Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 Jul 1;178(1):355–360. doi: 10.1084/jem.178.1.355

Expression of tumor necrosis factor by different tumor cell lines results either in tumor suppression or augmented metastasis

PMCID: PMC2191077  PMID: 8315391

Abstract

Tumor necrosis factor (TNF) produced by tumor cells after gene transfer can effectively suppress the growth of locally growing tumors. We wanted to test the effects of "local" TNF on the growth of a highly metastatic cell line. Therefore, a recombinant retrovirus allowing expression of the TNF gene by the beta-actin promotor has been constructed and used to infect the two tumor cell lines EB and ESB, which grow as solid tumor or metastasize, respectively. Expression of TNF by EB cells resulted in their rapid and dose-dependent rejection. In sharp contrast, mice injected with ESB cells producing similar amounts of TNF showed no signs of tumor suppression, but rather had reduced survival rates that correlated with enhanced hepatic metastases. The accelerated formation of liver metastases by ESB TNF cells could be reversed by an anti-TNF mAb. These results demonstrate the opposite effects TNF may have on tumor growth: suppression of a locally growing tumor and promotion of metastasis formation.

Full Text

The Full Text of this article is available as a PDF (1.7 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson C. Gene therapy researcher under fire over controversial cancer trials. Nature. 1992 Dec 3;360(6403):399–400. doi: 10.1038/360399a0. [DOI] [PubMed] [Google Scholar]
  2. Armentano D., Yu S. F., Kantoff P. W., von Ruden T., Anderson W. F., Gilboa E. Effect of internal viral sequences on the utility of retroviral vectors. J Virol. 1987 May;61(5):1647–1650. doi: 10.1128/jvi.61.5.1647-1650.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Asher A. L., Mulé J. J., Kasid A., Restifo N. P., Salo J. C., Reichert C. M., Jaffe G., Fendly B., Kriegler M., Rosenberg S. A. Murine tumor cells transduced with the gene for tumor necrosis factor-alpha. Evidence for paracrine immune effects of tumor necrosis factor against tumors. J Immunol. 1991 May 1;146(9):3227–3234. [PMC free article] [PubMed] [Google Scholar]
  4. Awwad M., North R. J. Immunologically mediated regression of a murine lymphoma after treatment with anti-L3T4 antibody. A consequence of removing L3T4+ suppressor T cells from a host generating predominantly Lyt-2+ T cell-mediated immunity. J Exp Med. 1988 Dec 1;168(6):2193–2206. doi: 10.1084/jem.168.6.2193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Beutler B., Cerami A. The biology of cachectin/TNF--a primary mediator of the host response. Annu Rev Immunol. 1989;7:625–655. doi: 10.1146/annurev.iy.07.040189.003205. [DOI] [PubMed] [Google Scholar]
  6. Blankenstein T., Qin Z. H., Uberla K., Müller W., Rosen H., Volk H. D., Diamantstein T. Tumor suppression after tumor cell-targeted tumor necrosis factor alpha gene transfer. J Exp Med. 1991 May 1;173(5):1047–1052. doi: 10.1084/jem.173.5.1047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Colombo M. P., Maccalli C., Mattei S., Melani C., Radrizzani M., Parmiani G. Expression of cytokine genes, including IL-6, in human malignant melanoma cell lines. Melanoma Res. 1992 Sep;2(3):181–189. doi: 10.1097/00008390-199209000-00006. [DOI] [PubMed] [Google Scholar]
  8. Dixit V. M., Green S., Sarma V., Holzman L. B., Wolf F. W., O'Rourke K., Ward P. A., Prochownik E. V., Marks R. M. Tumor necrosis factor-alpha induction of novel gene products in human endothelial cells including a macrophage-specific chemotaxin. J Biol Chem. 1990 Feb 15;265(5):2973–2978. [PubMed] [Google Scholar]
  9. Echtenacher B., Falk W., Männel D. N., Krammer P. H. Requirement of endogenous tumor necrosis factor/cachectin for recovery from experimental peritonitis. J Immunol. 1990 Dec 1;145(11):3762–3766. [PubMed] [Google Scholar]
  10. Giavazzi R., Garofalo A., Bani M. R., Abbate M., Ghezzi P., Boraschi D., Mantovani A., Dejana E. Interleukin 1-induced augmentation of experimental metastases from a human melanoma in nude mice. Cancer Res. 1990 Aug 1;50(15):4771–4775. [PubMed] [Google Scholar]
