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. 1996 May;122(5):257–265. doi: 10.1007/BF01261401

Stage-specific gene expression during hepatocarcinogenesis in the rat

Henry C Pitot 1,✉
PMCID: PMC12201377  PMID: 8609148

Abstract

The alteration of genetic expression ubiquitously seen in both preneoplastic and neoplastic tissues has been investigated for many years in the hope that the critical molecular changes resulting in cancer can be elucidated. The alteration of the expression of specific genes has already been employed in diagnostic and even screening procedures for this disease. In the past many observations of such alterations have led to a variety of theories but not definitive generalizations. Studies of the alteration of genetic expression may now be viewed in the light of our understanding of the multistage nature of neoplastic development. This brief review describes a number of genes the expressions of which are altered during the stages of initiation and promotion, in contrast to the alteration of expression of genes during the stage of progression. The promotion stage is concerned primarily with the chronic interaction of promoting agents in the environment with the genetic apparatus of the cell, played out on the altered genetic background resulting from the stage of initiation. In contrast, the progression stage is characterized primarily by an evolving karyotypic instability resulting in continual genetic changes during this stage. On the basis of these distinctions it is possible to identify genes the altered expression of which is unique to the stage of progression. The identification of these genes and an understanding of mechanisms resulting in their altered expression will allow not only a better molecular characterization of the progression stage but also the quantitative analysis of neoplastic development in several model animal systems as well as eventually in the human.

Key words: Initiation, Promotion, Progression, Gene expression

Abbreviations

GSTP

glutathioneS-transferase placental form

GTT

ψ-glutamyltranspeptidase

TGF

transforming growth factor

References

  1. Aldaz, CM, Chen, A, Gollahon, LS, Russo, J, Zappler K (1992) Nonrandom abnormalities involving chromosome 1 andHarveyras-1 alleles in rat mammary tumor progression. Cancer Res 52:4791–4798 [PubMed] [Google Scholar]
  2. Anderson MW, Reynolds SH, You M, Maronpot M (1992) Role of proto-oncogene activation in carcinogenesis. Environ Health Perspect 98:13–24 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barrow BJ, O'Riordan MA, Stellato TA, Calkins BM, Pretlow TP (1990) Enzyme-altered foci in colons of carcinogen-treated rats. Cancer Res 50:1911–1916 [PubMed] [Google Scholar]
  4. Bax J, Feringa AW, van Garderen-Hoetmer A, Woutersen RA, Scherer E (1986) Adenosine triphosphatase, a new marker for the differentiation of putative precancerous foci induced in rat pancreas by azaserine. Carcinogenesis 7:457–462 [DOI] [PubMed] [Google Scholar]
  5. Bianchi AB, Fischer SM, Robles AI, Rinchik EM, Conti CJ (1993) Overexpression of cyclin D1 in mouse skin carcinogenesis. Oncogene 8:1127–1133 [PubMed] [Google Scholar]
  6. Boutwell RK (1964) Some biological aspects of skin carcinogenesis. Prog Exp Tumor Res 4:207–250 [DOI] [PubMed] [Google Scholar]
  7. Brown K, Buchmann A, Balmain A (1990) Carcinogen-induced mutations in the mouse c-Ha-ras gene provide evidence of multiple pathways for tumor progression. Proc Natl Acad Sci USA 87:538–542 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Burmer GC, Loeb LA (1989) Mutations in theKRAS2 oncogene during progressive stages of human colon carcinoma. Proc Natl Acad Sci USA 86:2403–2407 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Campbell HA, Xu YD, Hanigan MH, Pitot HC (1986) Application of quantitative stereology to the evaluation of phenotypically heterogeneous enzyme-altered foci in the rat liver. J. Natl Cancer Inst 76:751–767 [DOI] [PubMed] [Google Scholar]
  10. Cavenee WK, Dryja TP, Phillips RA, Benedict WF, Godbout R, Gallie BL, Murphree AL, Strong LC, White RL (1983) Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305:779–784 [DOI] [PubMed] [Google Scholar]
  11. Chang WWL (1984) Histogenesis of colon cancer in experimental animals. Scnad J. Gastroenterol 19:27–43 [PubMed] [Google Scholar]
  12. Cohen SM (1985) Multi-stage carcinogenesis in the urinary bladder. Fd Chem Toxicol 23:521–528 [DOI] [PubMed] [Google Scholar]
  13. Deamant FD, Iannaccone PM (1987) Clonal origin of chemically induced papillomas: separate analysis of epidermal and dermal components. J Cell Sci 88:305–312 [DOI] [PubMed] [Google Scholar]
  14. DiGiovanni J (1992) Multistage carcinogenesis in mouse skin. Pharmacol Ther 54:63–128 [DOI] [PubMed] [Google Scholar]
  15. Dragan YP, Pitot HC (1992) The role of the stages of initiation and promotion in phenotypic diversity during hepatocarcinogenesis in the rat. Carcinogenesis 13:739–750 [DOI] [PubMed] [Google Scholar]
  16. Dragan YP, Laufer C, Koleske AJ, Drinkwater N, Pitot HC (1993) Quantitative comparison of initiation and mutation phenotypes in hepatocytes of the analbuminemic rat. Jpn J Cancer Res 84:175–183 [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Dragan YP, Campbell, HA, Baker K, Vaughan J, Mass M, Pitot HC (1994) Focal and non-focal hepatic expression of placental glutathione S-transferase in carcinogen-treated rats. Carcinogenesis 15:2587–2591 [DOI] [PubMed] [Google Scholar]
