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Cancer cachexia

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Abstract

Causative factors

Nutritional supplementation or pharmacological manipulation of appetite are unable to control the muscle atrophy seen in cancer cachexia. This suggests that tumour and/or host factors might be responsible for the depression in protein synthesis and the increase in protein degradation. An increased expression of the ubiquitin–proteasome proteolytic pathway is responsible for the increased degradation of myofibrillar proteins in skeletal muscle, and this may be due to tumour factors, such as proteolysis-inducing factor (PIF), or host factors such as tumour necrosis factor-α (TNF-α). In humans loss of adipose tissue is due to an increase in lipolysis rather than a decrease in synthesis, and this may be due to tumour factors such as lipid-mobilising factor (LMF) or TNF-α, both of which can increase cyclic AMP in adipocytes, leading to activation of hormone-sensitive lipase (HSL). Levels of mRNA for HSL are elevated twofold in adipose tissue of cancer patients, while there are no changes in lipoprotein lipase (LPL), involved in extraction of fatty acids from plasma lipoproteins for storage.

Treatment for cachexia

This has concentrated on increasing food intake, although that alone is unable to reverse the metabolic changes. Agents interfering with TNF-α have not been very successful to date, although more research is required in that area. The only agent tested clinically that is able to interfere with the action of PIF is eicosapentaenoic acid (EPA). EPA attenuates protein degradation in skeletal muscle by preventing the increased expression of the ubiquitin–proteasome pathway, but has no effect on protein synthesis. When used alone EPA prevents further wasting in cachectic patients, and, when it is combined with an energy- and protein-dense nutritional supplement, weight gain is seen, which is totally lean body mass. These results suggest that mechanistic studies into the causes of cancer cachexia will allow appropriate therapeutic intervention.

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References

  1. De Wys WD, Begg C, Lavin PT et al (1980) Prognostic effect of weight loss prior to chemotherapy in cancer patients. Am J Med 69:491–497

    CAS  PubMed  Google Scholar 

  2. Monitto CL, Berkowitz D, Lee KM, Pin S, Li D, Breslow M (2001) Differential gene expression in a murine model of cancer cachexia. Am J Physiol 281:E289–E297

    CAS  Google Scholar 

  3. Persson C, Glimeluis B (2002) The relevance of weight loss for survival and quality of life in patients with advanced gastrointestinal cancer treated with palliative chemotherapy. Anticancer Res 22:3661–3668

    PubMed  Google Scholar 

  4. De Wys WD (1972) Anorexia as a general effect of cancer. Cancer 45:2013–2019

    Google Scholar 

  5. Evans WK, Makuch R, Clamon GH, et al (1985) Limited impact of total parenteral nutrition on nutritional status during treatment for small cell lung cancer. Cancer Res 45:3347–3353

    CAS  PubMed  Google Scholar 

  6. Loprinzi CL, Schaid DJ, Dose AM, Burnham NL, Jensen MD (1993) Body-composition changes in patients who gain weight while receiving megestrol acetate. J Clin Oncol 11:152–154

    CAS  PubMed  Google Scholar 

  7. Okusaka T, Okada S, Ishii H, Ikeda M, Kosakomoto H, Yoshimori M (1998) Prognosis of advanced pancreatic cancer patients with reference to calorie intake. Nutr Cancer 32:55–58

    CAS  PubMed  Google Scholar 

  8. Fearon KCH (1992) The mechanism and treatment of weight loss in cancer. Proc Nutr Soc 51:251–265

    CAS  PubMed  Google Scholar 

  9. Shaw JH, Wolfe RR (1987) Fatty acid and glycerol kinetics in septic patients and in patients with gastrointestinal cancer. The response to glucose infusion and parenteral feeding. Ann Surg 205:368–376

    CAS  PubMed  Google Scholar 

  10. Yam D, Ben-Hur H, Fink A, Dgani R, Shani A, Eliraz A, Insker V, Berry EM (1994) Insulin and glucose status, tissue and plasma lipids in patients with tumours of the ovary or endometrium: possible dietary implications. Br J Cancer 70:1186–1187

