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Tumour Promotion: Biology and Molecular Mechanisms

  • Chapter
Chemical Carcinogenesis and Mutagenesis II

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 94 / 2))

Abstract

A promoter can be operationally defined as a compound which enhances the tumour yield in an animal exposed to a low dose of a carcinogen. Promoters act at an early stage in the step-wise induction of malignant cancers, by favouring the cloncal expansion of initiated cells to benign lesions such as papillomas, nodules and polyps. Although mouse skin has been most extensively studied, a number of animal models have been developed in order to study promotion at several other organ sites (Slaga 1983). The restricted aim of this review is to discuss what is known about promotion by some specific agents in two organs (skin and liver) at both the biological and molecular levels. This summary will not be encyclopedic but will attempt to highlight the important unresolved issues. One characteristic of tumour promotion is that there is frequently tissue specificity associated with a particular promoter (see Table 1), and certainly promotion in skin and liver is achieved by different groups of compounds. Consequently, we believe it would also be useful to consider whether the same, different or overlapping mechanisms are involved.

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References

  • Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ, Jonat C, Herrlich P, Karin M (1987) Phorbol ester-inducible genes contain a commoncis element recognised by a TPA-modulated trans-acting factor. Cell 49:729–739

    Article  PubMed  CAS  Google Scholar 

  • Argyris TS (1985) Regeneration and the mechanism of epidermal tumor promotion. CRC Crit Rev Toxicol 14:211–257

    Article  CAS  Google Scholar 

  • Armato U, Andreis PG, Romano F (1985) The stimulation by the tumor promoters 12-O- tetradecanoylphorbol-13-acetate and phenobarbital of the growth of primary neonatal rat hepatocytes. Carcinogenesis 6:811–821

    Article  PubMed  CAS  Google Scholar 

  • Barbason H, Rassenfosse C, Betz EH (1983) Promotion mechanism of phenobarbital and partial hepatectomy in DNEA hepatocarcinogenesis cell kinetics effect. Br J Cancer 47:517–525

    Article  PubMed  CAS  Google Scholar 

  • Beer DG, Schwarz M, Sawada N, Pitot HC (1986) Expression of H-ras and c-myc protooncogenes in isolated γ-glutamyl transpeptidase-positive rat hepatoeytes and in hepatocellular carcinomas induced by diethylnitrosamine. Cancer Res 46:2435–2441

    PubMed  CAS  Google Scholar 

  • Berkow RL, Kraft AS (1985) Bryostatin, a non-phorbol macrocyclic lactone, activates intact human polymorphonuclear leukocytes and binds to the phorbol ester receptor. Biochem Biophys Res Commun 131:1109–1116

    Article  PubMed  CAS  Google Scholar 

  • Berridge MJ (1987) Inositol triphosphate and diacylglycerol: two interacting second messengers. Ann Rev Biochem 56:159–193

    Article  PubMed  CAS  Google Scholar 

  • Besterman JM, Duronio V, Cuatrecasas P (1986) Rapid formation of diacylglycerol from phosphatidylcholine: a pathway for generation of a second messenger. Proc Natl Acad Sci USA 83:6785–6789

    Article  PubMed  CAS  Google Scholar 

  • Betschart JM, Gupta C, Shinozuka H, Virji MA (1987) Modulation of hepatocyte insulin and glucagon receptors in rats fed phenobarbital, a tumor promoter. Proc Am Assoc Cancer Res 28:165

    Google Scholar 

  • Blumberg PM (1981) In vitro studies on the mode of action of the phorbol esters, potent tumor promoters, part 2. CRC Crit Rev Toxicol 8:199–234

    Article  CAS  Google Scholar 

  • Blumberg PM, Dunn J A, Jaken S, Jeng AY, Leach KL, Sharkey NA, Yeh E (1984) Specific receptors for phorbol ester tumor promoters and their involvement in biological responses. In: Slaga TJ (ed) Mechanisms of tumor promotion, vol 3. Tumor promotion and carcinogenesis in vitro. CRC Press, Baton Rouge, p 143

    Google Scholar 

  • Boutwell RK (1964) Some biological aspects of skin carcinogenesis. Prog Exp Tumor Res 4:207–250

    PubMed  CAS  Google Scholar 

  • Boutwell RK (1974) The function and mechanism of promoters of carcinogenesis. CRC Crit Rev Toxicol 2:419–443

    Article  PubMed  CAS  Google Scholar 

  • Boynton AL, Whitfield JF (1980) Stimulation of DNA synthesis in calcium-deprived T51B liver cells by the tumor promoters phenobarbital, saccharin and 12–0- tetradecanoylphorbol-13-acetate. Cancer Res 40:4541–4545

    PubMed  CAS  Google Scholar 

  • Brandt SJ, Niedel JE, Bell RM, Young WS (1987) Distinct patterns of different protein kinase C mRNAs in rat tissues. Cell 49:57–63

    Article  PubMed  CAS  Google Scholar 

  • Brooks RC, Morell P, DeGeorge J J, McCarthy KD, Lapetina EG (1987) Differential effects of phorbol ester and diacylglycerols on inositol phosphate formation in C62B glioma cells. Biochem Biophys Res Commun 148:701–708

    Article  PubMed  CAS  Google Scholar 

  • Brown K, Quintanilla M, Ramsden M, Kerr IB, Young S, Balmain A (1986) v-ras genes from Harvey and BALB murine sarcoma viruses can act as initiators of two-stage mouse skin carcinogenesis. Cell 46:447–456

    Article  PubMed  CAS  Google Scholar 

  • Bursch W, Lauer B, Timmermann-Trosiener I, Barthel G, Schuppler J, Schulte-Hermann R (1984) Controlled death (apoptosis) of normal and putative preneoplastic cells in rat liver following withdrawal of tumor promoters. Carcinogenesis 5:453–458

