Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Dec;92(6):2783–2789. doi: 10.1172/JCI116897

Tumor necrosis factor-alpha mediates changes in tissue protein turnover in a rat cancer cachexia model.

P Costelli 1, N Carbó 1, L Tessitore 1, G J Bagby 1, F J Lopez-Soriano 1, J M Argilés 1, F M Baccino 1
PMCID: PMC288478  PMID: 8254032

Abstract

Rats bearing the Yoshida AH-130 ascites hepatoma showed enhanced fractional rates of protein degradation in gastrocnemius muscle, heart, and liver, while fractional synthesis rates were similar to those in non-tumor bearing rats. This hypercatabolic pattern was associated with marked perturbations of the hormonal homeostasis and presence of tumor necrosis factor in the circulation. The daily administration of a goat anti-murine TNF IgG to tumor-bearing rats decreased protein degradation rates in skeletal muscle, heart, and liver as compared with tumor-bearing rats receiving a nonimmune goat IgG. The anti-TNF treatment was also effective in attenuating early perturbations in insulin and corticosterone homeostasis. Although these results suggest that tumor necrosis factor plays a significant role in mediating the changes in protein turnover and hormone levels elicited by tumor growth, the inability of such treatment to prevent a reduction in body weight implies that other mediators or tumor-related events were also involved.

