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. 1993 May 1;177(5):1391–1398. doi: 10.1084/jem.177.5.1391

Enhancement of experimental metastasis by tumor necrosis factor

PMCID: PMC2191015  PMID: 8478614

Abstract

The influence of endogenous and exogenous tumor necrosis factor (TNF) on metastasis was investigated in an experimental fibrosarcoma metastasis model. A single intraperitoneal injection of recombinant human (rh) TNF or recombinant mouse (rm) TNF into mice 5 h before intravenous inoculation of methylcholanthrene-induced fibrosarcoma cells (CFS1) induced a significant enhancement of the number of metastases in the lung. Dose responses of rmTNF and rhTNF demonstrated a stronger metastasis-augmenting effect by rmTNF compared with rhTNF. This effect was time dependent, as administration of rmTNF 5 h before or 1 h but not 24 h after tumor cell inoculation caused an increase of tumor cell colony formation on the lung surface, suggesting an influence of TNF on the vascular adhesion and diapedesis of tumor cells. Since tumor-bearing mice showed an enhanced ability to produce TNF after endotoxin injection compared to control mice, tumor-bearing mice were treated with anti-mTNF antibodies. Neutralization of endogenous tumor-induced TNF led to a significant decrease of the number of pulmonary metastases. Histological analysis of micrometastases in the lung on day 5 by silver staining of proteins associated with nucleolar organizer regions revealed more metastatic foci and augmented proliferative activity of the tumor cells after rmTNF pretreatment of mice. However, no direct effect of rmTNF on the proliferation rate of tumor cells was seen in vitro. These findings suggest that low doses of endogenous TNF or administered TNF during cytokine therapy might enhance the metastatic potential of circulating tumor cells.

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Selected References

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  1. Andus T., Heinrich P. C., Bauer J., Tran-Thi T. A., Decker K., Männel D., Northoff H. Discrimination of hepatocyte-stimulating activity from human recombinant tumor necrosis factor alpha. Eur J Immunol. 1987 Aug;17(8):1193–1197. doi: 10.1002/eji.1830170817. [DOI] [PubMed] [Google Scholar]
  2. Balkwill F., Osborne R., Burke F., Naylor S., Talbot D., Durbin H., Tavernier J., Fiers W. Evidence for tumour necrosis factor/cachectin production in cancer. Lancet. 1987 Nov 28;2(8570):1229–1232. doi: 10.1016/s0140-6736(87)91850-2. [DOI] [PubMed] [Google Scholar]
  3. Bereta M., Bereta J., Cohen S., Zaifert K., Cohen M. C. Effect of inflammatory cytokines on the adherence of tumor cells to endothelium in a murine model. Cell Immunol. 1991 Sep;136(2):263–277. doi: 10.1016/0008-8749(91)90351-b. [DOI] [PubMed] [Google Scholar]
  4. Bertolini D. R., Nedwin G. E., Bringman T. S., Smith D. D., Mundy G. R. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature. 1986 Feb 6;319(6053):516–518. doi: 10.1038/319516a0. [DOI] [PubMed] [Google Scholar]
  5. Beutler B., Tkacenko V., Milsark I., Krochin N., Cerami A. Effect of gamma interferon on cachectin expression by mononuclear phagocytes. Reversal of the lpsd (endotoxin resistance) phenotype. J Exp Med. 1986 Nov 1;164(5):1791–1796. doi: 10.1084/jem.164.5.1791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bevilacqua M. P., Stengelin S., Gimbrone M. A., Jr, Seed B. Endothelial leukocyte adhesion molecule 1: an inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science. 1989 Mar 3;243(4895):1160–1165. doi: 10.1126/science.2466335. [DOI] [PubMed] [Google Scholar]
  7. Brouckaert P., Libert C., Everaerdt B., Fiers W. Selective species specificity of tumor necrosis factor for toxicity in the mouse. Lymphokine Cytokine Res. 1992 Aug;11(4):193–196. [PubMed] [Google Scholar]
  8. Carswell E. A., Old L. J., Kassel R. L., Green S., Fiore N., Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3666–3670. doi: 10.1073/pnas.72.9.3666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Crissman J. D., Hatfield J. S., Menter D. G., Sloane B., Honn K. V. Morphological study of the interaction of intravascular tumor cells with endothelial cells and subendothelial matrix. Cancer Res. 1988 Jul 15;48(14):4065–4072. [PubMed] [Google Scholar]
  10. Dayer J. M., Beutler B., Cerami A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med. 1985 Dec 1;162(6):2163–2168. doi: 10.1084/jem.162.6.2163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dejana E., Bertocchi F., Bortolami M. C., Regonesi A., Tonta A., Breviario F., Giavazzi R. Interleukin 1 promotes tumor cell adhesion to cultured human endothelial cells. J Clin Invest. 1988 Oct;82(4):1466–1470. doi: 10.1172/JCI113753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Derenzini M., Pession A., Farabegoli F., Trerè D., Badiali M., Dehan P. Relationship between interphasic nucleolar organizer regions and growth rate in two neuroblastoma cell lines. Am J Pathol. 1989 Apr;134(4):925–932. [PMC free article] [PubMed] [Google Scholar]
  13. Dinarello C. A., Cannon J. G., Wolff S. M., Bernheim H. A., Beutler B., Cerami A., Figari I. S., Palladino M. A., Jr, O'Connor J. V. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med. 1986 Jun 1;163(6):1433–1450. doi: 10.1084/jem.163.6.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dustin M. L., Springer T. A. Lymphocyte function-associated antigen-1 (LFA-1) interaction with intercellular adhesion molecule-1 (ICAM-1) is one of at least three mechanisms for lymphocyte adhesion to cultured endothelial cells. J Cell Biol. 1988 Jul;107(1):321–331. doi: 10.1083/jcb.107.1.321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. Fràter-Schröder M., Risau W., Hallmann R., Gautschi P., Böhlen P. Tumor necrosis factor type alpha, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5277–5281. doi: 10.1073/pnas.84.15.5277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Giavazzi R., Chirivi R. G., Garofalo A., Rambaldi A., Hemingway I., Pigott R., Gearing A. J. Soluble intercellular adhesion molecule 1 is released by human melanoma cells and is associated with tumor growth in nude mice. Cancer Res. 1992 May 1;52(9):2628–2630. [PubMed] [Google Scholar]
  18. 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]
  19. Haranaka K., Satomi N., Sakurai A. Antitumor activity of murine tumor necrosis factor (TNF) against transplanted murine tumors and heterotransplanted human tumors in nude mice. Int J Cancer. 1984 Aug 15;34(2):263–267. doi: 10.1002/ijc.2910340219. [DOI] [PubMed] [Google Scholar]
  20. Kohase M., Henriksen-DeStefano D., May L. T., Vilcek J., Sehgal P. B. Induction of beta 2-interferon by tumor necrosis factor: a homeostatic mechanism in the control of cell proliferation. Cell. 1986 Jun 6;45(5):659–666. doi: 10.1016/0092-8674(86)90780-4. [DOI] [PubMed] [Google Scholar]
  21. Kramer S. M., Aggarwal B. B., Eessalu T. E., McCabe S. M., Ferraiolo B. L., Figari I. S., Palladino M. A., Jr Characterization of the in vitro and in vivo species preference of human and murine tumor necrosis factor-alpha. Cancer Res. 1988 Feb 15;48(4):920–925. [PubMed] [Google Scholar]
  22. Lollini P. L., De Giovanni C., Nicoletti G., Bontadini A., Tazzari P. L., Landuzzi L., Scotlandi K., Nanni P. Enhancement of experimental metastatic ability by tumor necrosis factor-alpha alone or in combination with interferon-gamma. Clin Exp Metastasis. 1990 Mar-Apr;8(2):215–224. doi: 10.1007/BF00117794. [DOI] [PubMed] [Google Scholar]
  23. Malik S. T., Griffin D. B., Fiers W., Balkwill F. R. Paradoxical effects of tumour necrosis factor in experimental ovarian cancer. Int J Cancer. 1989 Nov 15;44(5):918–925. doi: 10.1002/ijc.2910440529. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Marlor C. W., Webb D. L., Bombara M. P., Greve J. M., Blue M. L. Expression of vascular cell adhesion molecule-1 in fibroblastlike synoviocytes after stimulation with tumor necrosis factor. Am J Pathol. 1992 May;140(5):1055–1060. [PMC free article] [PubMed] [Google Scholar]
  26. Miyata K., Kato M., Shikama H., Nishimura K., Sakae N., Kawagoe K., Nishikawa T., Kuroda K., Yamaguchi K., Aoyama Y. A YIGSR-containing novel mutein without the detrimental effect of human TNF-alpha of enhancing experimental pulmonary metastasis. Clin Exp Metastasis. 1992 Jul;10(4):267–272. doi: 10.1007/BF00133562. [DOI] [PubMed] [Google Scholar]
  27. Männel D. N., Jänicke R., Westenfelder U., Echtenacher B., Kist A., Falk W. Tumor-induced tumor necrosis factor production in macrophages. Lymphokine Res. 1990 Winter;9(4):485–489. [PubMed] [Google Scholar]
  28. Naylor M. S., Malik S. T., Stamp G. W., Jobling T., Balkwill F. R. In situ detection of tumour necrosis factor in human ovarian cancer specimens. Eur J Cancer. 1990;26(10):1027–1030. doi: 10.1016/0277-5379(90)90043-s. [DOI] [PubMed] [Google Scholar]
  29. Old L. J. Tumor necrosis factor (TNF). Science. 1985 Nov 8;230(4726):630–632. doi: 10.1126/science.2413547. [DOI] [PubMed] [Google Scholar]
  30. Osborn L., Hession C., Tizard R., Vassallo C., Luhowskyj S., Chi-Rosso G., Lobb R. Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell. 1989 Dec 22;59(6):1203–1211. doi: 10.1016/0092-8674(89)90775-7. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Pfizenmaier K., Scheurich P., Schlüter C., Krönke M. Tumor necrosis factor enhances HLA-A,B,C and HLA-DR gene expression in human tumor cells. J Immunol. 1987 Feb 1;138(3):975–980. [PubMed] [Google Scholar]
  33. Rakhmilevich A. L., North R. J. Rapid acquisition of an enhanced capacity to produce tumor necrosis factor, alpha/beta interferon, and interleukin 6 after implantation of tumor cells. Cytokine. 1991 Sep;3(5):398–406. doi: 10.1016/1043-4666(91)90043-d. [DOI] [PubMed] [Google Scholar]
  34. Reibnegger G., Hetzel H., Fuchs D., Fuith L. C., Hausen A., Werner E. R., Wachter H. Clinical significance of neopterin for prognosis and follow-up in ovarian cancer. Cancer Res. 1987 Sep 15;47(18):4977–4981. [PubMed] [Google Scholar]
  35. Reibnegger G., Krainer M., Herold M., Ludwig H., Wachter H., Huber H. Predictive value of interleukin-6 and neopterin in patients with multiple myeloma. Cancer Res. 1991 Dec 1;51(23 Pt 1):6250–6253. [PubMed] [Google Scholar]
  36. 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]
  37. Rothlein R., Czajkowski M., O'Neill M. M., Marlin S. D., Mainolfi E., Merluzzi V. J. Induction of intercellular adhesion molecule 1 on primary and continuous cell lines by pro-inflammatory cytokines. Regulation by pharmacologic agents and neutralizing antibodies. J Immunol. 1988 Sep 1;141(5):1665–1669. [PubMed] [Google Scholar]
  38. Rüschoff J., Neumann K., Contractor H., Plate K., Thomas C. Assessment of nucleolar organizer regions by automatic image analysis in breast cancer: correlation with DNA content, proliferation rate, receptor status and histopathological grading. J Cancer Res Clin Oncol. 1990;116(5):480–485. doi: 10.1007/BF01612998. [DOI] [PubMed] [Google Scholar]
  39. Schultz R. M., Altom M. G. Protective activity of recombinant murine tumor necrosis factor-alpha and interferon-gamma against experimental murine lung carcinoma metastases. J Interferon Res. 1990 Apr;10(2):229–236. doi: 10.1089/jir.1990.10.229. [DOI] [PubMed] [Google Scholar]
  40. Spitalny G. L., Havell E. A. Monoclonal antibody to murine gamma interferon inhibits lymphokine-induced antiviral and macrophage tumoricidal activities. J Exp Med. 1984 May 1;159(5):1560–1565. doi: 10.1084/jem.159.5.1560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Sylvester D. M., Liu S. Y., Meadows G. G. Augmentation of antimetastatic activity of interferon and tumor necrosis factor by heparin. Immunopharmacol Immunotoxicol. 1990;12(2):161–180. doi: 10.3109/08923979009019667. [DOI] [PubMed] [Google Scholar]
  42. Tartaglia L. A., Goeddel D. V. Two TNF receptors. Immunol Today. 1992 May;13(5):151–153. doi: 10.1016/0167-5699(92)90116-O. [DOI] [PubMed] [Google Scholar]
  43. Tomazic V. J., Farha M., Loftus A., Elias E. G. Anti-tumor activity of recombinant tumor necrosis factor on mouse fibrosarcoma in vivo and in vitro. J Immunol. 1988 Jun 1;140(11):4056–4061. [PubMed] [Google Scholar]
  44. Wexler H. Accurate identification of experimental pulmonary metastases. J Natl Cancer Inst. 1966 Apr;36(4):641–645. doi: 10.1093/jnci/36.4.641. [DOI] [PubMed] [Google Scholar]

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