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Cytokines as Mediators and Targets for Cancer Cachexia

  • Chapter
Book cover The Link Between Inflammation and Cancer

Part of the book series: Cancer Treatment and Research ((CTAR,volume 130))

Abstract

The cachexia syndrome, characterized by a marked weight loss, anorexia, asthenia and anaemia, is invariably associated with the growth of a tumour and leads to a malnutrition status caused by the induction of anorexia or decreased food intake. In addition, the competition for nutrients between the tumour and the host results in a state of accelerated catabolism, which promotes severe metabolic disturbances in the patient. The search for the cachectic factor(s) started a long time ago, and many scientific and economic efforts have been devoted to its discovery, but we are still a long way from a complete answer. The present review aims to evaluate the different molecular mechanisms and catabolic mediators (both humoural and tumoural) that are involved in cancer cachexia and to discuss their potential as targets for future clinical investigations.

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8. References

  • Aleman, M.R. et al. (2002). Leptin role in advanced lung cancer. A mediator of the acute phase response or a marker of the status of nutrition? Cytokine. 19: 21–26.

    Article  PubMed  CAS  Google Scholar 

  • Alvarez, B. et al. (2002). Tumor necrosis factor-alpha exerts interleukin-6-dependent and-independent effects on cultured skeletal muscle cells. Biochim. Biophys. Acta. 1542: 66–72.

    Article  PubMed  CAS  Google Scholar 

  • Anker, S.D. and Coats, A.J. (2002). How to RECOVER from RENAISSANCE? The significance of the results of RECOVER, RENAISSANCE, RENEWAL and ATTACH. Int. J. Cardiol 86: 123–130.

    Article  PubMed  Google Scholar 

  • Argilés, J.M. and López-Soriano, F.J. (1998). Catabolic proinflammatory cytokines. Curr. Opin. Clin. Nutr. Metab. Care. 1: 245–251.

    Article  PubMed  Google Scholar 

  • Badger, A.M. et al. (1994). Beneficial effects of the phosphodiesterase inhibitors BRL 61063, pentoxifylline, and rolipram in a murine model of endotoxin shock. Circ. Shock 44: 188–195.

    PubMed  CAS  Google Scholar 

  • Balazs, C. and Kiss, E. (1994). Immunological aspects of the effect of pentoxifylline. Acta Microbiol. Immunol. Hung. 41: 121–126.

    PubMed  CAS  Google Scholar 

  • Baracos, V.E. (2000). Regulation of skeletal-muscle-protein turnover in cancer-associated cachexia. Nutrition. 16: 1015–1018.

    Article  PubMed  CAS  Google Scholar 

  • Barton, B.E. et al. (2000). A model that reproduces syndromes associated with human multiple myeloma in nonirradiated SCID mice. Proc. Soc. Exp. Biol. Med. 223: 190–197.

    Article  PubMed  CAS  Google Scholar 

  • Barton, B.E. and Murphy, T.F. (2001). Cancer cachexia is mediated in part by the induction of IL-6-like cytokines from the spleen. Cytokine. 16: 251–257.

    Article  PubMed  CAS  Google Scholar 

  • Belizario, J.E. et al. (2001). Cleavage of caspases-1,-3,-6,-8 and-9 substrates by proteases in skeletal muscles from mice undergoing cancer cachexia. Br. J. Cancer. 84: 1135–1140.

    Article  PubMed  CAS  Google Scholar 

  • Bielefeldt-Ohmann, H. et al. (1995). Interleukin-6 involvement in mesothelioma pathobiology: inhibition by interferon alpha immunotherapy. Cancer Immunol. Immunother. 40: 241–250.

    Article  PubMed  CAS  Google Scholar 

  • Bing, C. et al. (2001). Cachexia in MAC16 adenocarcinoma: suppression of hunger despite normal regulation of leptin, insulin and hypothalamic neuropeptide Y. J. Neurochem. 79: 1004–1012.

    Article  PubMed  CAS  Google Scholar 

  • Brenner, D.A. et al. (1989). Prolonged activation of jun and collagenase genes by tumor necrosis factor-alpha. Nature. 337: 661–663.

    Article  PubMed  CAS  Google Scholar 

  • Brown, D.R. et al. (2001). Weight loss is not associated with hyperleptinemia in humans with pancreatic cancer. J. Clin. Endocrinol. Metab. 86: 162–166.