Full text

PDF
2784

Selected References

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

  1. Amenta J. S., Sargus M. J., Baccino F. M. Inhibition of basal protein degradation in rat embryo fibroblasts by cycloheximide: correlation with activities of lysosomal proteases. J Cell Physiol. 1978 Dec;97(3 Pt 1):267–283. doi: 10.1002/jcp.1040970302. [DOI] [PubMed] [Google Scholar]
  2. Argilés J. M., Garcia-Martínez C., Llovera M., López-Soriano F. J. The role of cytokines in muscle wasting: its relation with cancer cachexia. Med Res Rev. 1992 Nov;12(6):637–652. doi: 10.1002/med.2610120605. [DOI] [PubMed] [Google Scholar]
  3. Argilés J. M., López-Soriano F. J., Wiggins D., Williamson D. H. Comparative effects of tumour necrosis factor-alpha (cachectin), interleukin-1-beta and tumour growth on amino acid metabolism in the rat in vivo. Absorption and tissue uptake of alpha-amino[1-14C]isobutyrate. Biochem J. 1989 Jul 15;261(2):357–362. doi: 10.1042/bj2610357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baccino F. M., Tessitore L., Cecchini G., Messina M., Zuretti M. F., Bonelli G., Gabriel L., Amenta J. S. Control of cell protein catabolism in rat liver. Effects of starvation and administration of cycloheximide. Biochem J. 1982 Aug 15;206(2):395–405. doi: 10.1042/bj2060395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bagby G. J., Plessala K. J., Wilson L. A., Thompson J. J., Nelson S. Divergent efficacy of antibody to tumor necrosis factor-alpha in intravascular and peritonitis models of sepsis. J Infect Dis. 1991 Jan;163(1):83–88. doi: 10.1093/infdis/163.1.83. [DOI] [PubMed] [Google Scholar]
  6. Beck S. A., Smith K. L., Tisdale M. J. Anticachectic and antitumor effect of eicosapentaenoic acid and its effect on protein turnover. Cancer Res. 1991 Nov 15;51(22):6089–6093. [PubMed] [Google Scholar]
  7. Beutler B., Cerami A. Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature. 1986 Apr 17;320(6063):584–588. doi: 10.1038/320584a0. [DOI] [PubMed] [Google Scholar]
  8. Charters Y., Grimble R. F. Effect of recombinant human tumour necrosis factor alpha on protein synthesis in liver, skeletal muscle and skin of rats. Biochem J. 1989 Mar 1;258(2):493–497. doi: 10.1042/bj2580493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Darling G., Fraker D. L., Jensen J. C., Gorschboth C. M., Norton J. A. Cachectic effects of recombinant human tumor necrosis factor in rats. Cancer Res. 1990 Jul 1;50(13):4008–4013. [PubMed] [Google Scholar]
  10. Evans R. D., Argilés J. M., Williamson D. H. Metabolic effects of tumour necrosis factor-alpha (cachectin) and interleukin-1. Clin Sci (Lond) 1989 Oct;77(4):357–364. doi: 10.1042/cs0770357. [DOI] [PubMed] [Google Scholar]
  11. Flick D. A., Gifford G. E. Comparison of in vitro cell cytotoxic assays for tumor necrosis factor. J Immunol Methods. 1984 Mar 30;68(1-2):167–175. doi: 10.1016/0022-1759(84)90147-9. [DOI] [PubMed] [Google Scholar]
  12. Flores E. A., Bistrian B. R., Pomposelli J. J., Dinarello C. A., Blackburn G. L., Istfan N. W. Infusion of tumor necrosis factor/cachectin promotes muscle catabolism in the rat. A synergistic effect with interleukin 1. J Clin Invest. 1989 May;83(5):1614–1622. doi: 10.1172/JCI114059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fong Y., Moldawer L. L., Marano M., Wei H., Barber A., Manogue K., Tracey K. J., Kuo G., Fischman D. A., Cerami A. Cachectin/TNF or IL-1 alpha induces cachexia with redistribution of body proteins. Am J Physiol. 1989 Mar;256(3 Pt 2):R659–R665. doi: 10.1152/ajpregu.1989.256.3.R659. [DOI] [PubMed] [Google Scholar]
  14. Fraker D. L., Sheppard B. C., Norton J. A. Impact of tolerance on antitumor efficacy of tumor necrosis factor in mice. Cancer Res. 1990 Apr 15;50(8):2261–2267. [PubMed] [Google Scholar]
  15. Garlick P. J., McNurlan M. A., Preedy V. R. A rapid and convenient technique for measuring the rate of protein synthesis in tissues by injection of [3H]phenylalanine. Biochem J. 1980 Nov 15;192(2):719–723. doi: 10.1042/bj1920719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gelin J., Moldawer L. L., Lönnroth C., Sherry B., Chizzonite R., Lundholm K. Role of endogenous tumor necrosis factor alpha and interleukin 1 for experimental tumor growth and the development of cancer cachexia. Cancer Res. 1991 Jan 1;51(1):415–421. [PubMed] [Google Scholar]
  17. Goldberg A. L., Kettelhut I. C., Furuno K., Fagan J. M., Baracos V. Activation of protein breakdown and prostaglandin E2 production in rat skeletal muscle in fever is signaled by a macrophage product distinct from interleukin 1 or other known monokines. J Clin Invest. 1988 May;81(5):1378–1383. doi: 10.1172/JCI113466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hall-Angerås M., Angerås U., Zamir O., Hasselgren P. O., Fischer J. E. Interaction between corticosterone and tumor necrosis factor stimulated protein breakdown in rat skeletal muscle, similar to sepsis. Surgery. 1990 Aug;108(2):460–466. [PubMed] [Google Scholar]
  19. Kettelhut I. C., Goldberg A. L. Tumor necrosis factor can induce fever in rats without activating protein breakdown in muscle or lipolysis in adipose tissue. J Clin Invest. 1988 May;81(5):1384–1389. doi: 10.1172/JCI113467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  21. Lawson D. H., Richmond A., Nixon D. W., Rudman D. Metabolic approaches to cancer cachexia. Annu Rev Nutr. 1982;2:277–301. doi: 10.1146/annurev.nu.02.070182.001425. [DOI] [PubMed] [Google Scholar]
