The Role of Oncogenes in Multistage Carcinogenesis

  • K. Brown
  • M. Quintanilla
  • M. Ramsden
  • A. Balmain
Part of the NATO ASI Series book series (NSSA, volume 124)


The existence of specific genes which could transform normal cells into tumour cells was first demonstrated in studies of retroviruses isolated from avian or rodent tumours (1). The prototype oncogene is the src gene of the avian Rous Sarcoma virus. This virus induces tumours with a short latent period in chickens and it has been demonstrated using temperature sensitive mutants that the sre gene has to be expressed in order that transformation should occur (2). Over twenty additional oncogenes have subsequently been discovered in different retrovirus isolates. The products of these oncogenes can be classified into several categories according to their cellular localization or biochemical function as tyrosine kinases (src family) or GTP-binding proteins (ras family). The biological role of these products in cellular transformation is unknown, and the only oncogenes to which a function has been ascribed are those related to growth factors (sis gene) or growth factor receptors (erb B gene). Some oncogenes, for example those belonging to the ras family or the myc gene, have been isolated on several occasions in entirely independent viruses, suggesting that they play a very important role in tumour induction.


Animal Model System Cellular Oncogene Multistage Carcinogenesis Murine Sarcoma Virus Skin Papilloma 
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  1. 1.
    J. M. Bishop, Cellular oncogenes and retroviruses, Ann. Rev. Biochem. 52:301–354 (1983).PubMedCrossRefGoogle Scholar
  2. 2.
    R. L. Erikson, A. F. Purchio, E. Erikson, M. S. Collett, and J. S. Brugge, Molecular events in cells transformed by Rous sarcoma virus, J. Cell Biol. 87:319–325 (1980).PubMedCrossRefGoogle Scholar
  3. 3.
    J. M. Bishop, Enemies within: The genesis of retrovirus oncogenes, Cell 23:5–6 (1981).PubMedCrossRefGoogle Scholar
  4. 4.
    J. M. Bishop and H. E. Varmus, Functions and origins of retroviral transforming genes, in: “Molecular Biology of Tumour-Viruses,” R. Weiss et al., eds., Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (1982), pp. 999–1108.Google Scholar
  5. 5.
    A. Balmain, Transforming ras oncogenes and multistage carcinogenesis, Brit. J. Cancer 51:1–7 (1985).PubMedCrossRefGoogle Scholar
  6. 6.
    G. Klein and E. Klein, Oncogene activation and tumour progress, Carcinogenesis 5:429–435 (1984).PubMedCrossRefGoogle Scholar
  7. 7.
    J. D. Rowley, Human oncogene locations and chromosome aberrations, Nature 301:290–291 (1983).PubMedCrossRefGoogle Scholar
  8. 8.
    J. Groffen, J. R. Stephenson, N. Heisterkamp, A. de Klein, C. R. Bartram, and G. Grosveld, Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22, Cell 36:93–99 (1984).PubMedCrossRefGoogle Scholar
  9. 9.
    K. Alitalo, Amplification of cellular oncogenes in cancer cells, Trends Biochem. Sciences 10:194–197 (1985).CrossRefGoogle Scholar
  10. 10.
    B. G. Neel, W. S. Hayward, H. L. Robinson, J. Fang, and S. M. Astrin, Avian leukosis virus-induced tumours have common proviral integration sites and synthesize discrete new RNAs: Oncogenesis by promoter insertion, Cell 23:323–334 (1981).PubMedCrossRefGoogle Scholar
  11. 11.
    C. S. Cooper, M. Park, D. G. Blair, M. A. Tainsky, K. Huebner, C. M. Croce, and G. F. Vande Woude, Molecular cloning of a new transforming gene from a chemically transformed human cell line, Nature 311:29–33 (1984).PubMedCrossRefGoogle Scholar
  12. 12.
    A. L. Schechter, D. F. Stern, L. Vaidyanathan, S. J. Decker, J. A. Drebin, M. I. Greene, and R. A. Weinberg, The neu oncogene: An erb-B-related gene encoding a 185,000-Mr tumour antigen, Nature 312:513 (1984).PubMedCrossRefGoogle Scholar
  13. 13.
