Skip to main content
SpringerLink
Log in

The Control of Cell Transformation, Mutagenesis, and Differentiation by Chemicals that Initiate or Promote Tumor Formation

  • Chapter
Mutation, Cancer, and Malformation

Part of the book series: Environmental Science Research ((ESRH,volume 31))

  • 356 Accesses

Summary

Transformation of normal cells to malignant cells in vitro by chemical agents has been achieved in a number of fibroblastic and epithelial cell systems. The commonly sused assays for cell transformation employ either diploid Syrian hamster embryo fibroblasts or cells from some permanent mouse fibroblast lines. Under culture conditions these cells have an oriented pattern of growth, are cell density (or contact) inhibited, and are not tumorigenic when implanted in host animals. During cell transformation, these “normal” or control cells are converted into cells that have a hereditary random pattern of cell growth and can form tumors in appropriate hosts. The random pattern of growth of the transformed cells in either a colony or a focus is used as an end point for quantitatively determining cell transformation.

Carcinogenesis (and in vitro cell transformation) is at present believed to be a multistage process in which the initial step is due to a “mutation-like event” caused by the activated carcinogen. Using an in vitro mammalian cell-mediated mutagenicity assay, we were able to establish a relationship between the degree of mutagenesis in this assay, using Chinese hamster V79 cells as target cells, and the degree of activity of carcinogens (initiators) in experimental animal. This assay has also provided the means to study the organ specificity of chemical carcinogens. It is possible, however, that some environmental agents may act not as primary tumor initiating agents, but as tumor promoters, at a later stage of the carcinogenic process. Tumor promoters, including phorbol diesters and teleocidin, which also enhance cell transformation in vitro, usually do not bind to DNA and because they are devoid of mutagenic activity cannot be detected with mutagenicity assays. However, these agents can induce various effects, including a modulation of differentiation processes, in a number of cell types. In some human melanoma and leukemia cells in culture these tumor promoters, after binding to specific cellular receptors, induce the treated cells to diffrentiate into cells with characteristics of mature cells. This property of the tumor promoter to induce cell differentiation suggests that tumor promotion may, among other things, involve the expression of “mutated tumor genes” in a process similar to gene expression during cell differentiation. This paper discusses the usefulness of in vitro cell transformation, differentiation, and mutagenesis systems for studies of the mechanisms of carcinogenesis.

This work is supported by the United States Department of Energy under Contract No. W-31-109-ENG-38.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ames, B. N. , F. D. Lee, and W. E. Durston (1973) An improved bacterial test system for the detection and classification of mutagens and carcinogens.Proc. Natl. Acad. Sci. USA70: 782 – 786.

    Google Scholar 

  2. Armuth, V. , and I. Berenblum (1974) Promotion of mammaryCarcinogenesisand leukemogenic action by phorbol in virgin female Wistar rats.Cancer Res. 34: 2704 – 2707.

    Google Scholar 

  3. Berenblum, I. (1969) A re-evaluation of the concept of coCarcinogenesis.Prog. Exp. Tumor Res. 11: 21 – 30.

    Google Scholar 

  4. Barrett, J. C. , B. D. Crawford, D. L. Grady, L. D. Hester, P. A. Jones, W. F. Benedict, and P. O. P. Ts’o (1977) Temporal acquisition of enhanced fibrinolytic activity by Syrian hamster embryo cells following treatment with benzo(a)pyrene.Cancer Res. 37: 3815 – 3823.

    Google Scholar 

  5. Barrett, J. C. , and P. O. P. Ts’o (1978) Evidence for the progressiveNatureof neoplastic transformationin vitro.Proc. Natl. Acad. Sci. USA75: 3761 – 3765.

    Google Scholar 

  6. Barrett, J. C. , and P. O. P. Tsfo (1978) The relationship between somatic mutation and neoplastic transformation.Proc. Natl. Acad. Sci. USA75: 3297 – 3301.

    Google Scholar 

  7. Berwald, Y. , and L. Sachs (1965)In vitrotransformation of normal cells to timor cells by carcinogenic hydrocarbons.J.Natl.Cancer Inst. 35:641–661.

    Google Scholar 

  8. Borek, C. (1979) Malignant transformationin vitro: Criteria, biological markers, and application in environmental screening of carcinogens. Radiat. Res. 79: 209 – 232.

    Google Scholar 

  9. Bouck, N. , and G. diMayorca (1976) Somatic mutation as the basis for malignant transformation of BHK cells by chemical carcinogens.Nature264: 722 – 727.

