Skip to main content
SpringerLink
Log in

Are cytokines possible mediators of cancer cachexia?

  • Review Article
  • Published:
Surgery Today Aims and scope Submit manuscript

Abstract

The possible role of cytokines in the development of cancer cachexia was reviewed from the literature. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, interferon (IFN)-gamma and leukemia inhibitory factor (LIF) can elicit many but not all host changes seen in cancer cachexia, including loss of appetite, loss of body weight, and the induction of acute-phase protein synthesis. However, these cytokines are not always demonstrated in the circulation of the cancer patients. The inability to detect circulating cytokines may be due to their low rate of production, their short half-life and rapid clearance from plasma, or their mode of action (autocrine or paracrine). Different cytokines are induced to stimulate the same response. This is very different from hormonal regulation, where a hormone acts on a cell directly through a specific receptor without depending on other mediators. Specific antibodies including anti-IFN-gamma, anti-TNF and anti-IL-6 antibodies, as well as the cyclooxygenase inhibitor indomethacin, have been used to reverse cancer cachexia. Overlapping physiologic activities make it unlikely that a single substance is the sole cause of cancer cachexia. It is hoped that further investigation on other cytokines and their possible relationships with hormones will help to clarify the mechanisms of cancer cachexia in the near future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Moldawer LL, Andersson C, Gelin J, Lundholm KG (1988) Regulation of food intake and hepatic protein synthesis by recombinant-derived cytokines. Am J Physiol 254:450–456

    Google Scholar 

  2. Norton JA, Moley JF, Green MV, Carson RE, Morrison SD (1985) Parabiotic transfer of cancer anorexia/cachexia in male rats. Cancer Res 45:5547–5552

    Google Scholar 

  3. Sherry BA, Gelin J, Fong Y, Marano M, Wei H, Cerami A, Lowry SF, Lundholm KG, Moldawer LL (1989) Anticachectin/tumor necrosis factor-alpha antibodies attenuated development of cachexia in tumor models. FASEB J 3:1956–1962

    Google Scholar 

  4. Old LJ (1985) Tumor necrosis factor (TNF). Science 230:641–644

    Google Scholar 

  5. Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 72:3666–3670

    Google Scholar 

  6. Lehmmann V, Benninghoff B, Droge W (1988) Tumor necrosis factor-induced activation of peritoneal macrophage is regulated by prostaglandin E2 and cAMP. J Immunol 141:587–591

    Google Scholar 

  7. Oliff A (1988) The role of tumor necrosis factor (cachectin) in cachexia. Cell 54:141–142

    Google Scholar 

  8. Beutler B, Cerami A (1986a) Cachectin and tumor necrosis factor as two sides of the same biological coin. Nature 320:584–588

    Google Scholar 

  9. Flick O, Gifford G (1986) Pharmacokinetics of murine tumor necrosis factor. J Immunopharmacol 8:89–97

    Google Scholar 

  10. Sugarman BJ, Aggarwal BB, Hass PE, Figart IS, Palladon Jr MA, Shepard HM (1985) Recombinant human tumor necrosis factoralpha: Effects on proliferation of normal and transformed cells in vitro. Science 230:943–945

    Google Scholar 

  11. Van Damme J, Opdenakker G, Simpson RJ, Rubira MR, Cayphas S, Vink A, Billan A, Van Snick J (1987) Identification of the human 26-KD protein, interferon beta-2 (IFN beta-2), as B cell hybridoma/plasmacytoma growth factor induced by interleukin 1 and tumor necrosis factor. J Exp Med 165:914–919

    Google Scholar 

  12. Leibovich SJ, Polverinio PJ, Shepard HM, Wisoman DM, Shively V, Nuseir N (1987) Macrophage-induced angiogenesis is mediated by tumor-necrosis factor-alpha. Nature 329:630–632

    Google Scholar 

  13. Mahony SM, Tisdale MJ (1989) Role of prostaglandins in tumor necrosis factor induced weight loss. Br J Cancer 60:51–55

    Google Scholar 

  14. Michie HR, Sherman ML, Spriggs DR, Christie RJ, Wilmore DW (1989) Chronic TNF infusion causes anemia and not accelerated nitrogen loss. Ann Surg 104:280–286

    Google Scholar 

  15. Darling G, Fraker DL, Jensen JC, Gorschboth CM, Norton JA (1990) Cachectic effects of recombinant tumor necrosis factor in rats. Cancer Res 50:4008–4013

    Google Scholar 

  16. Norton JA (1991) Mechanisms of cancer cachexia. Hematol Oncol Clin North Am 103–123

  17. Mahony SM, Tisdale MJ (1988) Induction of weight loss and metabolic alterations by human recombinant tumor necrosis factor. Br J Cancer 58:345–349

    Google Scholar 

  18. Kawakami M, Cerami A (1981) Studies of endotoxin-induced decrease in lipoprotein lipase activity. J Exp Med 154:631–637

    Google Scholar 

  19. Feingold KR, Grunfeld C (1987) Tumor necrosis factor-alpha stimulates hepatic lipogenesis in the rat in vitro. J Clin Invest 80:184–190

    Google Scholar 

  20. Oliff A, Defeo-Jones D, Boyer M, Martinez D, Kiefer D, Vuocolo G, Wolfe A, Socher SH (1987) Tumor secreting human TNF-cachectin induced cachexia in mice. Cell 50:555–563

    Google Scholar 

  21. Stovroff ML, Fraker DL, Norton JA (1989) Cachectin activity in the serum of cachectic, tumor-bearing rats. Arch Surg 124:94–99

    Google Scholar 

  22. Lönnroth C, Moldawer LL, Gelin J, Kindholm L-G, Sherry B, Lundholm K (1990) Tumor necrosis factor and interleukin 1 alpha production in cachectic, tumor-bearing mice. Int J Cancer 46:889–896

    Google Scholar 

  23. Fulton AM (1988) Inhibition of experimental metastasis with indomethacin; role of macrophages and natural killer cells. Prostaglandins 35:413–425

    Google Scholar 

  24. Balkwill F, Burk F, Talbert D, Tavernier J, Osborne R, Naylor S, Durbin H, Fiers W (1987) Evidence for tumor necrosis factor-cachectin production in cancer. Lancet ii:1229–1232

    Google Scholar 

  25. Aderka D, Fisher S, Levo Y, Holtmann H, Hahn T, Wallach D (1987) Cachectin; tumor necrosis factor production by cancer patients. Lancet ii:1190

    Google Scholar 

  26. Moldawer L, Drott C, Lundholm K (1988) Monocytic production and plasma bioactivities of interleukin-1 and tumor necrosis factor in human cancer. Eur J Clin Invest 18:486–492

    Google Scholar 

  27. Socher SH, Martinez D, Craig JB, Kahn JG, Oliff A (1988). Tumor necrosis factor not detectable in patients with clinical cachexia. J Natl Cancer Inst 80:595–598

    Google Scholar 

  28. Mulligan HD, Mahony SM, Ross JA, Tisdale MJ (1992) Weight loss in a murine cachexia model is not associated with the cytokine tumour necrosis factor-alpha or interleukin-6. Cancer Lett 65:239–243

    Google Scholar 

  29. Sheppard BC, Venzon D, Fraker DL, Langstein HN, Jensen JC, Norton JA (1990) Prolonged survival of tumor-bearing rats with repetitive low-dose recombinant tumor necrosis factor. Cancer Res 50:3928–3933

    Google Scholar 

  30. Naylor MS, Stamp GWH, Balkwill FR (1990) Investigation of cytokine gene expression in human colorectal cancer. Cancer Res 50:4436–4440

    Google Scholar 

  31. Nordan RP, Pumphrey JG, Rundikoff S (1987) Purification and NH3 terminal sequence of a plasmacytoma growth factor derived from the murine macrophage cell line P388D1. J Immunol 139:813–817

    Google Scholar 

  32. Hirano T, Yasukawa K, Harada H, Taga T, Watanabe Y, Masuda T, Kashiwamura S, Nakajima K, Koyama K, Iwamatsu A, Tsunagawa S, Shikiyama F, Masui H, Takahara Y, Taniguchi T, Kishimoto T (1986) Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 324:73–76

    Google Scholar 

  33. Schreiber G, Tsyklin A, Aldred AR, Thomas T, Fung WP, Dickson PW, Cole T, Birch H, De JF, Milland J (1989) The acute phase response in the rodent. Ann NY Acad Sci 557:61–85