    Article  PubMed  CAS  Google Scholar 

  • Bruera, E. et al. (1999) Thalidomide in patients with cachexia due to terminal cancer: preliminary report. Ann. Oncol. 10: 857–859.

    Article  PubMed  CAS  Google Scholar 

  • Busquets, S. et al. (1998). In the rat, TNF-α administration results in an increase in both UCP2 and UCP3 mRNAs in skeletal muscle: a possible mechanism for cytokine-induced thermogenesis? FEBS Lett. 440: 348–350.

    Article  PubMed  CAS  Google Scholar 

  • Busquets, S. et al. (2001). Curcumin, a natural product present in turmeric, decreases tumor growth but does not behave as an anticachectic compound in a rat model. Cancer Lett. 167: 33–38.

    Article  PubMed  CAS  Google Scholar 

  • Busquets, S. et al. (2003). Tumour necrosis factor-alpha uncouples respiration in isolated rat mitochondria. Cytokine. 22: 1–4.

    Article  PubMed  CAS  Google Scholar 

  • Cahlin, C. et al. (2000). Experimental cancer cachexia: the role of host-derived cytokines interleukin (IL)-6, IL-12, interferon-gamma, and tumor necrosis factor alpha evaluated in gene knockout, tumor-bearing mice on C57 B1 background and eicosanoid-dependent cachexia. Cancer Res. 60: 5488–5493.

    PubMed  CAS  Google Scholar 

  • Carbó, N. et al. (1994). Anti-tumour necrosis factor-alpha treatment interferes with changes in lipid metabolism in a tumour cachexia model. Clin. Sci. 87: 349–355.

    PubMed  Google Scholar 

  • Carbó, N. et al. (2000). Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats. Br. J. Cancer. 83: 526–531.

    Article  PubMed  Google Scholar 

  • Carbó, N. et al. (2002). TNF-α is involved in activating DNA fragmentation in murine skeletal muscle. Br. J. Cancer. 86: 1012–1016.

    Article  PubMed  Google Scholar 

  • Chance, W.T. et al. (1994). Hypothalamic concentration and release of neuropeptide Y into microdialysates is reduced in anorectic tumor-bearing rats. Life Sci. 54: 1869–1874.

    Article  PubMed  CAS  Google Scholar 

  • Coletti, D. et al. (2002). TNFalpha inhibits skeletal myogenesis through a PW1-dependent pathway by recruitment of caspase pathways. EMBO J. 21: 631–642.

    Article  PubMed  CAS  Google Scholar 

  • Costa, G. and Holland, J.F. (1966). Effects of Krebs-2 carcinoma on the lipid metabolism of male Swiss mice. Cancer Res. 22: 1081–1083.

    Google Scholar 

  • Costelli, P. et al. (1993). Tumor necrosis factor-alpha mediates changes in tissue protein turnover in a rat cancer cachexia model. J. Clin. Invest. 92: 2783–2789.

    Article  PubMed  CAS  Google Scholar 

  • Costelli, P. et al. (1995). Interleukin-1 receptor antagonist (IL-1ra) is unable to reverse cachexia in rats bearing an ascites hepatoma (Yoshida AH-130). Cancer Lett. 95: 33–38.

    Article  PubMed  CAS  Google Scholar 

  • Costelli, P. and Baccino, F.M. (2000). Cancer cachexia: from experimental models to patient management. Curr. Opin. Clin. Nutr. Metab. Care. 3: 177–181.

    Article  PubMed  CAS  Google Scholar 

  • Dezube, B.J. et al. (1993). Pentoxifylline decreases tumor necrosis factor expression and serum triglycerides in people with AIDS. NIAID AIDS Clinical Trials Group. J. Acquir. Immune. Defic. Syndr. 6: 787–794.

    PubMed  CAS  Google Scholar 

  • Dunlop, R.J. and Campbell, C.W. (2000). Cytokines and advanced cancer. J. Pain Symptom Manage. 20: 214–232.

    Article  PubMed  CAS  Google Scholar 

  • Emilie, D. et al. (1994). Administration of an anti-interleukin-6 monoclonal antibody to patients with acquired immunodeficiency syndrome and lymphoma: effect on lymphoma growth and on B clinical symptoms. Blood. 84: 2472–2479.

    PubMed  CAS  Google Scholar 

  • Evans, R.D. et al. (1989). Metabolic effects of tumour necrosis factor-alpha (cachectin) and interleukin-1. Clin. Sci. 77: 357–364.

    PubMed  CAS  Google Scholar 

  • Fearon, K. and Moses, A. (2002). Cancer cachexia. Int. J. Cardiol. 85: 73–81.

    Article  PubMed  Google Scholar 

  • Fernandez-Celemin, L. et al. (2002). Inhibition of muscle insulin-like growth factor I expression by tumor necrosis factor-alpha. Am. J. Physiol. 283: E1279–E1290.

    CAS  Google Scholar 

  • Fujimoto-Ouchi, K. et al.. (1995). Establishment and characterization of cachexia inducing and non-inducing clones of murine colon 26 carcinoma. Int. J. Cancer. 61: 522–528.

    Article  PubMed  CAS  Google Scholar 

  • García-Martínez, C. et al. (1994). Interleukin-6 does not activate protein breakdown in rat skeletal muscle. Cancer Lett. 76:1–4.

    Article  PubMed  Google Scholar 

  • Goldberg, R.M. et al. (1995). Pentoxifylline for treatment of cancer anorexia and cachexia? A randomized, double-blind, placebo-controlled trial. J. Clin. Oncol 13: 2856–2859.

    PubMed  CAS  Google Scholar 

  • Gullestad, L. et al. (2002). Effect of thalidomide in patients with chronic heart failure. Am. Heart J. 144: 847–850.

    PubMed  CAS  Google Scholar 

  • Guttridge, D.C. et al. (2000). NF-kappaB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science. 289: 2363–2366.

    Article  PubMed  CAS  Google Scholar 

  • Henderson, J.T. et al. (1996). Physiological effects of CNTF-induced wasting. Cytokine. 8: 784–793.

    Article  PubMed  CAS  Google Scholar 

  • Hirai, K. et al. (1997). Mechanism of depletion of liver glycogen in cancer cachexia. Biochem. Biophys. Res. Commun. 241: 49–52.

    Article  PubMed  CAS  Google Scholar 

  • Hirai, K. et al. (1998). Biological evaluation of a lipid-mobilising factor isolated from the urine of cancer patients. Cancer Res. 58: 2359–2365.

    PubMed  CAS  Google Scholar 

  • Ishiko, O. et al. (1999). Lipolytic activity of anemia-inducing susbtance from tumor-bearing rabbits. Nutr. Cancer. 33: 201–205.

    Article  PubMed  CAS  Google Scholar 

  • Kawamura, I. et al. (1999). Intratumoral injection of oligonucleotides to the NF-kappaB binding site inhibits cachexia in a mouse tumor model. Gene Ther. 6: 91–97.

    Article  PubMed  CAS  Google Scholar 

  • Kawamura, I. et al. (2001). Intravenous injection of oligodeoxynucleotides to the NF-kappaB binding site inhibits hepatic metastasis of M5076 reticulosarcoma in mice. Gene Ther. 8: 905–912.

    Article  PubMed  CAS  Google Scholar 

  • Khan, S. and Tisdale, M.J. (1999). Catabolism of adipose tissue by a tumour-produced lipid metabolising factor. Int. J. Cancer. 80: 444–447.

    Article  PubMed  CAS  Google Scholar 

  • Khan, Z.H. et al. (2003). Oesophageal cancer and cachexia: the effect of short-term treatment with thalidomide on weight loss and lean body mass. Aliment. Pharmacol. Ther. 17: 677–682.

    Article  PubMed  CAS  Google Scholar 

  • King, P.J. et al. (2000). Effect of cytokines on hypothalamic neuropeptide Y release in vitro. Peptides. 21 143–146.

    Article  PubMed  CAS  Google Scholar 

  • Kitada, S. et al. (1981). Characterization of a lipid mobilizing factor from tumors. Prog. Lipid Res. 20: 823–826.

    Article  PubMed  CAS  Google Scholar 

  • Klausner, J.D. et al. (1996). The effect of thalidomide on the pathogenesis of human immunodeficiency virus type 1 and M. tuberculosis infection. J. Acquir. Immune. Defic. Syndr. Hum. Retrovirol. 11: 247–257.

    Article  PubMed  CAS  Google Scholar 

  • Kowalczuk, A. et al. (2001). Plasma concentration of leptin, neuropeptide Y and tumour necrosis factor alpha in patients with cancers, before and after radio-and chemotherapy. Pol. Arch. Med. Wewn. 106: 657–668.

    PubMed  CAS  Google Scholar 

  • Laviano, A. et al. (2002). Neurochemical mechanisms for cancer anorexia. Nutrition. 18: 100–105.

    Article  PubMed  CAS  Google Scholar 

  • Li, Y.P. et al. (1998). Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-kappaB activation in response to tumor necrosis factor alpha. FASEB J. 12: 871–880.

    PubMed  CAS  Google Scholar 

  • López-Soriano, J. et al. (1999). Leptin and tumour growth in the rat. Int. J. Cancer. 81: 726–729.

    Article  PubMed  Google Scholar 

  • Lorite, M.J. et al. (1997). Induction of muscle protein degradation by a tumour factor. Br. J. Cancer. 76: 1035–1040.

    Article  PubMed  CAS  Google Scholar 

  • Lorite, M.J. et al. (1998). Mechanism of muscle protein degradation induced by a cancer cachectic factor. Br. J. Cancer. 78: 850–856.

    Article  PubMed  CAS  Google Scholar 

  • Mantovani, G. et al. (2000). Serum levels of leptin and proinflammatory cytokines in patients with advanced-stage cancer at different sites. J. Mol. Med. 78: 554–561.

    Article  PubMed  CAS  Google Scholar 

  • Mantovani, G. et al. (2001). Serum values of proinflammatory cytokines are inversely correlated with serum leptin levels in patients with advanced stage cancer at different sites. J. Mol. Med. 79: 406–414.

    Article  PubMed  CAS  Google Scholar 

  • Masuno, H. et al. (1981). Purification and characterization of a lipolytic factor (toxohormone L) from cell free fluid of ascites sarcoma 180. Cancer Res. 41: 284–288.

    PubMed  CAS  Google Scholar 

  • Matthys, P. et al. (1991). Anti-interferon-γ antibody treatment, growth of Lewis lung tumours in mice and tumour-associated cachexia. Eur. J. Cancer. 27: 182–187.

    Article  PubMed  CAS  Google Scholar 

  • Moreira, A.L. et al. (1993). Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. Exp. Med. 177: 1675–1680.

    Article  CAS  Google Scholar 

  • Mori, K. et al. (1996). Murine interleukin-12 prevents the development of cancer cachexia in a murine model. Int. J. Cancer. 67: 849–855.

    Article  PubMed  CAS  Google Scholar 

  • Negri, D.R. et al. (2001). Role of cytokines in cancer cachexia in a murine model of intracerebral injection of human tumours. Cytokine. 15: 27–38.

    Article  PubMed  CAS  Google Scholar 

  • Oliff, A. et al. (1987). Tumors secreting human TNF/cachectin induce cachexia in mice. Cell. 50: 555–563.

    Article  PubMed  CAS  Google Scholar 

  • Penner, C.G. et al. (2001) The transcription factors NF-kappaB and AP-1 are differentially regulated in skeletal muscle during sepsis. Biochem. Biophys. Res. Commun. 281: 1331–1336.

    Article  PubMed  CAS  Google Scholar 

  • Penner, G. et al. (2002). C/EBP DNA-binding activity is upregulated by a glucocorticoid-dependent mechanism in septic muscle. Am. J. Physiol. 282: R439–R444.

    CAS  Google Scholar 

  • Plata-Salaman, C.R. (2000). Central nervous system mechanisms contributing to the cachexia-anorexia syndrome. Nutrition. 16: 1009–1012.

    Article  PubMed  CAS  Google Scholar 

  • Puigserver, P. et al. (2001). Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1. Mol. Cell. 8: 971–982.

    Article  PubMed  CAS  Google Scholar 

  • Quinn, L.S. et al. (1995). Interleukin-15: a novel anabolic cytokine for skeletal muscle. Endocrinology. 136: 3669–3672.

    Article  PubMed  CAS  Google Scholar 

  • Reinhart, K. et al. (1996). Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody fragment, MAK 195F, in patients with sepsis and septic shock: a multicenter, randomized, placebo-controlled, dose-ranging study. Crit. Care Med. 24: 733–742.

    Article  PubMed  CAS  Google Scholar 

  • Sampaio, E.P. et al. (1993). The influence of thalidomide on the clinical and immunologic manifestation of erythema nodosum leprosum. J. Infect. Dis. 168: 408–414.

    Article  PubMed  CAS  Google Scholar 

  • Sampaio, E.P. et al. (1991). Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J. Exp. Med. 173: 699–703.

    Article  PubMed  CAS  Google Scholar 

  • Sato, T. et al. (2002). Does leptin really influence cancer anorexia? Nutrition. 18: 82–83.

    Article  PubMed  CAS  Google Scholar 

  • Semmler, J. et al. (1993). The specific type IV phosphodiesterase inhibitor rolipram suppresses tumor necrosis factor-alpha production by human mononuclear cells. Int. J. Immunopharmacol. 15: 409–413.

    Article  PubMed  CAS  Google Scholar 

  • Sharma, R. and Anker, S.D. (2002). Cytokines, apoptosis and cachexia: the potential for TNF antagonism. Int. J. Cardiol. 85: 161–171.

    Article  PubMed  Google Scholar 

  • Smith, H.J. et al. (1999). Effects of a cancer cachectic factor on protein synthesis/degradation in murine C2C12 myoblasts: modulation by eicosapentaenoic acid. Cancer Res. 59: 5507–5513.

    PubMed  CAS  Google Scholar 

  • Strassmann, G. et al. (1993). Suramin interferes with interleukin-6 receptor binding in vitro and inhibits colon-26-mediated experimental cancer cachexia in vivo. J. Clin. Invest. 92: 2152–2159.

    Article  PubMed  CAS  Google Scholar 

  • Tanaka, Y. et al. (1990). Experimental cancer cachexia induced by transplantable colon 26 adenocarcinoma in mice. Cancer Res. 50: 2290–2295.

    PubMed  CAS  Google Scholar 

  • Tessitore, L. et al. (2000). Leptin expression in colorectal and breast cancer patients. Int. J. Mol. Med. 5: 421–426.

    PubMed  CAS  Google Scholar 

  • Thinakaran, G. et al. (1993). Expression of c-jun/AP-1 during myogenic differentiation in mouse C2C12 myoblasts. FEBS Lett. 319: 271–276.

    Article  PubMed  CAS  Google Scholar 

  • Todorov, P. et al. (1996). Characterization of a cancer cachectic factor. Nature. 22: 739–742.

    Article  Google Scholar 

  • Van Royen, M. et al. (2000). DNA fragmentation occurs in skeletal muscle during tumour growth: a link with cancer cachexia? Biochem. Biophys. Res. Commun. 270: 533–537.

    Article  PubMed  Google Scholar 

  • Wang, M.C. and Forsberg, N.E. (2000). Effects of ciliary neurotrophic factor (CNTF) on protein turnover in cultured muscle cells. Cytokine. 12: 41–48.

    Article  PubMed  CAS  Google Scholar 

  • Wigmore, S.J. et al. (2000). Characteristics of patients with pancreatic cancer expressing a novel cancer cachexia factor. Br. J. Surgery. 87: 53–58.

    Article  CAS  Google Scholar 

  • Yamamoto, N. et al. (1998). Effect of FR143430, a novel cytokine suppressive agent, on adenocarcinoma colon26-induced cachexia in mice. Anticancer Res. 18: 139–144.

    PubMed  CAS  Google Scholar 

  • Yasumoto, K. et al. (1995). Molecular analysis of the cytokine network involved in cachexia in colon26 adenocarcinoma-bearing mice. Cancer Res. 55: 921–927.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain

    Josep M. Argilés, Sílvia Busquets & Francisco J. López-Soriano

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  1. Josep M. Argilés
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  2. Sílvia Busquets
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  3. Francisco J. López-Soriano
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Editors and Affiliations

  1. Division of Oncology, St. George’s Hospital Medical School, Cranmer Terrace, London, SW17 0RE, UK

    Angus G. Dalgleish MD

  2. Department of Oncology Johnson and Johnson Pharmaceutical, Research and Development, Turnhoutseweg 30, Box 6423, 2340, Beerse, Belgium

    Burkhard Haefner PhD

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Argilés, J.M., Busquets, S., López-Soriano, F.J. (2006). Cytokines as Mediators and Targets for Cancer Cachexia. In: Dalgleish, A.G., Haefner, B. (eds) The Link Between Inflammation and Cancer. Cancer Treatment and Research, vol 130. Springer, Boston, MA. https://doi.org/10.1007/0-387-26283-0_9

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