  22. MacDonald M. L., Augustine S. L., Burk T. L., Swick R. W. A comparison of methods for the measurement of protein turnover in vivo. Biochem J. 1979 Nov 15;184(2):473–476. doi: 10.1042/bj1840473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mahony S. M., Tisdale M. J. Induction of weight loss and metabolic alterations by human recombinant tumour necrosis factor. Br J Cancer. 1988 Sep;58(3):345–349. doi: 10.1038/bjc.1988.216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Matthys P., Dijkmans R., Proost P., Van Damme J., Heremans H., Sobis H., Billiau A. Severe cachexia in mice inoculated with interferon-gamma-producing tumor cells. Int J Cancer. 1991 Aug 19;49(1):77–82. doi: 10.1002/ijc.2910490115. [DOI] [PubMed] [Google Scholar]
  25. Matthys P., Heremans H., Opdenakker G., Billiau A. Anti-interferon-gamma antibody treatment, growth of Lewis lung tumours in mice and tumour-associated cachexia. Eur J Cancer. 1991;27(2):182–187. doi: 10.1016/0277-5379(91)90483-t. [DOI] [PubMed] [Google Scholar]
  26. Mealy K., van Lanschot J. J., Robinson B. G., Rounds J., Wilmore D. W. Are the catabolic effects of tumor necrosis factor mediated by glucocorticoids? Arch Surg. 1990 Jan;125(1):42–48. doi: 10.1001/archsurg.1990.01410130044006. [DOI] [PubMed] [Google Scholar]
  27. Moldawer L. L., Svaninger G., Gelin J., Lundholm K. G. Interleukin 1 and tumor necrosis factor do not regulate protein balance in skeletal muscle. Am J Physiol. 1987 Dec;253(6 Pt 1):C766–C773. doi: 10.1152/ajpcell.1987.253.6.C766. [DOI] [PubMed] [Google Scholar]
  28. Mori M., Yamaguchi K., Honda S., Nagasaki K., Ueda M., Abe O., Abe K. Cancer cachexia syndrome developed in nude mice bearing melanoma cells producing leukemia-inhibitory factor. Cancer Res. 1991 Dec 15;51(24):6656–6659. [PubMed] [Google Scholar]
  29. Old L. J. Tumour necrosis factor. Polypeptide mediator network. 1987 Mar 26-Apr 1Nature. 326(6111):330–331. doi: 10.1038/326330a0. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Perlmutter D. H., Dinarello C. A., Punsal P. I., Colten H. R. Cachectin/tumor necrosis factor regulates hepatic acute-phase gene expression. J Clin Invest. 1986 Nov;78(5):1349–1354. doi: 10.1172/JCI112721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Pomposelli J. J., Flores E. A., Bistrian B. R. Role of biochemical mediators in clinical nutrition and surgical metabolism. JPEN J Parenter Enteral Nutr. 1988 Mar-Apr;12(2):212–218. doi: 10.1177/0148607188012002212. [DOI] [PubMed] [Google Scholar]
  33. Selby P., Hobbs S., Viner C., Jackson E., Jones A., Newell D., Calvert A. H., McElwain T., Fearon K., Humphreys J. Tumour necrosis factor in man: clinical and biological observations. Br J Cancer. 1987 Dec;56(6):803–808. doi: 10.1038/bjc.1987.294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sheppard B. C., Venzon D., Fraker D. L., Langstein H. N., Jensen J. C., Norton J. A. Prolonged survival of tumor-bearing rats with repetitive low-dose recombinant tumor necrosis factor. Cancer Res. 1990 Jul 1;50(13):3928–3933. [PubMed] [Google Scholar]
  35. Sherry B. A., Gelin J., Fong Y., Marano M., Wei H., Cerami A., Lowry S. F., Lundholm K. G., Moldawer L. L. Anticachectin/tumor necrosis factor-alpha antibodies attenuate development of cachexia in tumor models. FASEB J. 1989 Jun;3(8):1956–1962. doi: 10.1096/fasebj.3.8.2721856. [DOI] [PubMed] [Google Scholar]
  36. Strain A. J. Cancer cachexia in man: a review. Invest Cell Pathol. 1979 Jul-Sep;2(3):181–193. [PubMed] [Google Scholar]
  37. Swick R. W., Ip M. M. Measurement of protein turnover in rat liver with (14C)carbonate. Protein turnover during liver regeneration. J Biol Chem. 1974 Nov 10;249(21):6836–6841. [PubMed] [Google Scholar]
  38. Tessitore L., Bonelli G., Baccino F. M. Early development of protein metabolic perturbations in the liver and skeletal muscle of tumour-bearing rats. A model system for cancer cachexia. Biochem J. 1987 Jan 1;241(1):153–159. doi: 10.1042/bj2410153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Tessitore L., Costelli P., Baccino F. M. Humoral mediation for cachexia in tumour-bearing rats. Br J Cancer. 1993 Jan;67(1):15–23. doi: 10.1038/bjc.1993.4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Theologides A. Cancer cachexia. Cancer. 1979 May;43(5 Suppl):2004–2012. doi: 10.1002/1097-0142(197905)43:5+<2004::aid-cncr2820430708>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  41. Tisdale M. J. Newly identified factors that alter host metabolism in cancer cachexia. Trends Pharmacol Sci. 1990 Dec;11(12):473–475. doi: 10.1016/0165-6147(90)90134-t. [DOI] [PubMed] [Google Scholar]
  42. Tracey K. J., Wei H., Manogue K. R., Fong Y., Hesse D. G., Nguyen H. T., Kuo G. C., Beutler B., Cotran R. S., Cerami A. Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation. J Exp Med. 1988 Mar 1;167(3):1211–1227. doi: 10.1084/jem.167.3.1211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Warren R. S., Starnes H. F., Jr, Gabrilove J. L., Oettgen H. F., Brennan M. F. The acute metabolic effects of tumor necrosis factor administration in humans. Arch Surg. 1987 Dec;122(12):1396–1400. doi: 10.1001/archsurg.1987.01400240042007. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES