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Transfected lymphocyte extracts of patients with urological tumours: Complement temperature-sensitive adenovirus mutantsin vitro

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Abstract

Patients with renal or bladder cancers exhibit a unique association with adenovirus (Ad) infections. About 60% of them contain antibodies to Ad early antigens Both in their tumour cells and peripheral blood lymphocytes (PBL) they have detectable early Ad antigens known to be involved in malignant cell transformation. Transfection of tumour cell extracts resulted in complementing temperature-sensitive (ts) Ad mutants at nonpermissive temperatures (39 °C) indicating that some cells of the tumour mass possess active functions for Ad. Only 4 to 18% of control subjects were positive in these tests. Here we studied whether lymphocytes might be involved in tumourigenesis by Ad. PBL extracts of patients were transfected into HEp-2 culture cells, which were subsequently superinfected with Ad-5ts 18 andts19 mutants at 39°C. Titration of virus yields indicated complementation in 76% of patients with renal and bladder cancers in contrast to 20% of control individuals. Complementing ability of lymphocytes which had been prestimulated with phytohaemagglutinin (PHA) approached that of tumour extracts. It means that both specimens contain advanced functions in contrast to resting lymphocytes. Lymphocytes are nonpermissive for latently carried Ad infections. Expression, possible transfer of early Ad gene products via frequent contacts with tissue cells can result in removal of tumour suppressor gene products from complexes regulating cell cycle negatively. Further interaction with hormone-sensitive protooncogenes explains tissue, age and gender specificity of urological malignancies. These phenomena suggest an important cofactorial role for Ad in kidney and bladder tumours.

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References

  1. Braithwaite, A., Nelson, C., Skulimowski, A., McGovern, J., Pigott, D., Jenkins, J.: Transactivation of the p53 oncogene by Ela gene products.Virology, 177, 595 (1990).

    Article  PubMed  CAS  Google Scholar 

  2. Csata, S., Kulcsár, G., Dán, P., Nász, I., Verebélyi, A.: Latent virus carrying lymphocytes of patients with urological tumours.Acta Chir. Hung., 28, 321 (1987).

    PubMed  CAS  Google Scholar 

  3. Csata, S., Kulcsár, G., Horváth, J., Nász, I., Ongrádi, J., Verebélyi, A.: Study of antibodies to adenoviruses in patients with tumours of the urogenital system.Int. Urol. Nephrol., 14, 115 (1982).

    Article  PubMed  CAS  Google Scholar 

  4. Deb, S., Jackson, C. T., Subler, M. A., Martin, D. W.: Modulation of cellular and viral promoters by mutant human p53 proteins found in tumor cells.J. Virol., 66, 6164 (1992).

    PubMed  CAS  Google Scholar 

  5. Dumont, D. J., Marcellus, R. C., Bayley, S. T., Branton, P. E.: Role of phosphorylation near the amino terminus of adenovirus type 5 early region 1A proteins.J. Gen. Virol., 74, 583 (1993).

    PubMed  CAS  Google Scholar 

  6. Dyson, N., Guida, P., Münger, K., Harlow, E.: Homologous sequences in adenovirus E1A and human papillomavirus E7 proteins mediate interaction with the same set of cellular proteins.J. Virol., 66, 6893 (1992).

    PubMed  CAS  Google Scholar 

  7. Elgavish, A.: Effects ofEscherichia coli andE. coli lipopolysaccharides on the function of human ureteral epithelial cell cultures in serum-free medium.Infect. Immun., 61, 3304 (1993).

    PubMed  CAS  Google Scholar 

  8. Ewen, M. E., Faha, B., Harlow, E., Livingston, D. M.: Interaction of p107 with cyclin A independent of complex formation with viral oncoproteins.Science, 255, 85 (1992).

    Article  PubMed  CAS  Google Scholar 

  9. Faha, B., Ewen, M. E., Tsai, L.-H., Livingston, D. M., Harlow, E.: Interaction between human cyclin A and adenovirus E1A-associated p107 protein.Science, 255, 87 (1992).