    A. Diamond, G. M. Cooper, J. Ritz, and M. A. Lane, Identification and molecular cloning of the human Blym Transforming gene activated in Burkitt’ s lymphoma, Nature 305:112–116 (1983).PubMedCrossRefGoogle Scholar
  14. 14.
    A. P. Albino, R. Le Strange, A. I. Oliff, M. E. Furth, and L. J. Old, Transforming ras genes from human melanoma: A manifestation of tumour heterogeneity?, Nature 308:69–72 (1984).PubMedCrossRefGoogle Scholar
  15. 15.
    T. Sekiya, M. Fushimi, H. Hori, S. Hirohashi, S. Nishimura, and T. Sugimura, Molecular cloning and the total nucleotide sequence of the human c-Ha-ras-1 gene activated in a melanoma from a Japanese patient, Proc. Natl. Acad. Sci. USA 81:4771–4775 (1984).PubMedCrossRefGoogle Scholar
  16. 16.
    K. H. Vousden and C. J. Marshall, Three different activated ras genes in mouse tumours; evidence for oncogene activation during progression of a mouse lymphoma EMBO J. 3:913–917 (1984).PubMedGoogle Scholar
  17. 17.
    R. K. Boutwell, The function and mechanism of promoters of carcinogenesis, CRC Crit. Rev. Toxicol. 2:419–431 (1974).PubMedCrossRefGoogle Scholar
  18. 18.
    B. L. Van Duuren, A. Sivak, C. Katz, I. Seidman, and S. Melchionne, The effect of aging and interval between primary and secondary treatment in two-stage carcinogenesis in mouse skin, Cancer Res. 35:502–505 (1975).PubMedGoogle Scholar
  19. 19.
    F. J. Burns, M. Vanderlaan, E. Snyder, and R. E. Albert, Induction and progression kinetics of mouse skin papillomas, in: “Carcinogenesis, Vol. 2,” T. J. Slaga, A. Sivak, R. K. Boutwell, eds., Raven Press, New York (1978), pg. 91.Google Scholar
  20. 20.
    H. Hennings, O. Michael, C. Cheng, P. Steinert, K. Holbrook, and S. H. Yuspa, Calcium regulation of growth and differentiation of mouse epidermal cells in culture, Cell 19:245–254 (1980).PubMedCrossRefGoogle Scholar
  21. 21.
    N. E. Fusenig, D. Breitkreug, R. T. Dzarlieva, P. Boukamp, A. Bohnert and W. Tilgen, Growth and differentiation characteristics of transformed keratinocytes from mouse and human skin in vitro and in vivo, J. Invest. Dermatol. 81:168s–175s (1983).PubMedCrossRefGoogle Scholar
  22. 22.
    A. Balmain and I. B. Pragnell, Mouse skin carcinomas induced in vivo by chemical carcinogens have a trans`forming Harvey-ras oncogene, Nature 303:72–74 (1983).PubMedCrossRefGoogle Scholar
  23. 23.
    A. Balmain, M. Ramsden, G. T. Bowden, and J, Smith, Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas, Nature 307:658–660 (1984).PubMedCrossRefGoogle Scholar
  24. 24.
    S. Sukumar, V. Notario, D. Martin-Zanca, and M. Barbacid, Induction of mammary carcinomas in rats by nitroso-methylurea involves malignant activation of H-ras-1 locus by single point mutations, Nature 306:658–661 (1983).PubMedCrossRefGoogle Scholar
  25. 25.
    H. Zarbl, S. Sukumar, A. V. Arthur, D. Martin-Zanca, and M. Barbacid, Direct mutagenesis of Ha-ras-1 oncogenes by N-nitroso-N-methylurea during initiation of mammary carcinogenesis in rats, Nature 315:382–386 (1985).PubMedCrossRefGoogle Scholar
  26. 26.