  18. Dragan Y, Teeguarden J, Campbell H, Hsia S, Pitot H (1995) The quantitation of altered hepatic foci during multistage hepatocarcinogenesis in the rat: transforming growth factor α expression as a marker for the stage of progression. Cancer Lett 93:73–83 [DOI] [PubMed] [Google Scholar]
  19. Ewing MW, Crysup SE, Phillips JL, Slaga TJ, DiGiovanni J (1988) Enhancement of mezerein-promoted papilloma formation by treatment with 12-0-tetradecanoylphorbol-13-acetate or mezerein prior to initiation. Carcinogenesis 9:405–410 [DOI] [PubMed] [Google Scholar]
  20. Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61:759–767 [DOI] [PubMed] [Google Scholar]
  21. Furuya K, Williams GM (1985) Iron exclusion by proliferative foci and neoplastic lesions induced by 7,12-dimethylbenz(a)anthracene in the rat adrenal cortex. Histochem J 17:213–221 [DOI] [PubMed] [Google Scholar]
  22. Glick AB, Kulkarni AB, Tennenbaum T, Hennings H, Flanders KC, O'Reilly M, Sporn MB, Karlsson S, Yuspa SH (1993) Loss of expression of transforming growth factor β in skin and skin tumors is associated with hyperproliferation and a high risk for malignant conversion. Proc Natl Acad Sci USA 90:6076–6080 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Goldsworthy TL, Pitot HC (1985) The quantitative analysis and stability of histochemical markers of altered hepatic foci in rat liver following initiation by diethylnitrosamine administration and promotion with phenobarbital. Carcinogenesis 6:1261–1269 [DOI] [PubMed] [Google Scholar]
  24. Gould MN (1993) Cellular and molecular aspects of the multistage progression of mammary carcinogenesis in humans and rats. Cancer Biol 4:161–169 [PubMed] [Google Scholar]
  25. Hartwell LH, Kastan MB (1994) Cell cycle control and cancer. Science 266:1821–1828 [DOI] [PubMed] [Google Scholar]
  26. Hirano T, Franzén B, Kato H, Ebihara Y, Auer G (1994) Genesis of squamous cell lung carcinoma. Sequential changes of proliferation, DNA ploidy, and p53 expression. Am J Pathol 144:296–302 [PMC free article] [PubMed] [Google Scholar]
  27. Horowitz JM, Park SH, Bogenmann E, Cheng JC, Yandell DW Kaye FJ, Minna JD, Dryja TP, Weinberg RA (1990) Frequent inactivation of the retinoblastoma antioncogene is restricted to a subset of human tumor cells. Proc Natl Acad Sci USA 87:2775–2779 [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Huber BE, Heilman CA, Thorgeirsson SS (1989) Poly(A+) RNA levels of growth-, differentiation- and transformation-associated genes in the progressive development of hepatocellular carcinoma in the rat. Hepatology 9:756–762 [DOI] [PubMed] [Google Scholar]
  29. Hunter T, Pines J (1994) Cyclins and cancer II: cyclin D and CDK inhibitors come of age. Cell 79:573–582 [DOI] [PubMed] [Google Scholar]
  30. Jang JJ, Henneman JR, Kurata Y, Uno H, Ward JM (1993) Alterations in populations of GST-p-immunoreactive single hepatocytes and hepatocellular foci after a single injection ofN-nitrosodiethylamine with or without phenobarbital promotion in male F344/NCr rats. Cancer Lett 71:89–95 [DOI] [PubMed] [Google Scholar]
  31. Kaufmann WK, Zhang Y, Kaufman DG (1992) Association between expression of transforming growth factor-alpha and progression of hepatocellular foci to neoplasms Carcinogenesis 13:1481–1483 [DOI] [PubMed] [Google Scholar]
  32. Kemp CJ, Donehower LA, Bradley A, Balmain A (1993) Reduction of p53 gene dosage does not increase initiation or promotion but enhances malignant progression of chemically induced skin tumors. Cell 74:813–822 [DOI] [PubMed] [Google Scholar]
  33. Kiguchi K, Beltrán LM, You J, Rho O, DiGiovanni J (1995) Elevation of transforming growth factor-α mRNA and protein expression by diverse tumor promoters in SENCAR mouse epidermis. Mol Carcinog 12:225–235 [DOI] [PubMed] [Google Scholar]