    Article  PubMed  CAS  Google Scholar 

  • Busser M-T, Lutz WK (1987) Stimulation of DNA synthesis in rat and mouse liver by various tumor promoters. Carcinogenesis 8:1433–1437

    Article  PubMed  CAS  Google Scholar 

  • Carr BI (1987) Pleiotropic drug resistance in hepatoeytes induced by carcinogenes administered to rats. Cancer Res 47:5577–5583

    PubMed  CAS  Google Scholar 

  • Carter TH (1987) The regulation of gene expression by tumor promoters. In: Barrett JC (ed) Mechanisms of environmental carcinogenesis, vol 1. CRC Press, Baton Rouge, p47

    Google Scholar 

  • Castagna M (1987) Phorbol esters as signal transducers and tumor promoters. Biol Cell 59:3–13

    PubMed  CAS  Google Scholar 

  • Castagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U, Nishizuka Y (1982) Direct activation of calcium-activated phospholipid-dependent protein kinase by tumor- promoting phorbol esters. J Biol Chem 257:7847–7851

    PubMed  CAS  Google Scholar 

  • Chandar N, Amenta J, Kandala JC, Lombardi B (1987) Liver cell turnover in rats fed a choline-devoid diet. Carcinogenesis 8:669–673

    Article  PubMed  CAS  Google Scholar 

  • Crutchley DY, Conan LB, Maynard JR (1980) Induction of plasminogen activator and prostaglandin biosynthesis in HeLa cells by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 40:849–852

    PubMed  CAS  Google Scholar 

  • de Bustros A, Baylin SB, Berger CL, Roos BA, Leong SS, Nelkin BD (1985) Phorbol esters increase calcitonin gene transcription and decrease c-myc mRNA levels in cultured human medullary thyroid carcinoma. J Biol Chem 260:98–104

    PubMed  Google Scholar 

  • de Gerlache J, Taper HS, Lans M, Preat V, Roberfroid M (1987) Dietary modulation of rat liver carcinogenesis. Carcinogenesis 8:337–340

    Article  PubMed  Google Scholar 

  • DellaPorta G, Dragani TA, Maneti G (1987) Two-stage liver carcinogenesis in the mouse. Toxicol Pathol 15:229–233

    Article  CAS  Google Scholar 

  • Diwan BA, Rice JM, Ohshima M, Ward JM, Dove LF (1985) Comparative tumor- promoting activities of phenobarbital, amobarbital, barbital sodium, and barbituric acid on livers and other organs of male F344/NCr rats following initiation with N- nitrosodiethylamine. JNCI 74:509–516

    PubMed  CAS  Google Scholar 

  • Donnelly TE, Pelling JC, Anderson CL, Dalby D (1987 a) Benzoyl peroxide activation of protein kinase C activity in epidermal cell membranes. Carcinogenesis 8:1871–1874

    Article  PubMed  CAS  Google Scholar 

  • Donnelly TE, Birt DF, Sittler R, Anderson CL, Choe M, Julius A (1987 b) Dietary fat regulation of the association of protein kinase C activity with epidermal cell membranes. Carcinogenesis 8:1867–1870

    Article  PubMed  CAS  Google Scholar 

  • Driedger PE, Blumberg PM (1980) Specific binding of phorbol ester tumor promoters. Proc Natl Acad Sci USA 77:567–571

    Article  PubMed  CAS  Google Scholar 

  • Eckl PM, Whitcomb WR, Meyer SA, Jirtle RL (1987) Effects of phenobarbital and calcium on the growth of normal and preneoplastic hepatocytes. Proc Am Assoc Cancer Res 28:171

    Google Scholar 

  • Edwards AM, Lucas CM (1985 a) Induction of γ-glutamyl transpeptidase in primary cultures of normal rat hepatocytes by liver tumor promoters and structurally related compounds. Carcinogenesis 6(5):733–739

    Article  PubMed  CAS  Google Scholar 

  • Edwards AM, Lucas CM (1985 b) Phenobarbital and some other liver tumor promoters stimulate DNA synthesis in cultured rat hepatocytes. Biochem Biophys Res Commun 131:103–108

    Article  PubMed  CAS  Google Scholar 

  • Edwards AM, Yusof YAM (1986) Stimulation of hepatocyte DNA synthesis by phorbol esters and mezerein: comparison with effects of xenobiotic liver tumour promoters. Proc Aust Biochem Soc 19:15

    Google Scholar 

  • Eriksson LC, Blanck A, Bock KW, Mannervik B (1987) Metabolism of xenobiotics in hepatocyte nodules. Toxicol Pathol 15:27–42

    Article  PubMed  CAS  Google Scholar 

  • Farber E (1980) The sequential analysis of liver cancer induction. Biochim Biophys Acta 605:149–166

    PubMed  CAS  Google Scholar 

  • Farber E (1984) The biochemistry of preneoplastic liver: a common metabolic pattern in hepatocyte nodules. Can J Biochem Cell Biol 62:486–494

    Article  PubMed  CAS  Google Scholar 

  • Farber E, Sarma DSR (1987) Hepatocarcinogenesis: a dynamic cellular perspective. Lab Invest 56:4–22

    PubMed  CAS  Google Scholar 

  • Fausto N, Thompson NL, Braun L (1987) Purification and culture of oval cells from rat liver. In: Pretlow TG, Pretlow TP (eds) Cell separation. Methods and selected applications. Academic, Orlando, p 45

    Google Scholar 

  • Fischer G, Ullrich D, Bock KW (1985) Effects of N-nitrosomorpholine and phenobarbital on UDP-glucuronyl-transferase in putative preneoplastic foci of rat liver. Carcinogenesis 6:605–609

    Article  PubMed  CAS  Google Scholar 

  • Fitzer CJ, O’Brian CA, Guillem JG, Weinstein IB (1987) The regulation of protein kinase C by chenodeoxycholate, deoxycholate and several structurally related bile acids. Carcinogenesis 8:217–220

    Article  PubMed  CAS  Google Scholar 

  • Fonne R, Meyer UA (1987) Mechanisms of phenobarbital-type induction of cytochrome P-450 isozymes. Pharmacol Ther 33:19–22

    Article  PubMed  CAS  Google Scholar 

  • Fournier A, Murray AW (1987) Application of phorbol ester to mouse skin causes a rapid and sustained loss of protein kinase C. Nature 330:767–769

    Article  PubMed  CAS  Google Scholar 

  • Fujiki H, Tanaka Y, Miyaka R, Kikkawa U, Nishizuka Y, Sugimura T (1984) Activation of protein kinase C by new classes of tumor promoters; teleocidin and debromaplysiatoxin. Biochem Biophys Res Commun 120:339–343

    Article  PubMed  CAS  Google Scholar 

  • Furstenberger G, Marks F (1983) Growth stimulation and tumor promotion in skin. J Invest Dermatol 81:157s-l61s

    Article  PubMed  CAS  Google Scholar 

  • Furstenberger G, Berry DL, Sorg B, Marks F (1981) Skin tumor promotion by phorbol esters is a two-stage process. Proc Natl Acad Sci USA 78:7722–7726

    Article  PubMed  CAS  Google Scholar 

  • Furstenberger G, Sorg B, Marks F (1983) Tumor promotion by phorbol esters in skin: evidence for a memory effect. Science 220:89–92

    Article  PubMed  CAS  Google Scholar 

  • Gainer HStC, Murray AW (1985) Diacylglycerol inhibits gap junctional communication in cultured epidermal cells: evidence for a role of protein kinase C. Biochem Biophys Res Commun 126:1109–1113

    Article  PubMed  CAS  Google Scholar 

  • Glauert HP, Schwarz M, Pitot HC (1986) The phenotypic stability of altered hepatic foci: effect of the short-term withdrawal of phenobarbital and of the long-term feeding of purified diets after the withdrawal of phenobarbital. Carcinogenesis 7:117–121

    Article  PubMed  CAS  Google Scholar 

  • Goerttler K, Loehrke H, Schweizer J, Hesse B (1979) Systemic two-stage carcinogenesis in the epithelium of the forestomach of mice using 7,12-dimethylbenz(a)anthracene as initiator and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate as promoter. Cancer Res 39:1293–1299

    PubMed  CAS  Google Scholar 

  • Goldsworthy T, Campbell HA, Pitot HC (1984) The natural history and dose response characteristics of enzyme-altered foci in rat liver following phenobarbital and diethyl- nitrosamine administration. Carcinogenesis 5:67–71

    Article  PubMed  CAS  Google Scholar 

  • Goldsworthy TL, Hanigan MH, Pitot HC (1986) Models of hepatocarcinogenesis in the rat-contrasts and comparisons. CRC Grit Rev Toxicol 17:61–89

    Article  CAS  Google Scholar 

  • Gschwendt M, Horn F, Kittstein W, Furstenberger G, Marks F (1983) Soluble phorbol ester binding sites and phospholipid- and calcium-dependent protein kinase activiy in cytosol of chick oviduct. FEBS Lett 162:147–150

    Article  PubMed  CAS  Google Scholar 

  • Gupta C, Hattori A, Betschart JM, Virji MA, Shinozuka H (1987) Inhibition of EGF binding in rat hepatocytes by liver tumor promoters. Proc Am Assoc Cancer Res 28:113

    Google Scholar 

  • Hardwick JP, Gonzalez F J, Kasper CB (1983) Transcriptional regulation of rat liver epoxide hydratase, NADPH-cytochrome P-450 oxidoreductase and cytochrome P- 450b genes by phenobarbital. J Biol Chem 258:8081–8085

    PubMed  CAS  Google Scholar 

  • Hartley J A, Gibson NW, Kilkenny A, Yuspa S (1987) 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. Carcinogenesis 8:1827–1830

    Article  PubMed  CAS  Google Scholar 

  • Hasegawa R, Tsuda H, Shirai T, Kurata Y, Masuda A, Ito N (1986) Effect of timing of partial hepatectomy on the induction of preneoplastic liver foci in rats given hepatocarcinogens. Cancer Lett 32:15–23

    Article  PubMed  CAS  Google Scholar 

  • Hayes MA, Lee G, Tatematsu M, Farber E (1987) Influences of diethylnitrosamine on longevity of surrounding hepatocytes and progression of transplanted persistent nodules during phenobarbital promotion of hepatocarcinogenesis. Int J Cancer 40:58–63

    Article  PubMed  CAS  Google Scholar 

  • Hendrich S, Glauert HP, Pitot HC (1986) The phenotypic stability of altered hepatic foci: effects of withdrawal and subsequent readministration of phenobarbital. Carcinogenesis 7:2041–2045

    Article  PubMed  CAS  Google Scholar 

  • Hendrich S, Campbell HA, Pitot HC (1987) Quantitative stereological evaluation of four histochemical markers of altered foci in multistage hepatocarcinogenesis in the rat. Carcinogenesis 8:1245–1250

    Article  PubMed  CAS  Google Scholar 

  • Hennings H (1987) Tumor promotion and progression in mouse skin. In: Barrett JC (ed) Mechanisms of environmental carcinogenesis, vol 2. CRC Press, Baton Rouge, p 59

    Google Scholar 

  • Hennings H, Yuspa SH (1985) Two-stage tumor promotion in mouse skin: an alternative interpretation. JNCI 74:735–740

    PubMed  CAS  Google Scholar 

  • Hennings H, Shores R, Wenk ML, Spangler EF, Tarone R, Yuspa SH (1983) Malignant conversion of mouse skin tumors is increased by tumor initiators and unaffected by tumor promoters. Nature 304:67–69

    Article  PubMed  CAS  Google Scholar 

  • Hennings H, Blumberg PM, Pettit GR, Herald CL, Shores R, Yuspa SH (1987 a) Bryostatin 1, an activator of protein kinase C, inhibits tumor promotion by phorbol esters in SENCAR mouse skin. Carcinogenesis 8:1343–1346

    Article  PubMed  CAS  Google Scholar 

  • Hennings H, Michael D, Lichti U, Yuspa SH (1987 b) Response of carcinogen-altered mouse epidermal cells to phorbol esters and calcium. J Invest Dermatol 88:60–65

    Article  PubMed  CAS  Google Scholar 

  • Hiasa Y, Kitahori Y, Ohshima M, Fujita T, Yuasa T, Konishi H, Miyashiro A (1982) Promoting effects of phenobarbital and barbital on development of thyroid tumors in rats treated with N-bis(2-hydroxypropyl)-nitrosamine. Carcinogenesis 3:1187–1190

    Article  PubMed  CAS  Google Scholar 

  • Ho IK, Harris RA (1981) Mechanism of action of barbiturates. Annu Rev Pharmacol Toxicol 21:83–111

    Article  PubMed  CAS  Google Scholar 

  • Huang CL, Ives HE (1987) Growth inhibition by protein kinase C late in mitogenesis. Nature 329:849–850

    Article  PubMed  CAS  Google Scholar 

  • Ito N, Fukushima S, Tsuda H (1984) Carcinogenicity and modification of carcinogenic response by BHA, BHT and other antioxidants. CRC Crit Rev Toxicol 15:109–150

    Article  Google Scholar 

  • Jacobs S, Cuatrecasas P (1986) Phosphorylation of receptors for insulin and insulin-like growth factor. 1. Effects of hormones and phorbol esters. J Biol Chem 261:934–939

    PubMed  CAS  Google Scholar 

  • Jeffrey AM, Liskamp RMJ (1986) Computer-assisted molecular modelling of tumor promoters: rationale for the activity of phorbol esters, teleocidin B, and aplysiatoxin. Proc Natl Acad Sci USA 83:241–245

    Article  PubMed  CAS  Google Scholar 

  • Jones MJ, Murray AW (1986) Effect of membrane perturbation on protein kinase C activation: treatment with exogenous phospholipase C decreases translocation of enzyme to cellular membranes. Biochem Biophys Res Commun 136:1083–1089

    Article  PubMed  CAS  Google Scholar 

  • Kaufmann WK, MacKenzie SA, Rahija RJ, Kaufman DG (1986 a) Quantitative relationship between initiation of hepatocarcinogenesis and induction of altered cell islands. J Cell Biochem 30:1–9

    Article  PubMed  CAS  Google Scholar 

  • Kaufmann WK, Tsao M-S, Novicki DL (1986 b) In vitro colonization ability appears soon after initiation of hepatocarcinogenesis in the rat. Carcinogenesis 7:669–671

    Article  PubMed  CAS  Google Scholar 

  • Kaufmann W, Rahija R, Kaufman D, Goyette M, Dolan M, Shank P, Fausto N (1987) Cellular and genetic alterations during hepatocarcinogenesis in the rat. Fed Proc 46:972

    Google Scholar 

  • King CS, Cooper J A (1986) Effects of protein kinase C activation after epidermal growth factor binding on epidermal growth factor receptor phosphorylation. J Biol Chem 261:10073–10078

    PubMed  CAS  Google Scholar 

  • Kinsella AR (1986) Multistage carcinogenesis and the biological effects of tumor promoters. In: Evans FJ (ed) Naturally occurring phorbol esters. CRC Press, Baton Rouge, p 33

    Google Scholar 

  • Kinzel V, Furstenberger G, Loehrke H, Marks F (1986) Three-stage tumorigenesis in mouse skin: DNA synthesis as a prerequisite for the conversion stage induced by TPA prior to initiation. Carcinogenesis 7:779–782

    Article  PubMed  CAS  Google Scholar 

  • Kitagawa T, Watanabe R, Kayano T, Sugano H (1980) In vitro carcinogenesis of hepatocytes obtained from acetylaminofluorene-treated rat liver and promotion of their growth by phenobarbital. Gann 71:747–754

    PubMed  CAS  Google Scholar 

  • Klaunig JE, Ruch RJ (1987) Strain and species effects on the inhibition of hepatocyte intercellular communication by liver tumor promoters. Cancer Lett 36:161–168

    Article  PubMed  CAS  Google Scholar 

  • Kleine LP, Whitfield JF, Boynton AL (1986) The glucocorticoid dexamethasone and the tumor promoting artifical sweetener saccharin stimulate protein kinase C from T51B rat liver cells. Biochem Biophys Res Commun 135:33–40

    Article  PubMed  CAS  Google Scholar 

  • Kunz HW, Tennekes HA, Port RE, Schwartz M, Lorke D, Schaude G (1983) Quantitative aspects of chemical carcinogenesis and tumor promotion in liver. Environ Health Perspect 50:113–122

    Article  PubMed  CAS  Google Scholar 

  • Lans M, De Gerlache J, Taper H, Preat V, Roberfroid MB (1983) Phenobarbital as a promoter in the initiation/selection process of experimental rat hepatocarcinogenesis. Carcinogenesis 4:141–144

    Article  PubMed  CAS  Google Scholar 

  • Lechner MC, Sinogas C, Osorio-Almeida ML, Freire MT, Chaumet-Riffaud P, Frain M, Sala-Trepat JM (1987) Phenobarbital-mediated modulation of gene expression in rat liver. Analysis of cDNA clones. Eur J Biochem 163:231–238

    Article  PubMed  CAS  Google Scholar 

  • Loehrke H, Schweizer J, Dederer E, Hesse B, Rosenkranz G, Goerttler K (1983) On the persistence of tumor initiation in two-stage carcinogenesis on mouse skin. Carcinogenesis 4:771–775

    Article  PubMed  CAS  Google Scholar 

  • Loury DJ, Goldsworthy TL, Butterworth BE (1987) The value of measuring cell replication as a predictive index of tissue-specific tumorigenie potential. In: Butterworth BE (ed) Nongenotoxic mechanisms in carcinogenesis. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA, pp 119–136 (Banbury report 25)

    Google Scholar 

  • Makino T, Obara T, Ura H, Kinugasa T, Kobayashi H, Takahashi S, Konishi Y (1986) Effects of phenobarbital and secondary bile acids on liver, gallbladder and pancreas carcinogenesis initiated by N-nitroso-bis(2-hydroxypropyl)amine in hamsters. JNCI 76:967–975

    PubMed  CAS  Google Scholar 

  • McGowan J A (1986) Hepatocyte proliferation in culture. In: Guillouzo A, Guguen-Guillouzo C (eds) Research in isolated and cultured hepatocytes. Libbey Eurotext, London, p 14

    Google Scholar 

  • Mentline R (1986) The tumor promoter 12-O-tetradecanoyl phorbol 13-acetate and regulatory diacylglycerols are substrates for the same carboxylesterase. J Biol Chem 261:7816–7818

    Google Scholar 

  • Miyaka R, Tanaka Y, Tsuda T, Kaibuchi K, Kikkawa U, Nishizuka Y (1984) Activation of protein kinase C by non-phorbol tumor promoter mezerein. Biochem Biophys Res Commun 121:649–656

    Article  Google Scholar 

  • Moore MA, Kitagawa T (1986) Hepatocarcinogenesis in the rat: the effect of promoters and carcinogens in vivo and in vitro. Int Rev Cytol 101:125–173

    Article  PubMed  CAS  Google Scholar 

  • Moore MA, Hacker H-J, Kunz HW, Bannasch P (1983) Enhancement of NNM-induced carcinogenesis in the rat liver by phenobarbital: a combined morphological and enzyme histochemical approach. Carcinogenesis 4:473–479

    Article  PubMed  CAS  Google Scholar 

  • Moore MA, Nakagawa K, Satoh K, Ishikawa T, Sato K (1987) Single GST-P positive liver cells — putative initiated hepatocytes. Carcinogenesis 8:483–486

    Article  PubMed  CAS  Google Scholar 

  • Morin MJ, Kreutter D, Rasmussen H, Sartorelli AC (1987) Disparate effects of activators of protein kinase C on HL-60 promyelocytic leukemia cell differentiation. J Biol Chem 262:11758–11763

    PubMed  CAS  Google Scholar 

  • Mufson RA, Fischer SM, Verma AK, Gleason GL, Slaga TJ, Boutwell RK (1979) Effects of 12–0-tetradecanoylphorbol-l 3-acetate and mezerein on epidermal ornithine decarboxylase activity, isoproterenol-stimulated levels of cyclic adenosine 3’: 5’- monophosphate, and induction of mouse skin tumors in vivo. Cancer Res 39:1979–1984

    Google Scholar 

  • Muir JG, Murray AW (1987) Bombesin and phorbol ester stimulate phosphatidylcholine hydrolysis by phospholipase C: evidence for a role of protein kinase C. J Cell Physiol 130:382–391

    Article  PubMed  CAS  Google Scholar 

  • Munir KM, Rao KV, Bhide SV (1984) Effect of hexachlorocyclohexane on diethylnitrosa- mine-induced hepatocarcinogenesis in rat and its failure to promote skin tumors on dimethylbenz(a)anthracene initiation in mouse. Carcinogenesis 5:479–481

    Article  PubMed  CAS  Google Scholar 

  • Murakami K, Chan SY, Routtenberg A (1986) Protein kinase C activation by cis-fatty acid in the absence of Ca2 + and phospholipids. J Biol Chem 261:15424–15429

    PubMed  CAS  Google Scholar 

  • Murray AW, Fournier A, Hardy SJ (1987) Proteolytic activation of protein kinase C: a physiological reaction? Trend Biochem Sci 12:53–54

    Article  CAS  Google Scholar 

  • Nakanishi K, Fukushima S, Hagiwara A, Tamamo S, Ito N (1982) Organ-specific promoting effects of phenobarbital sodium and sodium saccharin in the induction of liver and urinary bladder tumors in male F344 rats. JNCI 68:497–500

    PubMed  CAS  Google Scholar 

  • Nims RW, Devor DE, Henneman JR, Lubet RA (1987) Induction of alkoxyresorufm O-dealkylases, epoxide hydrolase and liver weight gain: correlation with liver tumor- promoting potential in a series of barbiturates. Carcinogenesis 8:67–71

    Article  PubMed  CAS  Google Scholar 

  • Nishizuka Y (1986) Studies and perspectives of protein kinase C. Science 233:305–311

    Article  PubMed  CAS  Google Scholar 

  • Ogawa K, Solt DB, Farber E (1980) Phenotypic diversity as an early property of putative preneoplastic hepatocyte populations in liver carcinogenesis. Cancer Res 40:725–733

    PubMed  CAS  Google Scholar 

  • Ohno S, Kawasaki H, Imajoh S, Inagaki M, Yokokura H, Sakoh T, Hidaka H (1987) Tissue-specific expression of three distinct types of rabbit protein kinase C. Nature 325:161–166

    Article  PubMed  CAS  Google Scholar 

  • Ono Y, Fujii T, Ogita K, Kikkawa U, Igarashi K, Nishizuka Y (1987) Identification of three additional members of rat protein kinase C family: δ-, ε-, and ζ-subspecies. FEBS Lett 226:125–128

    Article  PubMed  CAS  Google Scholar 

  • Pal BC, Topping DC, Griesemer RA, Nelson FP, Nettesheim P (1978) Development of a system for controlled release of benzo(a)pyrene,7,12-dimethylbenz(a)anthracene and phorbol ester for tumor induction in heterotopic tracheal grafts. Cancer Res 38:1376–1383

    PubMed  CAS  Google Scholar 

  • Pasti G, Lacal JC, Warren BS, Aaronson SA, Blumberg PM (1986) Loss of mouse fibroblast cell response to phorbol esters restored by microinjected protein kinase C. Nature 324:375–377

    Article  PubMed  CAS  Google Scholar 

  • Peraino C, Fry RJ, Staffeldt E (1971) Reduction and enhancement by phenobarbital of hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene. Cancer Res 31:1506–1513

    PubMed  CAS  Google Scholar 

  • Peraino C, Fry RJM, Staffeldt E (1977) Effects of varying the onset and duration of exposure to phenobarbital on its enhancement of 2-acetylaminofluorene-induced hepatic tumorigenesis. Cancer Res 37:3623–3627

    PubMed  CAS  Google Scholar 

  • Peraino C, Staffeldt EF, Haugen DA, Lombard LS, Stevens FJ, Fry RJM (1980) Effects of varying the dietary concentration of phenobarbital on its enhancement of 2-acetylaminofluorene-induced hepatic tumorigenesis. Cancer Res 40:3268–3273

    PubMed  CAS  Google Scholar 

  • Peraino C, Richards WL, Stevens FJ (1983) Multistage hepatocarcinogenesis. In: Slaga TJ (ed) Mechanisms of tumor promotion, vol 1. CRC Press, Baton Rouge, p 1

    Google Scholar 

  • Peraino C, Staffeldt EF, Carnes BA, Ludeman VA, Blomquist JA, Vesselinoviteh SD (1984) Characterization of histochemically detectable altered hepatocyte foci and their relationship to hepatic tumorigenesis in rats treated once with diethylnitrosamine or benzo(a)pyrene within one day after birth. Cancer Res 44:3340–3347

    PubMed  CAS  Google Scholar 

  • Peraino C, Grdina DJ, Staffeldt EF, Russell JF, Prapuolenis A, Carnes BA (1987) Effects of separate and combined treatments with gamma radiation and diethylnitrosamine in neonatal rats on the induction of altered hepatocyte foci and hepatic tumors. Carcinogenesis 8:599–600

    Article  PubMed  CAS  Google Scholar 

  • Pitot HC, Sirica AE (1980) The stages of initiation and promotion in hepatocarcinogenesis. Biochim Biophys Acta 605:191–215

    PubMed  CAS  Google Scholar 

  • Pitot HC, Barsness L, Goldsworthy T, Kitagawa T (1978) Biochemical characterisation of stages of hepatocarcinogenesis after a single dose of diethylnitrosamine. Nature 271:456–458

    Article  PubMed  CAS  Google Scholar 

  • Pitot HC, Goldsworthy T, Campbell HA, Poland A (1980) Quantitative evaluation of the promotion by 2,3,7,8-tetrachlorodibenzo-p-dioxin of hepatocarcinogenesis from diethylnitrosamine. Cancer Res 40:3616–3620

    PubMed  CAS  Google Scholar 

  • Pitot HC, Glauert HP, Hanigan M (1985) The significance of selected biochemical markers in the characterization of putative initiated cell populations in rodent liver. Cancer Lett 29:1–14

    Article  PubMed  CAS  Google Scholar 

  • Pitot HC, Goldsworthy TL, Moran S, Kennan W, Glauert HP, Maronpot RR, Campbell HA (1987) A method to quantitate the relative initiating and promoting potencies of hepatocarcinogenic agents in their dose-response relationships to altered hepatic foci. Carcinogenesis 8:1491–1499

    Article  PubMed  CAS  Google Scholar 

  • Poland A, Mak I, Glover E (1981) Species differences in the responsiveness to l,4-bis[2- (3,5-dichloropyridyloxy)]-benzene, a potent phenobarbital-like inducer of microsome monooxygenase activity. Mol Pharmacol 20:442–450

    PubMed  CAS  Google Scholar 

  • Poland A, Palen D, Glover E (1982) Tumor promotion by TCDD in skin of HRS/J hairless mice. Nature 300:271–273

    Article  PubMed  CAS  Google Scholar 

  • Pound AW, McGuire LJ (1978) Repeated partial hepatectomy as a promoting stimulus for carcinogenic response of liver to nitrosamines in rats. Br J Cancer 37:585–594

    Article  PubMed  CAS  Google Scholar 

  • Preat V, Lans M, de Gerlache J, Taper H, Roberfroid M (1987) Influence of the duration and delay of administration of phenobarbital on its modulating effect on rat hepatocarcinogenesis. Carcinogenesis 8:333–335

    Article  PubMed  CAS  Google Scholar 

  • Pugh TD, Goldfarb S (1978) Quantitative histochemical and autoradiographic studies of hepatocarcinogenesis in rats fed 2-acetylaminofluorene followed by phenobarbital. Cancer Res 38:4450–4457

    PubMed  CAS  Google Scholar 

  • Quintanilla M, Brown K, Ramsden M, Balmain A (1986) Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature 322:78–80

    Article  PubMed  CAS  Google Scholar 

  • Rabes HM, Szymkowiak R (1979) Cell kinetics of hepatocytes during the preneoplastic period of diethylnitrosamine-induced liver carcinogenesis. Cancer Res 39:1298–1304

    PubMed  CAS  Google Scholar 

  • Raik AN, Thum K, Olivers BR (1972) Early effects of 12–0-tetradecanoylphorbol-13- acetate on the incorporation of tritiated precursor into DNA and the thickness of the interfollicular epidermis, and their relation to tumor promotion in mouse skin. Cancer Res 32:1562–1568

    Google Scholar 

  • Rao MS, Reddy JK (1987) Peroxisome proliferation and hepatocarcinogenesis. Carcinogenesis 8:631–636

    Article  PubMed  CAS  Google Scholar 

  • Reddy BS, Watanabe K (1979) Effects of cholesterol metabolites and promoting effect of lithocholic acid in colon carcinogenesis in germ-free and conventional F344 rats. Cancer Res 39:1521–1524

    PubMed  CAS  Google Scholar 

  • Roghani M, DaSilva C, Guvelli D, Castagna M (1987 a) Benzene and toluene activate protein kinase C. Carcinogenesis 8:1105–1107

    Article  PubMed  CAS  Google Scholar 

  • Roghani M, DaSilva C, Castagna M (1987 b) Tumour promoter chloroform is a potent protein kinase C activator. Biochem Biophys Res Commun 142:738–744

    Article  PubMed  CAS  Google Scholar 

  • Rotstein J, Sarma DSR, Farber E (1986) Sequential alterations in growth control and cell dynamics of rat hepatocytes in early precancerous steps in hepatocarcinogenesis. Cancer Res 46:2377–2385

    PubMed  CAS  Google Scholar 

  • Sarma DSR, Rao PM, Rajalakshmi S (1986) Liver tumor promotion by chemicals: models and mechanisms. Cancer Surv 5:781–798

    PubMed  CAS  Google Scholar 

  • Sawada N, Staecker JL, Pitot HC (1987) Effects of tumor-promoting agents 12-O- tetradecanoylphorbol-13-acetate and phenobarbital on DNA synthesis of rat hepatocytes in primary culture. Cancer Res 47:5665–5671

    PubMed  CAS  Google Scholar 

  • Schulte-Hermann R (1985) Tumor promotion in the liver. Arch Toxicol 57:147–158

    Article  PubMed  CAS  Google Scholar 

  • Schulte-Hermann R, Ohde G, Schuppler J, Timmermann-Trosiener I (1981) Enhanced proliferation of putative preneoplastic cells in rat liver following treatment with the tumor promoters phenobarbital, hexachlorocyclohexane, steroid compounds and nafenopin. Cancer Res 41:2556–2562

    PubMed  CAS  Google Scholar 

  • Schulte-Hermann R, Timmermann-Trosiener I, Schuppler J (1986) Facilitated expression of adaptive responses to phenobarbital in putative pre-stages of liver cancer. Carcinogenesis 7:1651–1655

    Article  PubMed  CAS  Google Scholar 

  • Schwarz M, Bannasch P, Kunz W (1983) The effect of pre- and post-treatment with phenobarbital on the extent of γ-glutamyl transpeptidase positive foci induced in rat liver by N-nitrosomorpholine. Cancer Lett 21:17–21

    Article  PubMed  CAS  Google Scholar 

  • Sell S, Leffert HL (1982) An evaluation of cellular lineages in the pathogenesis of experimental hepatocellular carcinoma. Hepatology 2:77–86

    Article  PubMed  CAS  Google Scholar 

  • Serra M, Smith TL, Yamamura HI (1986) Phorbol esters alter muscarinic receptor binding and inhibit polyphosphoinositide breakdown in human neuroblastoma (SH-5Y5Y) cells. Biochem Biophys Res Commun 140:160–166

    Article  PubMed  CAS  Google Scholar 

  • Shirai T, Tsuda H, Ogiso T, Hirose M, Ito N (1987) Organ specific modifying potential of ethinyl estradiol on carcinogenesis initiated with different carcinogens. Carcinogenesis 8:115–119

    Article  PubMed  CAS  Google Scholar 

  • Shubik P (1984) Progression and promotion. JNCI 73:1005–1011

    PubMed  CAS  Google Scholar 

  • Siebert PD, Fukuda M (1985) Regulation of glycophorin gene expression by a tumor promoting phorbol ester in human leukemic K562 cells. J Biol Chem 260:640–645

    PubMed  CAS  Google Scholar 

  • Sirica AE, Jicinsky JK, Heyer EF (1984) Effect of chronic phenobarbital administration on the gamma-glutamyl transpeptidase activity of hyperplastic liver lesions induced in rats by the Solt/Farber initiation selection process of hepatocarcinogenesis. Carcinogenesis 5:1737–1740

    Article  PubMed  CAS  Google Scholar 

  • Slaga TJ (1983) Mechanisms of tumor promotion, vol 1. Tumor promotion in internal organs. CRC Press, Baton Rouge

    Google Scholar 

  • Slaga TJ, Fischer SM, Nelson K, Gleason GL (1980) Studies on the mechanism of skin tumor promotion: evidence for several stages in promotion. Proc Natl Acad Sci USA 77:3659–3663