    Google Scholar 

  10. Boutwell, R. K. (1974) The function and mechanism of promoters ofCarcinogenesis.Critical Reviews in Toxicology2: 419 – 443.

    Article  Google Scholar 

  11. Brookes, P. , and P. D. Lawley (1964) Evidence for the binding of polynuclear aromatic hydrocarbons to the nucleic acids of mouse skin: Relation between carcinogenic power of hydrocarbons and their binding to deoxyribonucleic acid.Nature202: 781 – 784.

    Google Scholar 

  12. Cabot, M. C. , C. J. Welsh, M. F. Callaham, and E. Huberman (1980) Alterations in lipid metabolism induced by 12-0-tetradecanoylphorbol–13–acetate in differentiating human myeloid leukemia cells.Cancer Res. 40: 3674 – 3679.

    Google Scholar 

  13. Cohen, R. , M. Pacifici, N. Rubenstein, J. Biehl, and H. Holtzer (1977) Effect of a tumor promoter on myogenesis.Nature266: 538 – 540.

    Google Scholar 

  14. Colburn, N. H. , W. F. Vorder Bruegge, J. R. Bates, R. H. Gray, J. D. Rossen, W. H. Kelsey, and T. Shimada (1978) Correlation of anchorage-independent growth with tumorigenicity of chemically transformed mouse epidermal cells.Cancer Res. 38: 624 – 634.

    Google Scholar 

  15. Diamond, L. , T. G. O’Brien, and G. Rovera (1977) Inhibition of adipose conversion of 3T3 fibroblasts by tumor promoters.Nature269: 247 – 249.

    Google Scholar 

  16. DiPaolo, J. A. , R. L. Nelson, and P. J. Donovan (1969) Sarcoma producing cell lines derived from clones transformedin vitroby benzo[a]pyrene.Science165: 917 – 918.

    Google Scholar 

  17. DiPaolo, J. A. , R. L. Nelson, and P. J. Donovan (1971) Morphological, oncogenic, and karyological characteristics of Syrian hamster embryo cells transformedin vitroby carcinogenic polycyclic hydrocarbons.Cancer Res. 31: 1118 – 1127.

    Google Scholar 

  18. DiPaolo, J. A. , N. C. Popescu, and R. Nelson (1973) Chromosomal binding patterns andin vitrotransformation of Syrian hamster cells.Cancer Res. 33: 3250 – 3258.

    Google Scholar 

  19. Doll, R. , and R. Peto (1981) The causes of cancer: Quantitative estimates of avoidable risks of cancer in the United States today.J. Natl. Cancer Inst. 66: 1191 – 1308.

    Google Scholar 

  20. Dunphy, W. G. , K. B. Delclos, and P. M. Blumberg (1980) Characterization of specific binding of [H]phorbol 12,13-dibutyrate and [3H]phorbol 12-myristate 13-acetate to mouse brain.Cancer Res. 40: 3635 – 3641.

    Google Scholar 

  21. Farber, E. (1981) Sequential events in chemicalCarcinogenesis. InCancer-A Comprehensive Treatise, F. F. Becker, Ed. , 2nd Edition, Plenum Press, New York.

    Google Scholar 

  22. Foulds, L. (1975)Neoplastic Development, Vol. 2, Academic Press,-London.

    Google Scholar 

  23. Fugiki, H. , M. Suganuma, N. Matsukura, T. Sugimura, and S. Takayama (1982) Teleocidin fromStreptomycesis a potent promoter of mouse skinCarcinogenesis.Carcinogenesis3: 895 – 898.

    Google Scholar 

  24. Hass, B. S. , C. K. McKeown, D. J. Sardella, E. Boger, P. K. Ghoshal, and E. Huberman (1982) Cell-mediated mutagenicity in Chinese hamster V79 cells of dibenzopyrenes and their bay-region fluorine-substituted derivatives.Cancer Res. 42: 1646 – 1649.

    Google Scholar 

  25. Hecker, E. (1971) Isolation and characterization of the co-carcinogenic principles from croton oil, InMethodsinCancer Research, Vol. 6, H. Busch, Ed. , Academic Press, Inc. , New York, pp. 439 – 484.

    Google Scholar 

  26. Heidelberger, C. (1975) ChemicalCarcinogenesis.Ann. Rev. Biochem. 44: 79 – 122.

    Article  Google Scholar 

  27. Heidelberger, C. , A. E. Freeman, R. J. Pienta, A. Sivak, J. A. Bertram, B. C. Casto, V. C. Dunkel, M. C. Francis, T. Kakunaga, J. B. Little, and L. M. Schechbman (1982) Cell transformation by chemical agents: A review and analysis of the literature. Mutation Res. 114: 283 – 285.

    Google Scholar 

  28. Higginson, V. (1972) The role of geographical pathology in environmentalCarcinogenesis, InEnvironment and Cancer, 24th Symposium of Fundamental Cancer Research, Williams and Wilkins, Baltimore, pp. 62 – 92.

    Google Scholar 

  29. Hoffman, D. R. , and E. Huberman (1982) The control of phospholipid methylation by phorbol diesters in differentiating human myeloid HL-60 leukemia cells.Carcinogenesis3: 875 – 880.

    Google Scholar 

  30. Huberman, E. (1978) Mutagenesis and cell transformation of mammalian cells in culture by chemical carcinogens.J. Environ. Pathol. Toxicol. 2: 29 – 42.

    Google Scholar 

  31. Huberman, E. (1977) Viral antigen induction and mutability of different genetic loci by metabolically activated carcinogenic polycyclic hydrocarbons in cultured mammalian cells, InOrigins of Human Cancer, Vol. 4, H. H. Hiatt, J. D. Watson, and J. A. Winsten, Eds. , Cold Spring Harbor, New York, pp. 1521 – 1535.

    Google Scholar 

  32. Huberman, E. , G. R. Braslawsky, M. Callaham, and H. Fujiki (1982) Induction of differentiation of human promyelocytic leukemia (HL-60) cells by teleocidin and phorbol-12-myristate-13-acetate.Carcinogenesis3:111–114;

    Google Scholar 

  33. Huberman, E. , and M. F. Callaham (1979) Induction of terminal differentiation in human promyelocytic leukemia cells by tumor-promoting agents.Proc. Natl. Acad. Sci. USA76: 1293 – 1297.

    Google Scholar 

  34. Huberman, E. , C. Heckman, and R. Langenbach (1979) Stimulation of differentiated functions in human melanoma cells by tumor-promoting agents and dimethyl sulfoxide.Cancer Res. 39: 2618 – 2624.

    Google Scholar 

  35. Huberman, E. , and C. Jones (1980) The use of liver cell cultures in mutagenesis studies.Ann. N. Y. Acad. Sci. 349: 264 – 272.

    Google Scholar 

  36. Huberman, E. , R. Magerf and L. Sachs (1976) Mutagenesis and transformation of normal cells by chemical carcinogens.Nature264: 360 – 361.

    Google Scholar 

  37. Huberman, E. , and L. Sachs (1966) Cell susceptibility to transformation and cytotoxicity by the carcinogenic hydrocarbon benzo[a]pyrene.Proc. Natl. Acad. Sci. USA56: 1123 – 1129.

    Google Scholar 

  38. Huberman, E. , and L. Sachs (1976) DNA binding and its relationship toCarcinogenesisby different polycyclic hydrocarbons.Int. J. Cancer19: 122 – 127.

    Google Scholar 

  39. Huberman, E. , and L. Sachs (1976) Mutability of different genetic loci in mammalian cells by metabolically activated carcinogenic polycyclic hydrocarbons.Proc. Natl. Acad. Sci. USA73: 188 – 192.

    Google Scholar 

  40. Huberman, E. , L. Sachs, S. K. Yang, and H. V. Gelboin (1976) Identification of the mutagenic metabolites of benzo(a)pyrene in mammalian cells.Proc. Natl. Acad. Sci. USA73: 607 – 611.

    Google Scholar 

  41. Huberman, E. , S. Salzberg, and L. Sachs (1968) Thein vitroinduction of an increase in cell multiplication and cellular life span by the water-soluble carcinogen dimethylnitrosamine.Proc. Natl. Acad. Sci. USA59: 77 – 82.

    Google Scholar 

  42. Huberman, E. , and T. J. Slaga (1979) Mutagenicity and tumor-initiating activity of fluorinated derivatives of 7,12-dimethylbenz(a)anthracene.Cancer Res. 39: 411 – 414.

    Google Scholar 

  43. Jones, C. A. , P. J. Marlino, W. Lijinsky, and E. Huberman (1981) The relationship between the carcinogenicity and mutagenicity of nitrosamines in a hepatocyte-mediated mutagenicity assay.Carcinogenesis2: 1075 – 1077.

    Google Scholar 

  44. Jones, C. A. , R. M. Santella, E. Huberman, J. K. Selkirk, and D. Grunberger (1981) Cell specific activation of benzo(a)pyrene by fibroblasts and hepatocytes.Carcinogenesis4: 1351 – 1357.

    Google Scholar 

  45. Kakunaga, T. (1973) A quantitative system for assay of malignant transformation by chemical carcinogens using a clone derived from Balb/3T3.Int. J. Cancer12: 463 – 473.

    Google Scholar 

  46. Kakunaga, T. (1978) Neoplastic transformation of human diploid fibroblast cells by chemical carcinogens.Proc. Natl. Acad. Sci. USA75: 1334 – 1338.

    Google Scholar 

  47. Kakunaga, T. (1978) Neoplastic transformation of human diploid fibroblast cells by chemical carcinogens.Proc. Natl. Acad. Sci. USA75: 1334 – 1338.

    Google Scholar 

  48. Kuroki, T. , and H. Sato (1968) Transformation and neoplastic developmentin vitroof hamster embryonic cells by 4-nitroquinoline-l-oxide and its derivatives. Natl. Cancer Inst. 41: 53 – 71.

    Google Scholar 

  49. Landolph, J. R. , and C. Heidelberger (1979) Carcinogens produce mutations to ouabain resistance in transformable C3H/10T1/2 CI 8 mouse fibroblasts.Proc. Natl. Acad. Sci. USA76: 930 – 934.

    Google Scholar 

  50. Langenbach, R. , H. J. Freed, D. Raveh, and E. Huberman (1978) Cell specificity in metabolic activation of aflatoxin B. . and benzo(a)pyrene to mutagens for mammalian cells.Nature276: 277 – 280.

    Google Scholar 

  51. Lotem, J. , and L. Sachs (1979) Regulation of normal differentiation in mouse and human myeloid leukemic cells by phorbol esters and the mechanism of tumor promotion.Proc. Natl. Acad. Sci. USA76: 5158 – 5162.

    Google Scholar 

  52. Mager, R. , E. Huberman, S. K. Yang, H. V. Gelboin, and L. Sachs (1977) Transformation of normal hamster cells by benzo(a)pyrene diol-epoxide.Int. J. Cancer19: 814 – 817.

    Google Scholar 

  53. Marchok, A. C. , J. C. Photon, and P. Nettesheim (1978)In vitrodevelopment of oncogenicity in cell lines established from tracheal epithelium preexposed in vivo to 7,12-dimethylbenz(a)anthracene.Cancer Res. 38:2030–2037.

    Google Scholar 

  54. Mondal, S. , and C. Heidelberger (1970)In vitromalignant transformation by methylcholanthrene of the progeny of single cells derived from C3H mouse prostate.Proc.Natl.Acad.Sci.USA65:219–225.

    Google Scholar 

  55. Mondal, S. , D. W. Brankow, and C. Heidelberger (1976) Two-stage chemical oncogenesis in cultures of C3H/10T1/2 cells.Cancer Res. 36: 2254 – 2260.

    Google Scholar 

  56. Miller, J. A. (1970)Carcinogenesisby chemicals: An overview. G. H. A. Clowes Memorial Lecture.Cancer Res. 30:559–576.

    Google Scholar 

  57. Montesano, R. , L. Saint Vincent, C. Drevon, and L. Tomatis (1975) Production of epithelial and mesenchymal tumours with rat liver cells transformedin vitro.Int. J. Cancer16: 550 – 558.

    Google Scholar 

  58. Niedel, J. E. , L. T. Kuhn, and G. R. Vandenbark (1983) Phorbol diester receptor copurifies with protein kinase C.Proc. Natl. Acad. Sci. USA80: 36 – 40.

    Google Scholar 

  59. Peraino, C. , E. F. Staffeldt, D. A. Haugen, L. S. Lombard, F. J. Stevens, and R. J. M. Fry (1980) Effect of varying the dietary concentration of phenobarbital on its enhancement of 2-acetylaminofluorene-induced hepatic tumorigenesis.Cancer Res. 40: 3268 – 3273.

    Google Scholar 

  60. Pitot, H. C. , T. Goldsworthy, and S. Moran (1981) The natural history ofCarcinogenesis: Implications of experimental Carcinogenesis in the genesis of human cancer. J.Supramolec. Struct. Cell Biochem. 17: 133 – 146.

    Article  Google Scholar 

  61. Ravehf D. , T. J. Slaga, and E. Huberman (1982) Cell mediated mutagenesis and timor-initiating activity of the ubiquitous polycyclic hydrocarbon, cyclopenta[c,d]pyrene. Careinogenesis 3: 763 – 766.

    Article  Google Scholar 

  62. Rovera, G. , T. A. O’Brien, and L. Diamond (1977) Tumor promoters inhibit spontaneous differentiation of Friend erythroleukemia cells in cultures.Proc. Natl. Acad. Sci. USA74: 2894 – 2898.