  34. Kitagawa T, Sugano H (1973) Timetable for hepatocarcinogenesis in rat. In: Nakahara W, Hirayama T, Nishioka K, Sugano H (eds) Symposium of the Princess Takamatsu Cancer Research Fund. Analytical and experimental epidemiology of cancer, vol. 3. University Park Press. Baltimore, pp 91–104 [Google Scholar]
  35. Knudson AG (1993) Antioncogenes and human cancer. Proc Natl Acad Sci USA 90:10914–10921 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Kobusch A-B, Schrenk D, Gans G, Münzel P, Werringloer J, Ingelman-Sundberg M, Bock KW (1991) Immunochemical localization and functional characterization of cytochrome P450IIE1 in rat hepatocyte foci and nodules Carcinogenesis 12:2353–2356 [DOI] [PubMed] [Google Scholar]
  37. Kunze E (1979) Development of urinary bladder cancer in the rat. Curr Top Pathol 67:145–232 [DOI] [PubMed] [Google Scholar]
  38. Lang P, Maurer J, Höher D, Bornhöft G, Montenarh M, Berdel WE, Thiel E, Kreuser E-D (1993) Mutation and expression of the p53 tumor suppressor gene in tumor samples and cancer cell lines: comparison of non-isotopic direct DNA-sequencing, immunoblotting and immunohistochemistry. Int J Oncol 2: 347–355 [DOI] [PubMed] [Google Scholar]
  39. Lee DC, Luetteke NC, Petch LA (1993) Transforming growth factor-alpha and its role in neoplastic progression. In: Benz, CC, and Liu ET (eds) Oncogenes and tumor suppressor genes in human malignancies. Kluwer, Boston, pp 233–254 [DOI] [PubMed] [Google Scholar]
  40. Li ZH, Zheng J, Weiss LM, Shibata D (1994) c-K-ras and p53 mutations occur very early in adenocarcinoma of the lung. Am J Pathol 144:303–309 [PMC free article] [PubMed] [Google Scholar]
  41. Maskens AP (1981) Confirmation of the two-step nature of chemical carcinogenesis in the rat colon adenocarcinoma model. Cancer Res 41:1240–1245 [PubMed] [Google Scholar]
  42. Matsukura N, Suzuki K, Kawachi T, Aoyagi M, Sugimura T, Kitaoka H, Numajiri H, Shirota, A, Itabashi M, Hirota T (1980) Distribution of marker enzymes and mucin in intestinal metaplasia in human stomach and relation of complete and incomplete tupes of intestinal metaplasia to minute gastric carcinomas. J Natl Cancer Inst 65:231–240 [PubMed] [Google Scholar]
  43. Meyel DJ van, Ramsay DA, Casson AG, Keeney M, Chambers AF, Cairncross JG (1994) p53 Mutation, expression, and DNA ploidy in evolving gliomas: evidence for two pathways of progression. J Natl Cancer Inst 86:1011–1017 [DOI] [PubMed] [Google Scholar]
  44. Moore MA, Kitagawa T (1986) Hepatocarcinogenesis in the rat: the effect of promoters and carcinogensin vivo andin vitro. Int Rev Cytol 101:125–173 [DOI] [PubMed] [Google Scholar]
  45. Moore MA, Bannasch P, Satoh T, Hacker HJ, Ito N (1987a) Immunohistochemically demonstrated increase in glutathione S-transferase species in propylnitrosamine-induced focal proliferative and neoplastic syrian hamster pancreatic lesions. Virchows Arch 52:479–488 [DOI] [PubMed] [Google Scholar]
  46. Moore MA, Nakagawa K, Satoh K, Ishikawa T, Sato K (1987b) Single GST-P positive liver cells — putative initiated hepatocytes. Carcinogenesis 8:483–486 [DOI] [PubMed] [Google Scholar]
  47. Moore MA, Thamavit W, Ito N (1987c) Comparison of lesions induced in the Syrian golden hamster by diethylnitrosamine, dimethylhydrazine, and dibutylnitrosamine: influence of subsequent butylated hydroxyanisole treatment. J Natl Cancer Inst 78:295–301 [PubMed] [Google Scholar]
  48. Moriyama S, Kawaoi A, Hirota N (1983) Localization and significance of gamma-glutamyl transpeptidase during experimental thyroid carcinogenesis in rats. Acta Histochem Cytochem 16:567–576 [Google Scholar]
  49. Müller H, Lukas J, Schneider A, Warthoe, P, Bartek J, Eilers M, Strauss M (1994) Cyclin D1 expression is regulated by the retinoblastoma protein. Proc Natl Acad Sci USA 91: 2945–2949 [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Nakano H, Hatayama I, Satoh K, Suzuki S, Sato K, Tsuchida S (1994) c-Jun expression in single cells and preneoplastic foci induced by diethylnitrosamine in B6C3F1 mice: comparison with the expression of pi-class glutathione S-transferase. Carcinogenesis 15:1953–1957 [DOI] [PubMed] [Google Scholar]
  51. Navone NM, Troncoso P, Pisters LL, Goodrow TL, Palmer JL, Nichols WW, Eschenbach ACvon Conti CJ (1993) p53 Protein accumulation and gene mutation in the progression of human prostate carcinoma. J Natl Cancer Inst 85:1657–1669 [DOI] [PubMed] [Google Scholar]
  52. Neveu MJ, Hully JR, Paul DL, Pitot HC (1990) Reversible alteration in the expression of the gap junctional protein connexin 32 during tumor promotion in rat liver and its role during cell proliferation Cancer Commun 2:21–31 [DOI] [PubMed] [Google Scholar]
  53. Newman MJ (1993) Transforming growth factor beta and the cell surface in tumor progression. Cancer Metast Rev 12:239–254 [DOI] [PubMed] [Google Scholar]
  54. Nishimura S, Sekiya T (1987) Human cancer and cellular oncogenes. Biochem J 243:313–327 [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Ohmori T, Hiasa Y, Murata Y, Williams GM (1982) Gamma glutamyl transpeptidase activity in carcinogen-induced epithelial lesions of rat kidney. Gann 73:543–548 [PubMed] [Google Scholar]
  56. Ordman AB, Cleaveland JS, Boutwell RK (1985) 12-0-Tetradecanoylphorbol-13-acetate promotes tumors prior to initiation in two-stage promotion. Cancer Lett 29:79–84 [DOI] [PubMed] [Google Scholar]
  57. Ozanne B, Shum A, Richards CS, Cassells D, Grossman D, Trent J, Gusterson B, Hendler F (1985) Evidence for an increase of EGF receptors in epidermoid malignancies. In: Feremisco J, Ozanne B, Stiles C (eds) Cancer cells 3, Growth factors and transformation. Cold Spring harbor Laboratory, Cold Spring Harbor pp 41–48 [Google Scholar]
  58. Ozono S, Homma Y, Oyasu R (1985) Gamma glutamyl transpeptidase activity in rat urothelium treated with bladder carcinogens. Cancer Lett 29:49–57 [DOI] [PubMed] [Google Scholar]
  59. Peraino C, Staffeldt EF, Carnes BA, Ludeman VA, Blomquist JA, Vesselinovitch 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] [Google Scholar]
  60. Pitot HC (1986) Fundamentals of oncology, 3rd ed. Marcel, Dekker, New York [Google Scholar]
  61. Pitot HC (1989) Progression: the terminal stage in carcinogenesis. Jpn J Cancer Res 80:599–607 [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Pitot HC (1990) Altered hepatic foci: their role in murine hepatocarcinogenesis. Annu Rev Pharmacol Toxicol 30:465–500 [DOI] [PubMed] [Google Scholar]
  63. Pitot HC (1993) The molecular biology of carcinogenesis. Cancer 72:962–970 [DOI] [PubMed] [Google Scholar]
  64. Pitot HC (1995) The role of receptors in multistage carcinogenesis. Mutat Res (in press) [DOI] [PubMed]
  65. Pretlow TP, O'Riordan MA, Kolman MF, Jurcisek JA (1990) Colonic aberrant crypts in azoxymethane-treated F344 rats have decreased hexosaminidase activity. Am J Pathol 136:13–16 [PMC free article] [PubMed] [Google Scholar]
  66. Rainier S, Feinberg AP (1994) Genomic imprinting, DNA methylation, and cancer. J Natl Cancer Inst 86:753–759 [DOI] [PubMed] [Google Scholar]
  67. Rao MS, Reddy JK (1987) Phenotypic properties of preneoplastic and neoplastic hepatic lesions induced by peroxisome proliferators in rats. In: Fahimi HD, Sies H (eds) Peroxisomes in biology and medicine. Springer. Heidelberg, Berlin New York, pp 263–272 [Google Scholar]
  68. Reed JA, McNutt NS, Prieto VG, Albino AP (1994) Expression of transforming growth factor-β2 in malignant melanoma correlates with the depth of tumor invasion. Am J Pathol 145:97–104 [PMC free article] [PubMed] [Google Scholar]
  69. Rho O, Beltrán LM, Gimenez-Conti IB, DiGiovanni J (1994) Altered expression of the epidermal growth factor receptor and transforming growth factor-α during multistage skin carcinogenesis in SENCAR mice. Mol. Carcinog 11:19–28 [DOI] [PubMed] [Google Scholar]
  70. Robles AI, Conti CJ (1995) Early overexpression of cyclin D1 protein in mouse skin carcinogenesis. Carcinogenesis 16:781–786 [DOI] [PubMed] [Google Scholar]
  71. Roomi MW, Ho RK, Sarma DSR, Farber E (1985), A common biochemical pattern in preneoplastic hepatocyte nodules generated in four different models in the rat. Cancer Res 45:564–571 [PubMed] [Google Scholar]
  72. Ruggeri B, Caamano J, Goodrow T, DiRado M, Bianchi A Trono D, Conti CJ, Klein-Szanto AJP (1991) Alterations of thep53 tumor suppressor gene during mouse skin tumor progression. Cancer Res 51:6615–6621 [PubMed] [Google Scholar]
  73. Ruggeri B, Caamano J, Slaga TJ, Conti CJ, Nelson WJ, Klein-Szanto AJP (1992) Alterations in the expression of uvomorulin and Na+, K+-adenosine triphosphatase during mouse skin tumor progression. Am J Pathol 140:1179–1185 [PMC free article] [PubMed] [Google Scholar]
  74. Said TK, Medina D (1995) Cell cyclins and cyclin-dependent kinase activities in mouse mammary tumor development. Carcinogenesis 16:823–830 [DOI] [PubMed] [Google Scholar]
  75. Sato K (1989) Glutathione, transferases as, markers of preneoplasia and neoplasia. Adv Cancer Res 52:205–255 [DOI] [PubMed] [Google Scholar]
  76. Satoh K, Hatayama I, Tateoka N, Tamai K, Shimizu T, Tatematsu M, Ito N, Sato K (1989) Transient induction of single GST-P positive hepatocytes by DEN Carcinogenesis 10:2107–2111 [DOI] [PubMed] [Google Scholar]
  77. Schaff Z, Hsia CC, Sarosi I, Tabor E (1994) Overexpression of transforming growth factor-α in hepatocellular carcinoma and focal nodular hyperplasia from European patients. Hum Pathol 25:644–651 [DOI] [PubMed] [Google Scholar]
  78. Scherer E, Feringa AW, Emmelot P (1984) Initiation-promotioninitiation. Induction of neoplastic foci within islands of precancerous liver cells in the rat. In: Börzsönyi M, Lapis K, Day NE, Yamasaki H (eds) Models, mechanisms and etiology of tumour promotion. International Agency for Research on Cancer, Lyon, pp 57–66 [Google Scholar]
  79. Schulte-Hermann R, Bursch W, Kraupp-Grasl B, Oberhammer F, Wagner A, Jirtle R (1993) Cell proliferation and apoptosis in normal liver and preneoplastic foci. Environ Health Perspect 101:87–90 [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Sidransky D, Mikkelsen T, Schwechheimer K, Rosenblum ML, Cavanee W, Vogelstein B (1992) Clonal expansion of p53 mutant cells is associated with brain tumour progression. Nature 355:846–847 [DOI] [PubMed] [Google Scholar]
  81. Silverman JA, Kuhlmann ET, Zurlo J, Yager JD, Longnecker DS (1990) Expression of c-myc, c-raf-1, and c-Ki-ras in azaserineinduced pancreatic carcinomas and growing pancreas in rats. Mol Carcinog 3:379–386 [DOI] [PubMed] [Google Scholar]
  82. Slaga TJ, Fischer SM, Weeks CE, Klein-Szanto AJP, Reiners J (1982) Studies on the mechanisms involved in multistage carcinogenesis in mouse skin. J Cell Biochem 18:99–119 [DOI] [PubMed] [Google Scholar]
  83. Solt DB, Calderon-Solt L, Odajima T (1985) Rapid induction of carcinomas and λ-glutamyl transpeptidase-rich clones inN-methyl-N-benzylnitrosamine-treated hamster buccal pouch. J Natl Cancer Inst 74:437–445 [PubMed] [Google Scholar]
  84. Srivastava S, Wang S, Tong YA, Hao Z-M, Chang EH (1993) Dominant negative effect of a germ-line mutantp53: a step fostering tumorigenesis. Cancer Res 53:4452–4455 [PubMed] [Google Scholar]
  85. Tanaka S, Toh Y, Adachi E, Matsumata T, Mori R, Sugimachi K (1993) Tumor progression in hepatocellular carcinoma may be mediated byp53 mutation. Cancer Res 53:2884–2887 [PubMed] [Google Scholar]
  86. Tendler Y, Reshef R, Cohen I, Barzilai M, Shasha SM, Rotter V, Shkolnik T (1994) Histochemical studies of progressive p53 mutations during colonic carcinogenesis in Sprague-Dawley rats induced byN-methyl-N-nitro-nitrosoguanidine or azoxymethane. Pathobiology 62:232–237 [DOI] [PubMed] [Google Scholar]
  87. Tsuda H, Hacker HJ, Katayama H, Masui T, Ito N, Bannasch P (1986) Correlative histochemical studies on preneoplastic and neoplastic lesions in the kidney of rats treated with nitrosamines. Virchows Arch 51:385–404 [DOI] [PubMed] [Google Scholar]
  88. Tsuda H, Inoue T, Asamoto M, Fukushima S, Ito N, Okamura T, Ohtaguro K, Washida H, Satoh K, Amelizad Z, Oesch F (1989) Comparison of enzyme phenotypes in human bladder tumours and experimentally induced hyperplastic and neoplastic lesions of the rat urinary bladder. Virchows Arch [B] Cell Pathol 56:307–316 [DOI] [PubMed] [Google Scholar]
  89. Tsuda H, Asamoto M, Baba H, Iwahori Y, Matsumoto K., Iwase T, Nishida Y, Nagao S., Hakoi K, Yamaguchi S, Ozaki K, Yamasaki H (1995) Cell proliferation and advancement of hepatocarcinogenesis in the rat are associated with a decrease in connexin 32 expression. Carcinogenesis 16:101–105 [DOI] [PubMed] [Google Scholar]
  90. Tsuji K, Gopalan P, Lehmann K, Kimura M, Horiuchi A., Sato K, Lotlikar PD (1992) Species and sex differences, of aflatoxin B1-induced glutathione S-transferase placental form in single hepatocytes. Cancer Lett 66:249–254 [DOI] [PubMed] [Google Scholar]
  91. Vesselinovitch SD, Hacker HJ Bannasch P (1985) Histochemical characterization of focal hepatic lesions induced by single diethylnitrosamine treatment in infant mice. Cancer Res 45:2774–2780 [PubMed] [Google Scholar]
  92. Weinberg WC, Berkwits L, Iannaccone PM (1987) The clonal nature of carcinogen-induced altered foci of λ-glutamyl transpeptidase expression in rat liver. Carcinogenesis 8: 565–570 [DOI] [PubMed] [Google Scholar]
  93. Wildrick DM, Boman BM (1994) Does the human retinoblastoma gene have a role in colon cancer? Mol Carcinog 10:10–7 [DOI] [PubMed] [Google Scholar]
  94. Yamaguchi F, Saya H, Bruner JM, Morrison RS (1994) Differential expression of two fibroblast growth factor-receptor genes is associated with malignant progression in human astrocytomas. Proc Natl Acad Sci USA 91:484–488 [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Yokota J, Sugimura T (1993) Multiple steps in carcinogenesis involving alterations of multiple tumor suppressor genes. FASEB J 7:920–925 [DOI] [PubMed] [Google Scholar]
  96. Yokota K, Singh U, Shinozuka H (1990) Effects of a choline-deficient diet and a hypolipidemic agent on single glutathioneS-transferase placental form-positive hepatocytes in rat liver. Jpn J Cancer Res 81:129–134 [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Yoshida T (1993) Über die serienweise Verfolgung der Veränderungen der Leber der experimentellen, Hepatomerzeugung durcho-amiazotoluol. Trans Japan Pathol Soc 23:636–638 [Google Scholar]
  98. Yuspa SH, Kilkenny A, Cheng C, Roop D, Hennings H, Kruszewski F, Lee E Trickland J, Greenhalgh DA (1991) Alterations in epidermal biochemistry as a consequence of stage-specific genetic changes in skin carcinogenesis. Environ Health Perspect 93:3–10 [DOI] [PMC free article] [PubMed] [Google Scholar]

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