    Article  PubMed  CAS  Google Scholar 

  10. Forslund, O., Hansson, B. G., Rymak, P., Bjerre, B.: Human papillomavirus DNA in urine samples compared with that in simultaneously collected urethra and cervix samples.J. Clin. Microbiol., 31, 1975 (1993).

    PubMed  CAS  Google Scholar 

  11. Goodrich, D. W., Lee, W.-H.: Abrogation by c-myc of G1 phase arrest induced byRb protein but not by p53.Nature 360, 177 (1992).

    Article  PubMed  CAS  Google Scholar 

  12. Graham, F. L., van der Eb, A. J. A new technique for the assay of infectivity of human adenovirus 5 DNA.Virology, 52, 456 (1973).

    Article  PubMed  CAS  Google Scholar 

  13. Gunthert, U., Hofman, M., Rudy, W.: A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells.Cell, 65, 13 (1991).

    Article  PubMed  CAS  Google Scholar 

  14. Hagemeier, C., Bannister, A. J., Cook, A., Kouzarides, T.: The activation domain of transcription factor PU. 1 binds the retinoblastoma (RB) protein and the transcription factor TFIIDin vitro: RB shows sequence similarity to TFIID and TFIIB.Proc. Natl. Acad. Sci. USA, 90, 1580 (1993).

    Article  PubMed  CAS  Google Scholar 

  15. Halpern, B., Ky, N. T., Lagrue, G., Amache, N.: Le test aux lymphocytes en allergologie.Méd. et Hyg., 25, 55 (1967).

    Google Scholar 

  16. Hart, I. R., Saini, A.: Biology of tumour metastasis.Lancet, 339, 1453 (1992).

    Article  PubMed  CAS  Google Scholar 

  17. Hawker, K. L., Pintzas, A., Hennigan, R. F., Gillespie, D. A. F., Ozanne, B. W.: Transformation by thefos andjun oncogene does not increase AP-1 DNA-binding activity.J. Virol., 67, 5487 (1993).

    PubMed  CAS  Google Scholar 

  18. Hoffman, P., Rajakumar, P., Hoffman, B., Heuerts, R., Wold, W. S. M., Carlin, C. R.: Evidence for intracellular down-regulation of the epidermal growth factor (EGF) receptor during adenovirus infection by an EGF-independent mechanism.J. Virol., 66, 197 (1992).

    PubMed  CAS  Google Scholar 

  19. Horváth, J., Faxing, C., Weber, J. M.: Complementation of adenovirus early region 1a and 2a mutants by Epstein-Barr virus immortalized lymphoblastoid cell lines.Virology, 184, 141 (1991).

    Article  PubMed  Google Scholar 

  20. Horwitz, M. S.: Adenoviridae and their replication. In: Fields, B. N., Knipe, D. M. (eds): Virology, 2nd ed. Raven Press, New York 1990, p. 1679.

    Google Scholar 

  21. Horwitz, M. S.: Adenoviruses. In: Fields, B. N., Knipe, D. M. (eds): Virology, 2nd ed. Raven Press, New York 1990, p. 1723.

    Google Scholar 

  22. Ibelgaufts, H., Jones, K. W., Maitland, N., Shaw, N. F.: Adenovirus-related RNA sequences in human neurogenic tumors.Acta Neuropathol. (Berlin), 56, 113 (1982).

    Article  CAS  Google Scholar 

  23. Javier, R., Raska, K., Shenk, T.: Requirement for the adenovirus type 9E4 region in production of mammary tumors.Science, 257, 1267 (1992).

    Article  PubMed  CAS  Google Scholar 

  24. Kannabiran, C., Morris, G. F., Labrie, C., Mathews, M. B.: The adenovirus E1A 12S product displays functional redundancy in activating the human proliferating cell nuclear antigen promoter.J. Virol., 67, 507 (1993).

    PubMed  CAS  Google Scholar 

  25. Kern, S. E., Pietenpol, J. A., Thiagalingam, S., Seymour, A., Kinzler, K. W., Vogelstein, B.: Oncogenic forms of p53 inhibit p53-regulated gene expression.Science, 256, 827 (1992).

    Article  PubMed  CAS  Google Scholar 

  26. Kim, S.-J., Wagner, S., Liu, F., O’Reilly, M. A., Robbins, P. D., Green, M. R.: Retinoblastoma gene product activates expression of the humanTGF-β2 gene through transcription factor ATF-2.Nature, 358, 331 (1992).

    Article  PubMed  CAS  Google Scholar 

  27. Körner, H. Fritzsche, U., Burgert, H.-G.: Tumor necrosis factor α stimulates expression of adenovirus early region 3 proteins: Implications for viral persistence.Proc. Natl. Acad. Sci. USA 89, 11857 (1992).

    Article  PubMed  Google Scholar 

  28. Kulcsár, G., Csata, S., Nász, I.: Isolation of an infectious oncogenic adenovirus strain from the stimulated lymphocytes of a patient with bladder tumour.Acta Microbiol. Hung., 38, 91 (1991).

    PubMed  Google Scholar 

  29. Kulcsár, G., Dán, P., Csata, S., Horváth, J., Nász, I., Verebélyi, A., Ongrádi, J.: Virological studies of malignant tumours of the urogenital system.Acta Microbiol. Hung., 30, 199 (1983).

    PubMed  Google Scholar 

  30. Kurnick, J. T., Kradin, R. L., Blumberg, R., Schneeberger, E. E., Boyle, L. A.: Functional characterization of T lymphocytes propagated from human lung carcinomas.Clin. Immunol. Immunopathol., 38, 367 (1986).

    Article  PubMed  CAS  Google Scholar 

  31. Lane, D. P.: p53, guardian of the genome.Nature, 358, 15 (1992).

    Article  PubMed  CAS  Google Scholar 

  32. Latchman, D. S.: Transcriptional regulation of viral gene expression.Rev. Med. Virol., 3, 115 (1993).

    Article  CAS  Google Scholar 

  33. Levine, A. J.: The p53 protein and its interactions with the oncogene products of the small DNA tumor viruses.Virology, 177, 419 (1990).

    Article  PubMed  CAS  Google Scholar 

  34. Mizoguchi, H., O’Shea, J. J., Longo, D. L., Loeffler, C. M., McVicar, D. W., Ochoa, A. C.: Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice.Science, 258, 1795 (1992).

    Article  PubMed  CAS  Google Scholar 

  35. Nevins, J. R.: E2F: A link between the Rb tumor suppressor protein and viral oncoproteins.Science, 258, 424 (1992).

    Article  PubMed  CAS  Google Scholar 

  36. Nigro, J. M., Baker, S. J., Preisinger, A. C., Jessup, J. M., Hostetter, R., Cleary, K., Bigner, S. H., Davidson, N., Baylin, S., Devilee, P., Glover, T., Collins, F. S., Weston, A., Modali, R., Harris, C. C., Vogelstein, B.: Mutations in thep53 gene occur in diverse human tumour types.Nature, 342, 705 (1989).

    Article  PubMed  CAS  Google Scholar 

  37. Ongrádi, J.: Characterization of virus mutants and their use in the study on biology of viruses (in Hungarian).Biológia, 33, 13 (1985).

    Google Scholar 

  38. Ongrádi, J., Bertók, L., Farkas, J., Nász, I., Bendinelli, M.: Endotoxins and prednisolone alter replication of type 5 adenovirus and its temperature-sensitive mutants.Acta Microbiol. Hung. (in press).

  39. Ongrádi, J., Farkas, J., Csata, S.: Complementability of temperature-sensitive adenovirus mutants with extracts of urogenital tumour cells.Acta Microbiol. Hung., 34, 187 (1987).

    PubMed  Google Scholar 

  40. Ongrádi, J., Farkas, J., Kulcsár, G., Vámos, R., Horváth, J., Sokolova, T. M., Nász, I., Bendinelli, M.: Suppressed phagocytosis but promoted bacterial growth upon the effect of virus free supernatants of infected lymphocytes.Acta Microbiol. Hung. (in press).

  41. Ongrádi, J., Kulcsár, G., Bertók, L.: Toxicity of microbial products in cell culture.Folia Microbiol., 29, 450 (1984).

    Google Scholar 

  42. Ongrádi, J., Telekes, A., Farkas, J., Nász, I., Bendinelli, M.: The effect of prostaglandins on the replication of adenovirus wild types and temperature-sensitive mutants.Acta Microbiol. Hung. (in press).

  43. Radeke, H. H., Schwinzer, B., Resch, K.: Activated T-lymphocytes induce growth inhibition and prostaglandin E2 release from syngeneic glomerular mesangial cells.Clin. Exp. Immunol., 90, 483 (1992).

    Article  PubMed  CAS  Google Scholar 

  44. Rüther, U., Nunnensiek, C., Müller, H. A. G., Rupp, W., Bader, H., Jipp, P.: Evidence of EBV DNA and adenovirus 2 E1A (types 2 and 5) in the mucous membrane of bronchial carcinoma and pleuramesothelioma. In: International Congress of Virology, Glasgow, Scotland, 8–13 August, 1993. Abstracts, p. 310.

  45. Seto, E., Usheva, A., Zambetti, G. P., Momand, J., Horikoshi, N., Weinmann, R., Levine, A. J., Shenk, T.: Wild type p53 binds to the TATA-binding protein and represses transcription.Proc. Natl. Acad. Sci. USA, 89, 12028 (1992).

    Article  PubMed  CAS  Google Scholar 

  46. Shepherd, S. E., Howe, J. A., Mymryk, J. S., Bayley, S. T.: Induction of the cell cycle in baby rat kidney cells by adenovirus type 5 E1A in the absence of E1B and possible influence of p53.J. Virol., 67, 2944 (1993).

    PubMed  CAS  Google Scholar 

  47. Soddu, Lewis, A. M. Jr.: Driving adenovirus type 12-transformed BALB/c mouse cells to express high levels of class I major histocompatibility complex proteins enhances, rather than abrogates, their tumorigenicity.J. Virol., 66, 2875 (1992).

    PubMed  CAS  Google Scholar 

  48. Straight, S. W., Hinkle, P. M., Jewers, R. J., McCance, D. J.: The E5 oncoprotein of human papillomavirus type 16 transforms fibroblasts and effects the downregulation of the epidermal growth factor receptor in keratinocytes.J. Virol., 67, 4521 (1993).

    PubMed  CAS  Google Scholar 

  49. Sugimura, T.: Multistep carcinogenesis: A 1992 perspective.Science, 258, 603 (1992).

    Article  PubMed  CAS  Google Scholar 

  50. Taródi, B., Blair, G. E., Rekosh, D. M., Russell, W. C.: Characterization of two temperature-sensitive mutants of adenovirus type 5.J. Gen. Virol., 43, 531 (1979).

    Article  PubMed  Google Scholar 

  51. Walker, C., Goldsworthy, Wolf, D. C., Everitt, J.: Predisposition to renal cell carcinoma due to alteration of a cancer susceptibility gene.Science, 255, 1693 (1993).

    Article  Google Scholar 

  52. Weber, J. M., Anderson, C. W.: Identification of the gene coding for the precursor of adenovirus core protein X.J. Virol., 62, 1741 (1988).

    PubMed  CAS  Google Scholar 

  53. Whitley, R. J.: Herpes simplex viruses. In: Fields, B. N., Knipe, D. M. (eds): Virology, 2nd ed. Raven Press, New York 1990, p. 1843.

    Google Scholar 

  54. Wigler, M., Pellicer, A., Silverstein, S., Axel, R.: Biochemical transfer of single-copy eukaryotic genes using total cellular DNA as donor.Cell, 14, 725 (1978).

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Institute of Microbiology, Semmelweis University Medical School, Budapest

    J. Ongrádi, J. Farkas & I. Nász

  2. Department of Biomedicine, University of Pisa, Italy

    J. Ongrádi & M. Bendinelli

  3. Department of Urology, Municipal Szent István Hospital, Budapest, Hungary

    S. Csata

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Ongrádi, J., Csata, S., Farkas, J. et al. Transfected lymphocyte extracts of patients with urological tumours: Complement temperature-sensitive adenovirus mutantsin vitro . International Urology and Nephrology 26, 361–373 (1994). https://doi.org/10.1007/BF02768003

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