    I. Guerrero, P. Calzada, A. Mayer, and A. Pellicer, A molecular approach to leukemogenesis: Mouse lymphomas contain an activated c-ras oncogene, Proc. Natl. Acad. Sci. USA 81:202–205 (1984).PubMedCrossRefGoogle Scholar
  27. 27.
    I. Guerrero, A. Villasante, V. Corces, and A. Pellicer, Activation of a c-K-ras oncogene by somatic mutation in mouse lymphomas induced by gamma radiation, Science 225:159–162 (1984).CrossRefGoogle Scholar
  28. 28.
    E. Santos, D. Martin-Zanca, E. P. Reddy, M. A. Pierotti, G. Delia Posta, and M. Barbacid, Malignant activation of a K-ras oncogene in lung carcinoma but not in normal tissue of the same patient, Science 223:661–664 (1984).PubMedCrossRefGoogle Scholar
  29. 29.
    J. Fujita, O. Yoshida, Y. Yuasa, J. S. Rhim, M. Hatanaka, and S. A. Aaronson, Ha-ras oncogenes are activated by somatic alteration in human urinary tract tumours, Nature 309:464–466 (1984).PubMedCrossRefGoogle Scholar
  30. 30.
    R. Muller, J. M. Tremblay, E. D. Adamson, and I. M. Verma, Tissue and cell type specific expression of two human c-onc genes, Nature 304:454–456 (1983).PubMedCrossRefGoogle Scholar
  31. 31.
    R. Muller, D. J. Shamon, J. M. Tremblay, M. J. Cline, and I. M. Verma. Differential expression of cellular oncogenes during pre-and postnatal development of the mouse, Nature 299:640–644 (1982).PubMedCrossRefGoogle Scholar
  32. 32.
    A. D. Riggs and P. A. Jones, 5-Methylcytosine, gene regulation and cancer, Adv. Cancer Res. 40:1 (1983).PubMedCrossRefGoogle Scholar
  33. 33.
    G. Felsenfeld and J. McGhee, Methylation and gene control, Nature 296:602–603 (1982).PubMedCrossRefGoogle Scholar
  34. 34.
    A. Razin and A. D. Riggs, DNA methylation and gene function, Science 210:604–610 (1980).PubMedCrossRefGoogle Scholar
  35. 35.
    M. Ramsden, G. Cole, J. Smith, and A. Balmain, Differential methylation of the c-H-ras gene in normal mouse cells and during skin tumor progression, EMBO J. 4:1449–1454 (1985).PubMedGoogle Scholar
  36. 36.
    A. Eva and S. A. Aaronson, Frequent activation of c-kis as a transforming gene in fibrosarcomas induced by methylcholanthrene, Science 220:955–956 (1983).PubMedCrossRefGoogle Scholar
  37. 37.
    L. F. Parada and R. A. Weinberg, Presence of a Kirsten murine sarcoma virus ras oncogene in cells transformed by 3-methylcholanthrene, Mol. Cell. Biol. 3:2298–2301 (1983).PubMedGoogle Scholar
  38. 38.
    G. P. Margison and P. J. O’Connor, Nucleic acid modifications by N-nitroso compounds, in: “Chemical Carcinogens and DNA, Vol. 1,” Grover, ed., CRC Press, Florida (1978).Google Scholar
  39. 39.
    B. Singer and J. T. Kusmierek, Chemical mutagenesis, Ann. Rev. Biochem. 51:655–693 (1982).PubMedCrossRefGoogle Scholar
  40. 40.
    A. Dipple, J. T. Sawicki, R. C. Moschel, and A. H. Bigger, 7,12-Dimethylbenz(a)anthracene-DNA interactions in mouse embryo cell cultures and mouse skins, in: “Extrahepatic Drug Metabolism and Chemical Carcinogenesis,” J. Rydstrom, J. Montelins, and Bengtsson, eds., Elsevier Science Publishers, B.V., Amsterdam (1983) pp. 439–448.Google Scholar
  41. 41.
    J. Doniger, R. S. Day, and J. A. DiPaolo, Quantitative assessment of the role of O6-methylguanine in the initiation of carcinogenesis by methylating agents, Proc. Natl. Acad. Sci. USA 82:421–425 (1985).PubMedCrossRefGoogle Scholar
  42. 42.
    J. Cairns, The origin of human cancers, Nature 289:353–357 (1981).PubMedCrossRefGoogle Scholar
  43. 43.
    L. Foulds, “Neoplastic Development, Vol. 1,” Academic Press, London (1969).Google Scholar
  44. 44.
    C. J. Der, T. G. Krontiris, and G. M. Cooper, Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses, Proc. Natl. Acad. Sci. USA 79:3637–3640 (1982).PubMedCrossRefGoogle Scholar
  45. 45.
    E. Santos, S. R. Tronick, S. A. Aaronson, S. Pulciani, and M. Barbacid, T24 human bladder carcinoma oncogene is an activated form of the normal human homologue of BALB-and Harvey-MSV transforming genes, Nature 298:343–347 (1982).PubMedCrossRefGoogle Scholar
  46. 46.
    L. F. Parada, C. J. Tabin, C. Shih, and R. A. Weinberg, Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature 297:474–478 (1982).PubMedCrossRefGoogle Scholar
  47. 47.
    S. Pulciani, E. Santos, A. V. Lauver, L. K. Long, S. A. Aaronson, and M. Barbacid, Oncogenes in solid human tumours, Nature 300:539–542 (1982).PubMedCrossRefGoogle Scholar
  48. 48.
    Y. Yuasa, S. K. Srivastava, C. Y. Dunn, J. S. Rhim, E. P. Reddy, and S. A. Aaronson, Acquisition of transforming properties by alternative point mutations within c-bas/has human proto-oncogene, Nature 303:775–779 (1983).PubMedCrossRefGoogle Scholar
  49. 49.
    M. S. McCoy, J. J. Toole, J. M. Cunningham, E. H. Chang, D. R. Lowy, and R. A. Weinberg, Characterization of a human colon/lung carcinoma oncogene, Nature 302:79–81 (1983).PubMedCrossRefGoogle Scholar
  50. 50.
    K. Shimizu, D. Birnbaum, M. A. Ruley, O. Fasano, Y. Suard, L. Edlund, E. Taparowsky, M. Goldfarb, and M. Wigler, Structure of the Ki-ras gene of the human lung carcinoma cell line Calu-1, Nature 304:497–500 (1983).PubMedCrossRefGoogle Scholar
  51. 51.
    K. Shimizu, M. Goldfarb, Y. Suard, M. Perucho, Y. Li, T. Kamata, J. Feramisco, E. Stavnezer, J. Fogh, and M. H. Wigler, Three human transforming genes are related to the viral ras oncogenes, Proc. Natl. Acad, Sci, USA 80:2112–2116 (1983).CrossRefGoogle Scholar
  52. 52.
    K. Shimizu, M. Goldfarb, M. Perucho, and M. Wigler, Isolation and preliminary characterization of the transforming gene of a human neuroblastoma cell line, Proc. Natl. Acad. Sci. USA 80:383–387 (1983).PubMedCrossRefGoogle Scholar
  53. 53.
    H. Nakano, F. Yamamoto, C. Neville, D. Evans, T. Mizuno, and M. Perucho, Isolation of transforming sequences of two human lung carcinomas: Structural and functional analysis of the activated c-K-ras oncogenes, Proc. Natl. Acad. Sci. USA 81:71–75 (1984).PubMedCrossRefGoogle Scholar
  54. 54.
    Y. Taya, K. Hosogai, S. Hirohashi, Y. Shimosato, R. Tsuchiya, N. Tsuchida, M. Fushimi, T. Sekiya, and S. Nishimura, A novel combination of K-ras and myc amplification accompanied by point mutational activation of K-ras in a human lung cancer, EMBO J. 3:2943–2946 (1984).PubMedGoogle Scholar
  55. 55.