    Google Scholar 

  34. Bladel AV, Libert C, Fiers W (1991) Interleukin-6 enhances the expression of tumor necrosis factor receptors on hepatoma cells and hepatocytes. Cytokine 3:149–154

    Google Scholar 

  35. Strassmann G, Fong M, Keny JS, Jacob CO (1992) Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J Clin Invest 89:1681–1684

    Google Scholar 

  36. Black K, Garrett IR, Mundy GR (1991) Chinese hamster ovarian cells transfected with the murine interleukin-6 gene cause hypercalcemia as well as cachexia, leukocytosis and thrombocytosis in tumor-bearing nude mice. Endocrinology 128:2657–2659

    Google Scholar 

  37. Greenberg AS, Nordan RP, McIntosh J, Calvo JC, Scow RD, Jablons D (1992) Interleukin 6 reduces lipoprotein lipase activity in adipose tissue of mice in vivo and in 3T3-L1 adipocytes: a possible role for interleukin 6 in cancer cachexia. Cancer Res 52:4113–4116

    Google Scholar 

  38. Tabibzadeh SS, Poubouridis AB, May LT, Sehgal PB (1989) Interleukin-6 immunoreactivity in human tumors. Am J Pathol 135:427–433

    Google Scholar 

  39. Monti G, Jauraud MC, Monnet I, Chrétien P, Saint-Etienne L, Zeng L, Portier A, Deviller P, Galanaud P, Bignon J, Emilie D (1994) Intrapleural production of interleukin 6 during mesothelioma and its modulation by gamma-interferon treatment. Cancer Res 54:4419–4423

    Google Scholar 

  40. Yoneda T, Nakai M, Moriyama K, Scott L, Ida N, Kunitomo T, Mundy GR (1993) Neutralizing antibodies to human interleukin 6 reverse hypercalcemia associated with a human squamous carcinoma. Cancer Res 53:737–740

    Google Scholar 

  41. Starnes HF, Warren RS, Jeevanandam M, Gabrilove JL, Larchian W, Oettgen HF, Brennan MF (1988) Tumor necrosis factor and acute metabolic response to tissue injury in man. J Clin Invest 82:1321–1325

    Google Scholar 

  42. Fong Y, Moldawer LL, Marano M, Wei H, Barber A, Manogue K, Tracey KJ, Kuo G, Fishman DA, Cerami A, Lowry SF (1989) Cachectin/TNF of IL-1 alpha induces cachexia with redistribution of body proteins. Am J Physiol 256:R659-R665

    Google Scholar 

  43. Belizario JE, Matz M, Chenker E, Raw I (1991) Bioactivity of skeletal muscle proteolysis-inducing factors in the plasma proteins from cancer patients with weight loss. Br J Cancer 63:705–710

    Google Scholar 

  44. Mrosovsky N, Molony LA, Conn LA, Kluger MJ (1989) Anorexic effects of interleukin 1 in the rat. Am J Physiol 257:R1315–1321

    Google Scholar 

  45. Murray MJ, Murray AB (1979) Anorexia of infection as a mechanisms of host defense. Am J Clin Nutr 32:593–596

    Google Scholar 

  46. Hoffman-Goetz L, McFarlane P, Bistrian BR, Blackburn GL (1981) Febrile and plasma iron responses to rabbits injected with endogenous pyrogens from malnourished patients. Am J Clin Nutr 34:1109–1116

    Google Scholar 

  47. Gelin J, Moldwer LL, Lönnroth C, Sherry B, Chizzonite R, Lundholm K (1991) Role of endogenous tumor necrosis factor alpha and interleukin 1 for experimental tumor growth and the development of cancer cachexia. Cancer Res 51:415–421

    Google Scholar 

  48. Strassmann G, Masui Y, Chizzonite R, Fong M (1993) Mechanisms of experimental cancer cachexia. J Immunol 150:2341–2345

    Google Scholar 

  49. Strassmann G, Jacob CO, Evans R, Beall D, Fong M (1992) Mechanisms of experimental cancer cachexia. J Immunol 148: 3674–3678

    Google Scholar 

  50. Langstein HN Norton JA (1991) Mechanisms of cancer cachexia. Hematol Oncol Clin North Am 5:103–123

    Google Scholar 

  51. Langstein HN, Doherty GM, Fraker DL, Buresh CM, Norton JA (1991) The roles of gamma-interferon and tumor necrosis factor alpha in an experimental rat model of cancer cachexia. Cancer Res 51:2302–2306

    Google Scholar 

  52. Matthys P, Heremans H, Opdenakker G, Billian A (1991) Anti-interferon-gamma antibody treatment, growth of Lewis lung tumours in mice and tumour-associated cachexia. Eur J Cancer 27:182–187

    Google Scholar 

  53. Matthys P, Dijkmans R, Proost P, Damme JV, Heremans H, Sobis H, Billiau A (1991) Severe cachexia in mice inoculated with interferon-gamma-producing tumor cells. Int J Cancer 49:77–82

    Google Scholar 

  54. Kawakami M, Kondo Y, Imai Y, Hashiguchi M, Ogawa H, Hiragun A, Aotsuka S, Shibata S, Oda T, Murase T, Takaku F (1991) Suppression of lipoprotein lipase in 3T3-L1 cells by a mediator produced by SEKI melanoma, a cachexia-inducing human melanoma cell line. J Biochem 109:78–82

    Google Scholar 

  55. Michie HR, Guillou PJ, Wilmore DW (1989) Tumor necrosis factor and bacterial sepsis, Br J Surg 76:670–671

    Google Scholar 

  56. Moldawer LL, Georgieff MM, Lundholm K (1987) Interleukin-1, tumor necrosis factor-alpha (cachectin) and the pathogenesis of cancer cachexia. Clin Physiol 7:263–274

    Google Scholar 

  57. Dinarello CA, Bernheim HA (1981) Ability of human leukocytic pyrogen to stimulate brain prostaglandin synthesis in vitro. J Neurochem 37:702–708

    Google Scholar 

  58. Callery MP, Mangino MJ, Kamei T, Flye MW (1990) Interleukin-6 production by endotoxin-stimulated kupffer cells is regulated by prostaglandin E2. J Surg Res 48:523–527

    Google Scholar 

  59. Endres S, Ghorbani R, Kelly VE, Georgilis K, Lonnemann G, Van Der Meer JWM, Cannon JG, Rogers TS, Klempner MS, Weber PC, Schaefer EJ, Wolff SM, Dinarells CA (1989) The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med 320:256–271

    Google Scholar 

  60. Godfrey RW, Johnson WJ, Hoffstein ST (1987) Recombinant tumor necrosis factor and interleukin-1 both stimulate human synovial cell arachidonic acid release and phospholipid metabolism. Biochem Biophys Res Comm 142:235–241

    Google Scholar 

  61. Kunkel SL, Spengler M, May MA, Spengler R, Larrick J, Remick D (1988) Prostaglandin E2 regulates macrophage-derived tumour necrosis factor gene expression. J Biol Chem 263:5380–5384

    Google Scholar 

  62. Stausser HR, Humes JL (1975) Prostaglandin synthesis inhibition: Effects on the bone change and sarcoma tumor induction in BALB/c mice. Int J Cancer 15:724

    Google Scholar 

  63. Hubbard NE, Chapkin RS, Erickson KL (1988) Inhibition of growth and linoleate-enhanced metastasis of a transplantable mouse mammary tumor by indomethacin. Cancer Lett 43:111

    Google Scholar 

  64. Gelin J (1990) Cancer cachexia. An experimental study with special reference to cytokines as endogenous mediators. Doctor's thesis, Göteborg University, Göteborg, pp 1–74

    Google Scholar 

  65. Fulton AM (1988) Inhibition of experimental metastasis with indomethacin: Role of macrophages and natural killer cells. Prostaglandins 35:413–425

    Google Scholar 

  66. Milas L, Furuta Y, Hunter N, Nishiguchi I, Runkel S (1990) Dependence of indomethacin-induced potentiation of murine tumor radioresponse on tumor host immunocompetence. Cancer Res 50:4473–4477

    Google Scholar 

  67. Folkman J (1986) How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clowes Memorial Award Lecture. Cancer Res 46:467

    Google Scholar 

  68. Tanaka Y, Tanaka T, Ishitsuka H (1989) Antitumor activity of indomethacin in mice bearing advanced colon 26 carcinoma compared with those with early transplants. Cancer Res 49:5935–5939

    Google Scholar 

  69. Gelin J, Andersson C, Lundholm K (1991) Effects of indomethacin, cytokines, and cyclosporin A on tumor growth and the subsequent development of cancer cachexia. Cancer Res 51:880–885

    Google Scholar 

  70. Karmali Ra, Welt S, Thaler HT, Lefevre F (1983). Prostaglandins in breast cancer: Relationship to disease stage and hormone status. Br J Cancer 48:689–696

    Google Scholar 

  71. Michie HR, Guillou PJ, Wilmorem DW (1989) Tumour necrosis factor and bacterial sepsis. Br J Surg 76:670–671

    Google Scholar 

  72. Grau G, Taylor T, Trop M, Molyneux ME, Wirima JJ, Vassalli P, Hommel M, Lambert PH (1989) Tumor necrosis factor and disease in children with falciparum malaria. N Engl J Med 320:1586–1598

    Google Scholar 

  73. Socher SH, Martinez D, Craig JB, Kuhn JG, Oliff A (1988) Tumor necrosis factor not detectable in patients with clinical cancer cachexia. J Natl Cancer Inst 80:595–598

    Google Scholar 

  74. Siimes MA, Toppo AM, Koskelo EK, Saarinen UM (1991) Serum tumor necrosis factor does not correlate with changes in muscle volume in children with malignancies. Pediatr Hematol Oncol 8:69–75

    Google Scholar 

  75. Cerami A (1992) Inflammatory cytokines. Clin Immunol Immunopathol 62:S3-S10

    Google Scholar 

  76. Balkwill FR, Burk F (1989) The cytokine network. Immunol Today 10:299–303

    Google Scholar 

  77. Michie HR, Manogue KA, Spriggs DR, Revhaug A, O'Dwyer S, Dinarello LA, Cerami A, Wolff SM, Wilmore DW (1988) Detection of tumor necrosis factor after endotoxin administration. N Engl J Med 318:1481–1486

    Google Scholar 

  78. Kettlehut IC, Fiers W, Goldberg AL (1987) The toxic effects of tumor necrosis factor in vivo and their prevention by cyclooxygenase inhibitors. Proc Natl Acad Sci USA 84:4273–4277

    Google Scholar 

  79. McNamara MJ, Alexander HR, Norton JA (1992) Cytokines and their role in the pathophysiology of cancer cachexia. JPEN 16:50s-55s

    Google Scholar 

  80. Tessitore L, Costelli P, Baccino FM (1993) Humoral mediation for cachexia in tumor-bearing rats. Br J Cancer 67:15–23

    Google Scholar 

  81. Mori M, Yamaguchi K, Honda S, Nagasaki K, Ueda M, Abe O, Abe K (1991) Cancer cachexia syndrome developed in nude mice bearing melanoma cells producing leukemia-inhibitory factor. Cancer Res 51:6656–6659

    Google Scholar 

  82. Ardizzoia A, Lissoni P, Brivis F, Tisi E, Perego MS, Grassi MG, Pittalis S, Crispino S, Barni S, Tancini G (1992) Tumor necrosis factor in solid tumors: increased blood levels in the metastatic disease. J Biol Regul Homeost Agents 6:103–107

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. First Department of Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236, Yokohama, Japan

    Yoshikazu Noguchi, Takaki Yoshikawa & Akihiko Matsumoto

  2. Department of Surgery, Sahgrenska Hospital, Bruna Straket 20, 413 45, Göteborg, Sweden

    Gösta Svaninger & Johan Gelin

Authors
  1. Yoshikazu Noguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takaki Yoshikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Akihiko Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gösta Svaninger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Johan Gelin
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This work was supported by a grant from the Japan-Sweden Foundation in 1991.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Noguchi, Y., Yoshikawa, T., Matsumoto, A. et al. Are cytokines possible mediators of cancer cachexia?. Surg Today 26, 467–475 (1996). https://doi.org/10.1007/BF00311551

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00311551

Key Words

Search

Navigation