  11. Guild B. C., Finer M. H., Housman D. E., Mulligan R. C. Development of retrovirus vectors useful for expressing genes in cultured murine embryonal cells and hematopoietic cells in vivo. J Virol. 1988 Oct;62(10):3795–3801. doi: 10.1128/jvi.62.10.3795-3801.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Havell E. A., Fiers W., North R. J. The antitumor function of tumor necrosis factor (TNF), I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity. J Exp Med. 1988 Mar 1;167(3):1067–1085. doi: 10.1084/jem.167.3.1067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hock H., Dorsch M., Kunzendorf U., Qin Z., Diamantstein T., Blankenstein T. Mechanisms of rejection induced by tumor cell-targeted gene transfer of interleukin 2, interleukin 4, interleukin 7, tumor necrosis factor, or interferon gamma. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2774–2778. doi: 10.1073/pnas.90.7.2774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Malik S. T., Naylor M. S., East N., Oliff A., Balkwill F. R. Cells secreting tumour necrosis factor show enhanced metastasis in nude mice. Eur J Cancer. 1990;26(10):1031–1034. doi: 10.1016/0277-5379(90)90044-t. [DOI] [PubMed] [Google Scholar]
  15. Mann R., Mulligan R. C., Baltimore D. Construction of a retrovirus packaging mutant and its use to produce helper-free defective retrovirus. Cell. 1983 May;33(1):153–159. doi: 10.1016/0092-8674(83)90344-6. [DOI] [PubMed] [Google Scholar]
  16. Miller A. D., Buttimore C. Redesign of retrovirus packaging cell lines to avoid recombination leading to helper virus production. Mol Cell Biol. 1986 Aug;6(8):2895–2902. doi: 10.1128/mcb.6.8.2895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Miller A. D. Human gene therapy comes of age. Nature. 1992 Jun 11;357(6378):455–460. doi: 10.1038/357455a0. [DOI] [PubMed] [Google Scholar]
  18. Oliff A., Defeo-Jones D., Boyer M., Martinez D., Kiefer D., Vuocolo G., Wolfe A., Socher S. H. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell. 1987 Aug 14;50(4):555–563. doi: 10.1016/0092-8674(87)90028-6. [DOI] [PubMed] [Google Scholar]
  19. Palladino M. A., Jr, Shalaby M. R., Kramer S. M., Ferraiolo B. L., Baughman R. A., Deleo A. B., Crase D., Marafino B., Aggarwal B. B., Figari I. S. Characterization of the antitumor activities of human tumor necrosis factor-alpha and the comparison with other cytokines: induction of tumor-specific immunity. J Immunol. 1987 Jun 1;138(11):4023–4032. [PubMed] [Google Scholar]
  20. Parr I. Response of syngeneic murine lymphomata to immunotherapy in relation to the antigenicity of the tumour. Br J Cancer. 1972 Jun;26(3):174–182. doi: 10.1038/bjc.1972.24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Platzer C., Richter G., Uberla K., Müller W., Blöcker H., Diamantstein T., Blankenstein T. Analysis of cytokine mRNA levels in interleukin-4-transgenic mice by quantitative polymerase chain reaction. Eur J Immunol. 1992 May;22(5):1179–1184. doi: 10.1002/eji.1830220511. [DOI] [PubMed] [Google Scholar]
  22. Rice G. E., Gimbrone M. A., Jr, Bevilacqua M. P. Tumor cell-endothelial interactions. Increased adhesion of human melanoma cells to activated vascular endothelium. Am J Pathol. 1988 Nov;133(2):204–210. [PMC free article] [PubMed] [Google Scholar]
  23. Schirrmacher V., Shantz G., Clauer K., Komitowski D., Zimmermann H. P., Lohmann-Matthes M. L. Tumor metastases and cell-mediated immunity in a model system in DBA/2 mice. I. Tumor invasiveness in vitro and metastasis formation in vivo. Int J Cancer. 1979 Feb;23(2):233–244. doi: 10.1002/ijc.2910230215. [DOI] [PubMed] [Google Scholar]
  24. Strieter R. M., Kunkel S. L., Showell H. J., Remick D. G., Phan S. H., Ward P. A., Marks R. M. Endothelial cell gene expression of a neutrophil chemotactic factor by TNF-alpha, LPS, and IL-1 beta. Science. 1989 Mar 17;243(4897):1467–1469. doi: 10.1126/science.2648570. [DOI] [PubMed] [Google Scholar]
  25. Teng M. N., Park B. H., Koeppen H. K., Tracey K. J., Fendly B. M., Schreiber H. Long-term inhibition of tumor growth by tumor necrosis factor in the absence of cachexia or T-cell immunity. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3535–3539. doi: 10.1073/pnas.88.9.3535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Tracey K. J., Morgello S., Koplin B., Fahey T. J., 3rd, Fox J., Aledo A., Manogue K. R., Cerami A. Metabolic effects of cachectin/tumor necrosis factor are modified by site of production. Cachectin/tumor necrosis factor-secreting tumor in skeletal muscle induces chronic cachexia, while implantation in brain induces predominantly acute anorexia. J Clin Invest. 1990 Dec;86(6):2014–2024. doi: 10.1172/JCI114937. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES