mouse. Carcinogenesis2: 511–512.
81.
81. Yuspa SH (1987). Gene amplification in skin carcinogenesis. Accomplishments in Oncology2: 31–34.
82.
82. Zayed S, Bigbee JW, Bigbee JW, and Bigbee JW (1977). New tigliane and daphnane derivatives from Pimelea prostrata and Pimelea simplex. Experientia33: 1554–1555.
83.
83. Zayed S, Bigbee JW, and Bigbee JW (1984). Structure-activity relations of polyfunctional diterpenes of the tigliane type. VI. Irritant and tumor promoting activities of semi-synthetic mono- and diesters fo 12-deoxyphorbol. Planta Med.1: 65–69.
84.
84. Zur Hausen H, Bigbee JW, Bigbee JW, and Bigbee JW (1979). Tumor initiators and promoters in the induction of Epstein-Barr-virus. Proc. Natl. Acad. Sci. USA76: 782–785.
85.
85. Zur Hausen H, O'Neill FJ, Bigbee JW, and Bigbee JW (1978). Persisting oncogenic herpesvirus induced by the tumor promoter TPA. Nature272: 373–375.
86.
86. Zur Hausen H, and Bigbee JW (1987). The Role of DNA Amplification in Tumor development: prospects from virological studies. Accomplishments in Oncology2: 1–8.