    CAS  PubMed  Google Scholar 

  11. Mitch WE, Goldberg AL (1996) Mechanisms of muscle wasting. The role of the ubiquitin–proteasome pathway. N Engl J Med 335:1897–1905

    CAS  PubMed  Google Scholar 

  12. Fearon KCH, Falconer JS, Slater C, McMillan DC, Ross JA, Preston T (1998) Albumin synthesis rates are not decreased in hypoalbuminemic cachectic cancer patients with an ongoing acute-phase protein response. Ann Surg 227:249–254

    Article  CAS  PubMed  Google Scholar 

  13. Falconer JS, Fearon KC, Ross JA, Elton R, Wigmore SJ, Garden OJ, et al (1995) Acute-phase protein response and survival duration of patients with pancreatic cancer. Cancer 75:2077–2082

    CAS  PubMed  Google Scholar 

  14. Yoshizawa F (2004) Regulation of protein synthesis by branched-chain amino acids in vivo. Biochem Biophys Res Commun 313:417–422

    Article  CAS  PubMed  Google Scholar 

  15. Bossola M, Muscaritoli M, Costelli P, Grieco G, Bonelli G, Pacelli F, Fanelli FR, Doglietto GB, Baccino FM (2003) Increased muscle proteasome activity correlates with disease severity in gastric cancer patients. Ann Surg 237:384–389

    Article  PubMed  Google Scholar 

  16. Jagoe RT, Redfern CPF, Roberts RG, Gibson GJ, Goodship THJ (2002) Skeletal muscle mRNA levels for cathepsins B, but not components of the ubiquitin–proteasome pathway, are increased in patients with lung cancer referred for thoracotomy. Clin Sci 102:353–361

    Article  CAS  PubMed  Google Scholar 

  17. Bodine SC, Latres E, Baumheuter S, et al (2001) Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294:1704–1708

    Article  CAS  PubMed  Google Scholar 

  18. Bing C, Bao Y, Jenkins J, Sanders P, Manieri M, Cinti S, Tisdale MJ, Trayhum P (2004) Zinc-(2-glycoprotein, a lipid mobilizing factor, is expressed in adipocytes and is up-regulated in mice with cancer cachexia. Proc Natl Acad Sci U S A 101:2500–2505

    Article  CAS  Google Scholar 

  19. Hirai K, Hussey HJ, Barber MD, Price SA, Tisdale MJ (1998) Biological evaluation of a lipid-mobilizing factor isolated from the urine of cancer patients. Cancer Res 58:2359–2365

    CAS  PubMed  Google Scholar 

  20. Todorov PT, Caruik P, McDevitt T, Coles B, Fearon K, Tisdale M (1996) Characterization of a cancer cachectic factor. Nature 379:739–742

    CAS  PubMed  Google Scholar 

  21. Watchorn TM, Waddell ID, Dowidar N, Ross JA (2001) Proteolysis-inducing factor regulates hepatic gene expression via the transcription factors NF-κB and STAT3. FASEB J 15:562–564

    CAS  PubMed  Google Scholar 

  22. Maltoni M, Fabbri L, Nani O, Scarpi E, Pezzi L, Flamini E, Riccobon A, Derni S, Pallotti G, Amadori D (1997) Serum levels of tumour necrosis factor and other cytokines do not correlate with weight loss and anorexia in cancer patients. Support Care Cancer 5:130–135

    CAS  PubMed  Google Scholar 

  23. Karayiannakis AJ, Syrigos KN, Polychronidis A, Pitiakoudis M, Bounovas A, Simppoulos K (2001) Serum levels of tumor necrosis factor-α and nutritional status in pancreatic cancer patients. Anticancer Res 21:1355–1358

    CAS  PubMed  Google Scholar 

  24. Sheen-Chen S-M, Chen W-J, Eng H-L, Chou F-F (1997) Serum concentrations of tumor necrosis factor in patients with breast cancer. Breast Cancer Res Treat 43:211–215