    Google Scholar 

  63. Rovera, G. , D. Santoli, and C. Damsky (1979) Human promyelocytic leukemia cells in culture differentiate into macrophage-like cells when treated with a phorbol diester.Proc. Natl. Acad. Sci. USA76: 2779 – 2783.

    Google Scholar 

  64. Ryffel, B. , C. B. Henning, and E. Huberman (1982) Differentiation of human T–lymphoid leukemia cells into cells that have a suppressor phenotype is induced by phorbol 12-myristate 13-acetate.Proc. Natl. Acad. Sci. USA79: 7336 – 7340.

    Google Scholar 

  65. Selkirk, J. K. (1977) Benzo[a]pyreneCarcinogenesis: A biochemical selection mechanism. J. Toxicol. Environ. Health 2: 1245 – 1258.

    Article  Google Scholar 

  66. Slaga, T. J. , S. M. Fischer, K. Nelson, and G. L. Gleason (1980) Studies on the mechanism of skin tumor promoters: Evidence for several stages in promotion.Proc. Natl. Acad. Sci. USA77: 3659 – 3663.

    Google Scholar 

  67. Slag, T. J. , E. Huberman, J. K. Selkirk, R. Harvey, and W. M. Bracken (1978) Carcinogenicity and mutagenicity of benzo(a)anthracene diols and diol-epoxides.Cancer Res. 38: 1699 – 1704.

    Google Scholar 

  68. Slaga, T. J. , A. Viaje, W. M. Bracken, S. G. Buty, D. R. Miller, S. M. Fischer, C. K. Richter, and J. N. Dumont (1978)In vitrotransformation of epidermal cells from newborn mice.Cancer Res. 38:2246–2252.

    Google Scholar 

  69. Solanki, V. , T. J. Slaga, M. Callaham, and E. Huberman (1981) Down regulation of specific binding of [20-H]phorbol 12,13-dibutyrate and phorbol ester-induced differentiation of human promyelocytic leukemia cells.Proc. Natl. Acad. Sci. USA78: 1722 – 1725.

    Google Scholar 

  70. Weinstein, I. , A. Horowitz, P. Fisher, V. Ivanovic, S. Gattanicelli, and P. Kirschmeier (1982) Mechanisms of multistage Carcinogenesis and their relevance to tumor cell heterogeneity, InTumor Cell Heterogeneity, Academic Press, New York, pp. 261 – 283.

    Google Scholar 

  71. Williams, G. M. , J. M. Elliott, and J. H. Weisburger (1973) Carcinoma after malignant conversionin vitroof epithelial– like cells from rat liver following exposure to chemical carcinogens.Cancer Res. 33: 606 – 612.

    Google Scholar 

  72. Yamaguchi, N. , and I. B. Weinstein (1975) Temperature-sensitive mutants of chemically transformed epithelial cells.Proc. Natl. Acad. Sci. USA72: 214 – 218.

    Google Scholar 

  73. Yamasaki, H. , E. Fibach, U. Nudel, I. B. Weinstein, R. A. Rifkind, and P. A. Marks (1977) Tumor promoters inhibit spontaneous and induced differentiation of murine erythroleukemia cells in cultures.Proc. Natl. Acad. Sci. USA74: 3451 – 3455.

    Google Scholar 

  74. Yuspa, S. H. , H. Hennings, and V. Lichti (1981) Initiator and promoter induced specific changes in epidermal function and biological potential. J. Supramolec. Struct. Cell. Biochem. 17: 245 – 257.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Biological and Medical Research, Argonne National Laboratory, Argonne, Illinois, USA

    Eliezer Huberman

Authors
  1. Eliezer Huberman
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of Michigan Medical School, Ann Harbor, Michigan, USA

    Ernest H. Y. Chu

  2. Oak Ridge National Laboratory, Oak Ridge, Tennesse, USA

    Walderico M. Generoso

Rights and permissions

Reprints and permissions

Copyright information

© 1984 Plenum Press, New York

About this chapter

Cite this chapter

Huberman, E. (1984). The Control of Cell Transformation, Mutagenesis, and Differentiation by Chemicals that Initiate or Promote Tumor Formation. In: Chu, E.H.Y., Generoso, W.M. (eds) Mutation, Cancer, and Malformation. Environmental Science Research, vol 31. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-2399-0_17

Download citation

  • DOI: https://doi.org/10.1007/978-1-4613-2399-0_17

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4612-9463-4

  • Online ISBN: 978-1-4613-2399-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation