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Clinical & Experimental Metastasis

, Volume 8, Issue 1, pp 13–25 | Cite as

The in vivo clearance of Ha-ras transformants by natural killer cells

  • P. W. Johnson
  • J. Stankova
  • D. Dexter
  • J. C. Roder
Article

Abstract

The experiments in this study were designed to test the hypothesis that natural killer (NK) cells play a role in host surveillance against early neoplastic changes in the malignant process. C3H 10T1/2 mouse fibroblasts were transfected with a pSV2-neo plasmid vector which contains EJ, the mutated c-Ha-ras, regulated by its own promoter. Control cells were transfected with pSV2-neo alone and did not contain the ras gene. Oncogene-transfected cells were compared with control cells for lung colony formation following tail vein injection into C3H mice. Intravenous injection of ras-transfected 10T1/2 cells induced marked lung colony formation in vivo, whereas C3H 10T1/2 parental lines or 10T1/2 cells transfected with pSV2-neo alone induced no lung colonies in C3H mice. The colonising potential of ras transfectants could be decreased by augmentation of NK activity by injection of polyinosinic cytidylic acid and increased by depletion of NK effectors with anti-asialo GM1. Experiments with beige mice demonstrated that the mortality of syngeneic, NK-deficient C3H-bg/bg mice injected with ras tranfectants was significantly greater than similarly treated NK-normal C3H-+/bg littermate controls. The results support the view that NK cells are capable in vivo of recognizing early defined stages in the neoplastic process initiated by oncogenes.

Keywords

Natural Killer Natural Killer Cell Natural Killer Activity Tail Vein Injection Beige Mouse 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. [1]
    Bradley, M. O., Kraynak, A. R., Storer, R. D., and Gibbs, J. R., 1986, Experimental metastasis in nude mice of NIH-3T3 cells containing various ras genes. Proceedings of the National Academy of Sciences, USA, 83, 5277–5281.CrossRefGoogle Scholar
  2. [2]
    Collins, J. L., Patek, P. Q., and Cohn, M., 1981, Tumorigenicity and lysis by natural killers. Journal of Experimental Medicine, 153, 89–109.PubMedCrossRefGoogle Scholar
  3. [3]
    Cook, J., Walker, T. A., Lewis, A. M., Ruley, H. E., Graham, F. L., and Pilder, S. H., 1986, Expression of the adenovirus EIA oncogene during cell transformation is sufficient to induce susceptibility to lysis by host inflammatory cells. Proceedings of the National Academy of Sciences, USA, 83, 6965–6969.CrossRefGoogle Scholar
  4. [4]
    Egan, S. E., McCarty, G. A., Jarolim, L., Wright, J., Spiro, I., Hagen, G., and Greenberg, A. H., 1987, Expression of H-ras correlates with metastatic potential: evidence for direct regulation of the metastatic phenotype in 10T1/2 and NIH/3T3 cells. Molecular Cell Biology, 7, 830–837.Google Scholar
  5. [5]
    Eva, A., and Aaronson, S. A., 1983, Frequent activation of c-kis as a transforming gene in fibrosarcomas induced by methylcholanthrene. Science, 220, 955–956.PubMedCrossRefGoogle Scholar
  6. [6]
    Gorelik, E., Wiltrout, R. H., Okumura, K., Habu, S., and Herberman, R. B., 1982, Role of NK cells in the control of metastatic spread and growth of tumor cells in mice. International Journal of Cancer, 30, 107–112.Google Scholar
  7. [7]
    Greenberg, A. H., Egan, S. E., Jarolim, L., Gingras, M., and Wright, J. A., 1987, NK cell regulation of implantation and early long growth of H-ras transformed 10T1/2 fibroblasts. Cancer Research, 47, 4801–4805.PubMedGoogle Scholar
  8. [8]
    Greig, R. G., Koestler, T. P., Trainer, D. L., Corwin, S. P., Miles, L., Kline, T., Sweet, R., Yokoyama, S., and Poste, G., 1985, Tumorigenic and metastatic properties of ‘normal’ and ras-transfected NIH/3T3 cells. Proceedings of the National Academy of Sciences, USA, 82, 3698–3701.CrossRefGoogle Scholar
  9. [9]
    Habu, S., Fubui, H., Shimamura, K., Kasai, M., Nagai, Y., Okumura, K., and Tamaoki, N., 1981, In vivo effects of anti-asialo GM1. I. Reduction of NK activity and enhancement of transplanted tumor growth in nude mice. Journal of Immunology, 127, 34–38.Google Scholar
  10. [10]
    Haliotis, T., Ball, J. K., Dexter, D., and Roder, J. C., 1985, Spontaneous and induced primary oncogenesis in natural killer (NK)-cell-deficient beige mutant mice. International Journal of Cancer, 35, 505–513.Google Scholar
  11. [11]
    Hanna, N., and Fidler, I. J., 1980, Role of natural killer cells in the destruction of circulating tumor emboli. Journal of the National Cancer Institute, 65, 801–809.PubMedGoogle Scholar
  12. [12]
    Hanson, M., Kiessling, R., Andersson, B., Karre, K., and Roder, J. C., 1979, NK-sensitive T cell subpopulation in thymus: Inverse correlations to host NK activity. Nature, 278, 174–176.CrossRefGoogle Scholar
  13. [13]
    Johnson, P. W., Baubock, C., and Roder, J. C., 1985, Transfection of a rat cell line with the v-Ki-ras oncogene is associated with enhanced susceptibility to natural killer cell lysis. Journal of Experimental Medicine, 162, 1732–1737.PubMedCrossRefGoogle Scholar
  14. [14]
    Johnson, P. W., Trimble, W. S., Hozumi, N., Pawson, A. J., and Roder, J. C., 1986, Correlation of natural killer cell recognition with ras oncogene expression. In: Development and Recognition of the Transformed Cell, edited by M. I. Greene and T. Hamaoka (New York: Plenum Publishing Corp.), chapter 16, pp. 243–259.Google Scholar
  15. [15]
    Johnson, P. W., Trimble, W. S., Hozumi, N., and Roder, J. C., 1987, Enhanced lytic susceptibility of Ha-ras transformants after oncogene induction is specific to activated NK cells. Journal of Immunology, 138, 3996–4003.Google Scholar
  16. [16]
    Karre, K., Klein, G. O., Kiessling, R., Klein, G., and Roder, J. C., 1980, Low natural in vivo resistance to syngeneic leukaemias in natural killer deficient mice. Nature, 284, 624–626.PubMedCrossRefGoogle Scholar
  17. [17]
    Kawase, I., Urdal, D. L., Brooks, C. G., and Henney, C. S., 1982, Selective depletion of NK cell activity in vivo and its effect on the growth of NK-sensitive and NK-resistant tumor cell variants. International Journal of Cancer, 29, 567–574.Google Scholar
  18. [18]
    Parada, L. F., and Weinberg, R. A., 1983, Presence of Kirsten murine sarcoma virus ras oncogene in cells transformed by 3-methylcholanthrene. Molecular Cell Biology, 3, 2298–2301.Google Scholar
  19. [19]
    Pozzatti, R., Muschel, R., William, J., Padmanabhan, R., Howard, B., Liotta, L., and Khoury, G., 1986, Primary rat embryo cells transformed by one or two oncogenes show different metastatic potentials. Science, 232, 223–227.PubMedCrossRefGoogle Scholar
  20. [20]
    Reznikoff, C. A., Braknow, D. W., and Heidelberg, C., 1973, Establishment and characterization of a cloned line of C3H mouse embryo cells sensitive to post confluence inhibition of division. Cancer Research, 33, 3231–3237.PubMedGoogle Scholar
  21. [21]
    Riccardi, C., Santoni, A., Barlozzari, T., Puccetti, P., and Herberman, R., 1980, In vivo natural reactivity of mice against tumor cells. International Journal of Cancer, 25, 475–486.Google Scholar
  22. [22]
    Roder, J. C., and Duwe, A., 1979, The beige mutation in the mouse selectively impairs natural killer cell function. Nature, 278, 451–453.PubMedCrossRefGoogle Scholar
  23. [23]
    Roder, J. C., and Haliotis, T., 1980, Do NK cells play a role in anti-tumor surveillance? Immunology Today, 1, 96–100.CrossRefGoogle Scholar
  24. [24]
    Saxena, R. K., Saxena, Q. B., and Adler, W. H., 1982, Defective T-cell response in beige mutant mice. Nature, 295, 240–241.PubMedCrossRefGoogle Scholar
  25. [25]
    Stanbridge, E. J., and Katayama, C., 1978, Principles of morphological and biochemical methods for the detection of mycoplasma contaminants of cell culture. Cellular senescence and somatic cell genetics. Mycoplasma infection of cell cultures, edited by G. J. McGarrity, D. G. Murphy and W. W. Nichols, Vol. 3 (New York: Plenum Press), p. 74.Google Scholar
  26. [26]
    Stern, P., Gidland, M., Orn, A., and Wigzell, H., 1980, Natural killer cells mediate lysis of embryonal carcinoma cells lacking MHC. Nature, 285, 341.PubMedCrossRefGoogle Scholar
  27. [27]
    Sukumar, S., Pulciani, S., Doniger, J., Dipaolo, J. A., Evans, C. H., Zbar, B., and Barbacid, M., 1984, A transforming ras gene in tumorigenic guinea pig cell lines initiated by diverse chemical carcinogens. Science, 223, 1197–1199.PubMedCrossRefGoogle Scholar
  28. [28]
    Talmadge, J. E., Meyers, K. M., Prieuer, D. J., and Starkey, J. R., 1980, Role of NK cells in tumor growth and metastatis in beige mice. Nature, 284, 622–624.PubMedCrossRefGoogle Scholar
  29. [29]
    Thorgeirsson, U. P., Turpeeniemi-Hujanen, W. J. E., Westin, E. H., Heilman, C. A., Talmadge, J. E., and Liotta, L. A., 1985, NIH/3T3 cells transfected with human tumor DNA containing activated ras oncogenes express the metastatic phenotype in nude mice. Molecular Cell Biology, 5, 259–262.Google Scholar
  30. [30]
    Trimble, W. S., Johnson, P. W., Hozumi, N., and Roder, J. C., 1986, Inducible cellular transformation by a metalliothionein-ras hybrid oncogene leads to NK susceptibility. Nature, 321, 782–784.PubMedCrossRefGoogle Scholar
  31. [31]
    Werkmeister, J., Helfand, S., Haliotis, T., Rubin, P., Pross, H., and Roder, J. C., 1982, Tumor cell differentiation modulates susceptibility to Natural Killer cells. Cell Immunology, 69, 122–128.CrossRefGoogle Scholar

Copyright information

© Taylor & Francis Ltd 1990

Authors and Affiliations

  • P. W. Johnson
    • 1
  • J. Stankova
    • 1
  • D. Dexter
    • 2
  • J. C. Roder
    • 1
  1. 1.Departments of Immunology and Medical GeneticsUniversity of Toronto, and The Mount Sinai Hospital Research InstituteToronto, OntarioCanada
  2. 2.Department of PathologyQueen's UniversityKingstonCanada

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