    Article  PubMed  CAS  Google Scholar 

  • Smith JB, Smith L, Pettit GR (1985) Bryostatins: potent new mitogens that mimic phorbol ester tumor promoters. Biochem Biophys Res Commun 132:939–945

    Article  PubMed  CAS  Google Scholar 

  • Sobczak J, Duguet M (1986) Molecular biology of liver regeneration. Biochimie 68:957–967

    Article  PubMed  CAS  Google Scholar 

  • Taguchi M, Thomas TP, Anderson WB, Farrar WL (1986) Direct phosphorylation of the interleukin 2 receptor TCA antigen epitope by protein kinase C. Biochem Biophys Res Commun 135:239–247

    Article  PubMed  CAS  Google Scholar 

  • Tatematsu M, Hasegawa R, Imaida K, Tsuda H, Ito N (1983 a) Survey of various chemicals from initiating and promoting activities in a short-term in vivo system based on generation of hyperplastic liver nodules in rats. Carcinogenesis 4:381–386

    Article  PubMed  CAS  Google Scholar 

  • Tatematsu M, Nagamine Y, Farber E (1983 b) Redifferentiation as a basis for remodelling of carcinogen-induced hepatocyte nodules to normal appearing liver. Cancer Res 43:5049–5058

    PubMed  CAS  Google Scholar 

  • Tsuda H, Fukushima S, Imaida K, Kurata Y, Ito N (1983) Organ specific promoting effects of phenobarbital and saccharin in induction of thyroid, liver and urinary bladder tumors in rats after initiation with N-nitrosodiethylurea. Cancer Res 43:3292–3296

    PubMed  CAS  Google Scholar 

  • Tsuda H, Hasegawa R, Imaida K, Masui T, Moore MA, Ito N (1984) Modifying potential of thirty-one chemicals on the short-term development of γ-glutamyl transpeptidase- positive foci in diethylnitrosamine-initiated rat liver. Gann 75:876–883

    PubMed  CAS  Google Scholar 

  • Van Duuren BL, Sivak A, Katz C, Siedman I, Melchionne S (1975) The effect of ageing and interval between primary and secondary treatment in two-stage carcinogenesis in mouse skin. Cancer Res 35:502–505

    PubMed  Google Scholar 

  • Verma IM, Sassone-Corsi P (1987) Proto-oncogene fos: complex but versatile regulation. Cell 51:513–514

    Article  PubMed  CAS  Google Scholar 

  • Verma AK, Pong RC, Erickson D (1986) Involvement of protein kinase C activation in ornithine decarboxylase gene expression in primary culture of newborn mouse epidermal cells and in skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res 46:6149–6155

    PubMed  CAS  Google Scholar 

  • Weinberg WC, Berkwits L, Iannaccone PM (1987) The clonal nature of carcinogen- induced altered foci of y-glutamyl transpeptidase expression in rat liver. Carcinogenesis 8:565–570

    Article  PubMed  CAS  Google Scholar 

  • Weinstein IB (1987) Growth factors, oncogenes and multistage carcinogenesis. J Cell Biochem 33:213–224

    Article  PubMed  CAS  Google Scholar 

  • Whitlock JP (1987) The regulation of gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Pharmacol Rev 39:147–161

    PubMed  CAS  Google Scholar 

  • Williams GM, Ohmori T, Katayama S, Rice JM (1980) Alteration by phenobarbital of membrane associated enzymes including gamma-glutamyl transpeptidase in mouse liver neoplasma. Carcinogenesis 1:813–818

    Article  PubMed  CAS  Google Scholar 

  • Yager JD, Roebuck BD, Paluszcyk TL, Memoli VA (1986) Effects of ethinyl estradiol and tamoxifen on liver DNA turnover and new synthesis and appearance of gamma glutamyl transpeptidase-positive foci in female rats. Carcinogenesis 7:2007–2014

    Article  PubMed  CAS  Google Scholar 

  • Yamasaki H, Enomoto T (1985) Role of intercellular communication in BALB/c 3T3 cell transformation. In: Barrett JC, Tennant RW (eds) Carcinogenesis, vol 9. Raven, New York, p 179

    Google Scholar 

  • Yoshimasa T, Sibley DR, Souvier M, Lefkowitz RJ, Caron MG (1987) Cross-talk between cellular signalling pathways suggested by phorbol-ester-induced adenylate cyclase phosphorylation. Nature 327:67–70

    Article  PubMed  CAS  Google Scholar 

  • Yuspa SH, Morgan DL (1981) Mouse skin cells resistant to terminal differentiation associated with initiation of carcinogenesis. Nature 293:72–74

    Article  PubMed  CAS  Google Scholar 

  • Yuspa SH, Kulesz-Martin M, Ben T, Hennings H (1983) Transformation of epidermal cells in culture. J Invest Dermatol 81:162s–l68s

    Article  PubMed  CAS  Google Scholar 

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  1. A. W. Murray
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  2. A. M. Edwards
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  3. C. S. T. Hii
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  1. Chester Beatty Laboratories, The Institute of Cancer Research: Royal Cancer Hospital, Fulham Road, SW3 6JB, London, Great Britain

    Colin S. Cooper Ph. D.  & Philip L. Grover D. Sc.  & 

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Murray, A.W., Edwards, A.M., Hii, C.S.T. (1990). Tumour Promotion: Biology and Molecular Mechanisms. In: Cooper, C.S., Grover, P.L. (eds) Chemical Carcinogenesis and Mutagenesis II. Handbook of Experimental Pharmacology, vol 94 / 2. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-74778-6_6

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