    Y. Yuasa, R. A. Gol, A. Chang, I. M. Chiu, E. P. Reddy, S. R. Tronick, and S. A. Aaronson, Mechanism of activation of an N-ras oncogene of SW-1271 human lung carcinoma cells, Proc. Natl. Acad. Sci. USA 8L:3670–3674 (1984).CrossRefGoogle Scholar
  56. 56.
    C. S. Cooper, D. G. Blair, M. K. Oskarsson, M. A. Tainsky, L. A. Eader, and G. F. Vande Woude, Characterization of human transforming genes from chemically transformed teratocarcinoma and pancreatic carcinoma cell lines, Cancer Res. 44:1–10 (1984).PubMedCrossRefGoogle Scholar
  57. 57.
    V. Notario, S. Sukumar, E. Santos, and M. Barbacid, A common mechanism for the malignant activation of ras oncogenes in human neoplasia and in chemically induced animal tumours, in: “Cancer Cells 2/Oncogenes and Viral Genes,” G. F. Vande Woude, A. J. Levine, W. C. Topp, and J. D. Watson, eds., Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (1984).Google Scholar
  58. 58.
    L. A. Feig, R. C. Bast, R. C. Knapp, and G. M. Cooper, Somatic activation of ras k gene in a human ovarian carcinoma, Science 223:698–701 (1984).PubMedCrossRefGoogle Scholar
  59. 59.
    M. H. Kraus, Y. Yuasa, and S. A. Aaronson, A position 12-activated H-ras oncogene in all HS578T mammary carcinosarcoma cells but not normal mammary cells of the same patient, Proc. Natl. Acad. Sci. USA 81:5384–5388 (1984).PubMedCrossRefGoogle Scholar
  60. 60.
    A. Hall, C. J. Marrshall, N. K. Spurr, and R. A. Weiss, Identification of transforming gene in two human sarcoma cell lines as a new member of the ras gene family located on chromosome 1, Nature 303:396–400 (1983).PubMedCrossRefGoogle Scholar
  61. 61.
    M. Souyri and E. Fleissner, Identification by transfection of transforming sequences in DNA of human T-cell leukemia, Proc. Natl. Acad. Sci. USA 80:6676–6679 (1983).PubMedCrossRefGoogle Scholar
  62. 62.
    A. Eva, S. R. Tronick, R. A. Gol, J. H. Pierce, and S. A. Aaronson, Transforming genes of human hematopoietic tumors: frequent detection of ras-related oncogenes whose activation appears to be independent of tumor phenotype, Proc. Natl. Acad. Sci. USA 80:4926–4930, (1983).PubMedCrossRefGoogle Scholar
  63. 63.
    M. J. Murray, J. M. Cunningham, L. F. Parada, F. Dautry, P. Lebowitz, and R. A. Weinberg, The HL-60 transforming sequence: A ras oncogene co-existing with altered myc genes in hematopoietic tumours, Cell 33:749–757 (1983).PubMedCrossRefGoogle Scholar
  64. 64.
    C. Gambke, E. Signer, and C. Moroni, Activation of N-ras gene in bone marrow cells from a patient with acute myeloblastic leukaemia, Nature 307:476–478 (1984).PubMedCrossRefGoogle Scholar
  65. 65.
    M. Quintanilla, K. Brown, M. Ramsden and A. Balmain, Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis, Nature 322:78–80 (1986).PubMedCrossRefGoogle Scholar
  66. 66.
    K. Brown, M. Quintanilla, M. Ramsden, I. B. Kerr, S. Young and A. Balmain, V-ras Genes from Harvey and BALB Murine Sarcoma Viruses can act as Initiators of Two-Stage Mouse Skin Carcinogenesis, Cell 46; 447–456 (1986).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1986

Authors and Affiliations

  • K. Brown
    • 1
  • M. Quintanilla
    • 1
  • M. Ramsden
    • 1
  • A. Balmain
    • 1
  1. 1.Beatson Institute for Cancer ResearchGarscube EstateGlasgowScotland

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