    Article  CAS  PubMed  Google Scholar 

  25. Shibata M, Takekawa M (1997) Increased serum concentrations of circulatory soluble receptors for interleukin-2 and its effect as a prognostic indicator in cachectic patients with gastric and colorectal cancer. Oncology 56:54–58

    Article  Google Scholar 

  26. Wigmore SJ, Todorov PT, Barber MD, Ross JA, Tisdale MJ, Fearon KCH (2000) Characteristics of patients with pancreatic cancer expressing a novel cancer cachectic factor. Br J Surg 87:53–58

    CAS  PubMed  Google Scholar 

  27. Caruik P, Lorite MJ, Todorov PT, Field WN, Wigmore SJ, Tisdale MJ (1997) Induction of cachexia in mice by a product isolated from the urine of cachectic cancer patients. Br J Cancer 76:606–613

    CAS  PubMed  Google Scholar 

  28. Grunfeld C, Feingold KR (1991) Tumor necrosis factor, cytokines and hyperlipidemia of infection. Trends Endocrinol Metab 2:213–219

    Google Scholar 

  29. Strassman G, Kambayashi T (1995) Inhibition of experimental cancer cachexia by anti-cytokine and anti-cytokine receptor therapy. Cytokines Mol Ther 1:107–113

    PubMed  Google Scholar 

  30. Russell ST, Hirai K, Tisdale MJ (2002) Role of β3-adrenergic receptors in the action of a tumour lipid mobilizing factor. Br J Cancer 86:424–428

    Article  CAS  PubMed  Google Scholar 

  31. Zhang HH, Halbleib M, Ahmad R et al (2002) Tumor necrosis factor-α stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and evaluation of intracellular cyclic AMP. Diabetes 51:2929–2935

    CAS  PubMed  Google Scholar 

  32. Legaspi A, Jeevanandam M, Starnes HF, Brennan MF (1987) Whole-body lipid and energy metabolism in the cancer patient. Metabolism 36:958–963

    Article  CAS  PubMed  Google Scholar 

  33. Thompson MP, Cooper ST, Parry BR, Tuckey JA (1993) Increased expression of the mRNA for hormone-sensitive lipase in adipose tissue of cancer patients. Biochem Biophys Acta 1180:236–242

    Article  CAS  PubMed  Google Scholar 

  34. Drott C, Perrson H, Lundholm K (1989) Cardiovascular and metabolic response to adrenaline infusion in weight-losing cancer patients with and without cancer. Clin Physiol 9:427–439

    CAS  PubMed  Google Scholar 

  35. Melville S, McNurlan MA, Calder AG, Garlick PJ (1990) Increased protein turnover despite normal energy metabolism and responses to feeding in patients with lung cancer. Cancer Res 50:1125–1131

    CAS  PubMed  Google Scholar 

  36. Garcia-Martinez C, Lopez-Soriano FJ, Argiles JM (1993) Acute treatment with tumour necrosis factor-α induces changes in protein metabolism in rat skeletal muscle. Mol Cell Biochem 125:11–18

    CAS  PubMed  Google Scholar 

  37. Lorite MJ, Cariuk P, Tisdale MJ (1997) Induction of muscle protein degradation by a tumour factor. Br J Cancer 76:1035–1040

    CAS  PubMed  Google Scholar 

  38. Lorite MJ, Smith HJ, Arnold JA, Morris A, Thompson MG, Tisdale MJ (2001) Activation of ATP-ubiquitin-dependent proteolysis in skeletal muscle in vivo and murine myoblasts in vitro by a proteolysis-inducing factor (PIF). Br J Cancer 85:297–302

    CAS  PubMed  Google Scholar 

  39. Llovera M, Carbo N, Lopez-Soriano J, Garcia-Martinez C, Busquets S, Alvarez B et al (1998) Different cytokines modulate ubiquitin gene expression in rat skeletal muscle. Cancer Lett 13:83–87

    Article  Google Scholar 

  40. Jentsch S, McGrath IP, Varshavsky A (1987) The yeast DNA repair gene RAD6 encodes a ubiquitin-conjugating enzyme. Nature 329:131–134

    CAS  PubMed  Google Scholar 

  41. Glotzer M, Murray AW, Kirschner MN (1991) Cyclin is degraded by the ubiquitin pathway. Nature 349:132–138

    CAS  PubMed  Google Scholar 

  42. Gomes-Marcondes MCC, Smith HJ, Cooper JC, Tisdale MJ (2002) Development of an in vitro model system to investigate the mechanism of muscle protein catabolism induced by proteolysis-inducing factor. Br J Cancer 86:1628–1633

    Article  CAS  PubMed  Google Scholar 

  43. Li Y-P, Schwartz RJ, Waddell ID, Holloway BR, Reid MB (1998) Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-κB activation in response to tumor necrosis factor α. FASEB J 12:871–880

    CAS  PubMed  Google Scholar 

  44. Llovera M, Garcia-Martinez C, Agell N, Lopez-Soriano FJ, Argiles JM (1997) TNF can directly induce the expression of the ubiquitin-dependent proteolytic system in rat soleus muscles. Biochem Biophys Res Commun 230:238–244

    Article  CAS  PubMed  Google Scholar 

  45. Whitehouse AS, Tisdale MJ (2003) Increased expression of the ubiquitin–proteasome pathway in murine myotubes by proteolysis-inducing factor (PIF) is associated with activation of the transcription factor NF-κB. Br J Cancer 89:1116–1122

    Article  CAS  PubMed  Google Scholar 

  46. Li Y-P, Reid MB (2000) NF-κB mediates the protein loss induced by TNF-α in differentiated skeletal muscle myotubes. Am J Physiol 279:R1165–R1170

    CAS  Google Scholar 

  47. Garcia-Martinez C, Lopez-Soriano FJ, Argiles JM (1994) Interleukin-6 does not activate protein breakdown in rat skeletal muscle. Cancer Lett 76 1–4

    Google Scholar 

  48. Goodman MN (1994) Interleukin-6 induces skeletal muscle protein breakdown in rats. Proc Soc Exp Biol Med 205:182–185

    CAS  PubMed  Google Scholar 

  49. Espat NJ, Auffenberg T, Rosenberg JJ, Martin RD, Fang CH, Hasselgren P-O, Copeland EM, Moldawer LL (1996) Ciliary neurotrophic factor is catabolic and shares with IL-6 the capacity to induce an acute phase response. Am J Physiol 271:R185–R190

    CAS  PubMed  Google Scholar 

  50. Fujita J, Tsujinaka T, Yano M, et al (1996) Anti-interleukin-6 receptor antibody prevents muscle atrophy in colon-26 adenocarcinoma-bearing mice with modulation of lysosomal and ATP-ubiquitin-dependent proteolytic pathways. Int J Cancer 68:637–643

    Article  CAS  PubMed  Google Scholar 

  51. Baracos V, Rodeman HP, Dinarello CA, Goldberg AL (1983) Stimulation of muscle protein degradation and prostaglandin E2 release by leukocyte pyrogen (interleukin-1). N Engl J Med 308:553–555

    CAS  PubMed  Google Scholar 

  52. Goldberg AL, Kettlehut IC, Foruno K, Fagan JM, Baracos V (1988) Activation of protein breakdown and prostaglandin E2 production in rat skeletal muscle in fever is signaled by a microphage product distinct from interleukin-1 or other known monokines. J Clin Invest 81:1378–1383

    CAS  PubMed  Google Scholar 

  53. Ling PK, Istfan N, Blackburn GL, Bistrian BR (1991) Effects of interleukin 1-β (IL-1) and combination of IL-1 and tumor necrosis factor on tumor growth and protein metabolism. J Nutr Biochem 2:553–559

    Article  CAS  Google Scholar 

  54. Bishop JF, Smith JG, Jeal PN, Murray R, Drummond RM, Pitt P, Olver IN, Bhowal AK (1993) The effect of danzol on tumour control and weight loss in patients on tamoxifen for advanced breast cancer: a randomised double-blind placebo controlled trial. Eur J Cancer 29A:814–818

    CAS  PubMed  Google Scholar 

  55. Kardinal CG, Loprinzi CL, Schaid DJ, Hass AC, et al (1990) A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia. Cancer 65:2657–2662

    CAS  PubMed  Google Scholar 

  56. Lundholm K, Gelin J, Hyltander A, et al (1994) Anti-inflammatory treatment may prolong survival in undernourished patients with metastatic solid tumours. Cancer Res 54:5602–5606

    CAS  PubMed  Google Scholar 

  57. Wigmore SJ, Falconer JS, Plester CE, Ross JA, Maingay JP, Carter DC, Fearon KCH (1995) Ibuprofen reduces energy expenditure and acute-phase protein production compared with placebo in pancreatic cancer patients. Br J Cancer 72:185–188

    CAS  PubMed  Google Scholar 

  58. McMillan DC, Wigmore SJ, Fearon KCH, O’Gorman P, Wright CE, McArdle CS (1999) A prospective randomized study of megestrol acetate and ibuprofen in gastrointestinal cancer patients with weight loss. Br J Cancer 79:495–500

    Article  CAS  PubMed  Google Scholar 

  59. Goldberg RM, Loprinzi CL, Malliard JA et al (1995) Pentoxifylline for treatment of cancer anorexia and cachexia? A randomized, double-blind, placebo-controlled trial. J Clin Oncol 13:2856–2859

    CAS  PubMed  Google Scholar 

  60. Reyo-Teran G, Sierra-Madero JG, Martinez del Cerro V, et al (1996) Effects of thalidomide on HIV-associated wasting syndrome: a randomized, double-blind, placebo-controlled trial. AIDS 10:1501–1507

    PubMed  Google Scholar 

  61. Lissoni P, Paolorossi F, Tancini G, Barni S, Ardizzoia A, Brivio F, Zubelewicz B, Chatikhine V (1996) Is there a role for melatonin in the treatment of neoplastic cachexia? Eur J Cancer 32A:1340–1343

    Article  CAS  PubMed  Google Scholar 

  62. Whitehouse AS, Smith HJ, Drake JL, Tisdale MJ (2001) Mechanism of attenuation of skeletal muscle protein catabolism in cancer cachexia by eicosapentaenoic acid. Cancer Res 61:3604–3609

    CAS  PubMed  Google Scholar 

  63. Wigmore SJ, Ross JA, Falconer JS, Plester CE, Tisdale MJ, Carter DC, Fearon KCH (1996) The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer. Nutrition 12:S27–S30

    CAS  PubMed  Google Scholar 

  64. Wigmore SJ, Barber MD, Ross JA, Tisdale MJ, Fearon KCH (2000) Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutr Cancer 36:177–184

    CAS  PubMed  Google Scholar 

  65. Barber MD, Ross JA, Voss AC, Tisdale MJ, Fearon KCH (1999) The effect of an oral nutritional supplement enriched with fish oil on weight-loss in patients with pancreatic cancer. Br J Cancer 81:80–86

    CAS  PubMed  Google Scholar 

  66. Barber MD, Fearon KCH, Tisdale MJ, McMillan DC, Ross JA (2001) Effect of a fish oil-enriched nutritional supplement on metabolic mediators in patients with pancreatic cancer cachexia. Nutr Cancer 40:118–124

    Article  CAS  PubMed  Google Scholar 

  67. Fearon KCH, von Megenfeldt MF, Moses AGW et al (2003) Effect of a protein and energy dense n-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double blind trial. Gut 52:1479–1486

    Article  CAS  PubMed  Google Scholar 

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  1. Pharmaceutical Sciences Research Institute, Aston University, Birmingham, B4 7ET, UK

    Michael J. Tisdale

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Tisdale, M.J. Cancer cachexia. Langenbecks Arch Surg 389, 299–305 (2004). https://doi.org/10.1007/s00423-004-0486-7

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