Download PDF
Z Gastroenterol 2008; 46(12): 1384-1392
DOI: 10.1055/s-2008-1027655
Übersicht

© Georg Thieme Verlag KG Stuttgart · New York

Molekulare Mechanismen und klinische Auswirkungen der Tumorkachexie

Molecular Mechanisms and its Clinical Impact in Cancer CachexiaJ. Bachmann1 , H. Friess1 , M. E. Martignoni1
  • 1Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar
Further Information

Publication History

Manuskript eingetroffen: 27.1.2008

Manuskript akzeptiert: 27.6.2008

Publication Date:
03 December 2008 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Kachexie beschreibt einen „schlechten Zustand” eines Patienten; dieses Syndrom kann bei chronischen benignen Erkrankungen (wie Morbus Crohn, Herzinsuffizienz, chronischen Nierenerkrankungen) sowie malignen Erkrankungen auftreten und stellt einen wesentlichen prognostischen Faktor dar. Anhand der vorliegenden Publikation soll der aktuelle Stand der Forschung zu pathophysiologischen Mechanismen der Kachexie insbesondere beim Pankreaskarzinom dargelegt werden. Der Gewichtsverlust bei malignen Erkrankungen ist vor allem auf Anorexie mit daraus resultierender Mangelernährung und einen progredienten Abbau von Muskel- und Fettgewebe zurückzuführen. An dieser Entwicklung sind verschiedene Zytokine beteiligt (u. a. TNF-α, IFN-γ, IL-1, IL-6). Über den Ubiquitin-Proteasom-Signalweg wird der wesentliche Anteil des Proteins abgebaut, in diesen greift auch der Proteolysis inducing Factor (PIF) ein; der Nachweis erhöhter Mengen einer hormonabhängigen Lipase bei kachektischen Tumorpatienten weist darauf hin, dass ein gesteigerter Fettkatabolismus für den Verlust von Fettgewebe wichtig zu sein scheint. Die Entwicklung einer effektiven pharmakologischen Therapie stellt die zentrale klinische Herausforderung dar; bisher konnte keine einen lang anhaltenden Effekt auf das Überleben bei Patienten mit einer Tumorkachexie erbringen. Kachexie ist eine schwerwiegende Erkrankung, die besonders häufig bei Patienten mit Pankreaskarzinom auftritt. Die Kachexie beeinträchtigt nachhaltig die Lebensqualität und verschlechtert wesentlich die Prognose. Ziel der Forschung muss sein, in zentrale Stellen der Kachexie-Regelkreise einzugreifen.

Abstract

Cachexia is a term used to describe the poor status of a patient suffering from a benign disease (Crohn’s disease, chronic heart and kidney failure) as well as from a malignant disease. Cachexia has an important impact on the survival and morbidity in patients with cancer. The aim of this study is to elucidate the pathophysiology in cancer cachexia with a special emphasis on pancreatic cancer. The dramatic weight loss in malignant diseases is due to anorexia resulting in malnutrition and is characterised by a progressive loss of muscle and fat tissue. Different cytokines like TNF-α, IFN-γ, IL-1, IL-6 are involved in this process. Via the ubiquitin-proteasome pathway, in which also the proteolysis inducing factor (PIF) is involved, the majority of protein is degraded. In patients with cancer cachexia we find an elevated level of lipases, which indicates that rather fat catabolism and not reduced fat synthesis is the main factor in fat metabolism. The development of an effective (pharmacological) treatment is still the main challenge. As yet, none of the used therapies show a long-lasting effect on weight stabilisation and survial. Cachexia is an important issue, especially in pancreatic cancer; it influences the qualitiy of life and has an important impact on survival. Today, there are only a few different pharmacological therapies used in the treatment of cancer cachexia, but each and every single treatment has failed to show a persistent effect on survival. The aim of research and treatment is to interrupt the natural clinical course of cachexia.

Schlüsselwörter

Kachexie - Survival - Pankreaskarzinom - Gewichtsverlust

Key words

cachexia - survival - pancreatic cancer - loss of weight

Literatur

  • 1 Camps C, Iranzo V, Bremnes R M. et al . Anorexia-Cachexia syndrome in cancer: implications of the ubiquitin-proteasome pathway.  Support Care Cancer. 2006;  14(12) 1173-1183
    Google Scholar
  • 2 Barber M D, Ross J A, Fearon K C. Changes in nutritional, functional, and inflammatory markers in advanced pancreatic cancer.  Nutr Cancer. 1999;  35 106-110
    Google Scholar
  • 3 Karthaus M, Frieler F. Eating and drinking at the end of life. Nutritional support for cancer patients in palliative care.  Wien Med Wochenschr. 2004;  154 192-198
    Google Scholar
  • 4 Deans C, Wigmore S J. Systemic inflammation, cachexia and prognosis in patients with cancer.  Curr Opin Clin Nutr Metab Care. 2005;  8 265-269
    Google Scholar
  • 5 Bossola M, Pacelli F, Tortorelli A. et al . Cancer Cachexia: It’s Time for More Clinical Trials.  Ann Surg Oncol. 2007;  14 276-285
    Google Scholar
  • 6 Laviano A, Meguid M M, Inui A. et al . Therapy insight: Cancer anorexia-cachexia syndrome – when all you can eat is yourself.  Nat Clin Pract Oncol. 2005;  2 158-165
    Google Scholar
  • 7 Dewys W D, Begg C, Lavin P T. et al . Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group.  Am J Med. 1980;  69 491-497
    Google Scholar
  • 8 Baldwin C, Parsons T, Logan S. Dietary advice for illness-related malnutrition in adults.  Cochrane Database Syst Rev. 2001;  (2) CD002008
    Google Scholar
  • 9 Uomo G, Galluci F, Rabitti P. Anorexia-cachexia syndrome in pancreatic cancer: recent development in research and management.  JOP. 2006;  7 157-162
    Google Scholar
  • 10 Tisdale M J. Cancer anorexia and cachexia.  Nutrition. 2001;  17 438-442
    Google Scholar
  • 11 Wilcock A. Anorexia: a taste of things to come?.  Palliat Med. 2006;  20 43-45
    Google Scholar
  • 12 Mitch W E. Cachexia in chronic kidney disease: a link to defective central nervous system control of appetite.  J Clin Invest. 2005;  115 1476-1478
    Google Scholar
  • 13 Kotler D P. Cachexia.  Ann Intern Med. 2000;  133 622-634
    Google Scholar
  • 14 Tisdale M J. Cachexia in cancer patients.  Nat Rev Cancer. 2002;  2 862-871
    Google Scholar
  • 15 Anker S D, Coats A J. Cardiac cachexia: a syndrome with impaired survival and immune and neuroendocrine activation.  Chest. 1999;  115 836-847
    Google Scholar
  • 16 Anker S D, Ponikowski P, Varney S. et al . Wasting as independent risk factor for mortality in chronic heart failure.  Lancet. 1997;  349 1050-1053
    Google Scholar
  • 17 Fearon K C, Von Meyenfeldt M F, Moses A G. et al . 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. 2003;  52 1479-1486
    Google Scholar
  • 18 Lorite M J, Smith H J, Arnold J A. et al . 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. 2001;  85 297-302
    Google Scholar
  • 19 Tisdale M J. Loss of skeletal muscle in cancer: biochemical mechanisms.  Front Biosci. 2001;  6 D164-D174
    Google Scholar
  • 20 Costelli P, Baccino F M. Mechanisms of skeletal muscle depletion in wasting syndromes: role of ATP-ubiquitin-dependent proteolysis.  Curr Opin Clin Nutr Metab Care. 2003;  6 407-412
    Google Scholar
  • 21 Ripamonti C. Management of dyspnea in advanced cancer patients.  Support Care Cancer. 1999;  7 233-243
    Google Scholar
  • 22 Dewys W D. Anorexia as a general effect of cancer.  Cancer. 1979;  43 2013-2019
    Google Scholar
  • 23 Wigmore S J, Plester C E, Ross J A. et al . Contribution of anorexia and hypermetabolism to weight loss in anicteric patients with pancreatic cancer.  Br J Surg. 1997;  84 196-197
    Google Scholar
  • 24 Argiles J M, Moore-Carrasco R, Busquets S. et al . Catabolic mediators as targets for cancer cachexia.  Drug Discov Today. 2003;  8 838-844
    Google Scholar
  • 25 Inui A. Cancer anorexia-cachexia syndrome: are neuropeptides the key?.  Cancer Res. 1999;  59 4493-4501
    Google Scholar
  • 26 Barber M D, Fearon K C, Tisdale M J. et al . Effect of a fish oil-enriched nutritional supplement on metabolic mediators in patients with pancreatic cancer cachexia.  Nutr Cancer. 2001;  40 118-124
    Google Scholar
  • 27 Cutsem van E, Arends J. The causes and consequences of cancer-associated malnutrition.  Eur J Oncol Nurs. 2005;  9 (Suppl 2) S51-S63
    Google Scholar
  • 28 Argiles J M, Meijsing S H, Pallares-Trujillo J. et al . Cancer cachexia: a therapeutic approach.  Med Res Rev. 2001;  21 83-101
    Google Scholar
  • 29 Inui A, Meguid M M. Cachexia and obesity: two sides of one coin?.  Curr Opin Clin Nutr Metab Care. 2003;  6 395-399
    Google Scholar
  • 30 Nelson K A. Modern management of the cancer anorexia-cachexia syndrome.  Curr Oncol Rep. 2000;  2 362-368
    Google Scholar
  • 31 Nelson K A, Walsh D. The cancer anorexia-cachexia syndrome: a survey of the Prognostic Inflammatory and Nutritional Index (PINI) in advanced disease.  J Pain Symptom Manage. 2002;  24 424-428
    Google Scholar
  • 32 Argiles J M, Almendro V, Busquets S. et al . The pharmacological treatment of cachexia.  Curr Drug Targets. 2004;  5 265-277
    Google Scholar
  • 33 Davidson W, Ash S, Capra S. et al . Weight stabilisation is associated with improved survival duration and quality of life in unresectable pancreatic cancer.  Clin Nutr. 2004;  23 239-247
    Google Scholar
  • 34 Martignoni M E, Kunze P, Friess H. Cancer cachexia.  Mol Cancer. 2003;  2 36
    Google Scholar
  • 35 Barber M D, McMillan D C, Wallace A M. et al . The response of leptin, interleukin-6 and fat oxidation to feeding in weight-losing patients with pancreatic cancer.  Br J Cancer. 2004;  90 1129-1132
    Google Scholar
  • 36 Falconer J S, Fearon K C, Plester C E. et al . Cytokines, the acute-phase response, and resting energy expenditure in cachectic patients with pancreatic cancer.  Ann Surg. 1994;  219 325-331
    Google Scholar
  • 37 Tisdale M J. The ‘cancer cachectic factor’.  Support Care Cancer. 2003;  11 73-78
    Google Scholar
  • 38 Bosaeus I, Daneryd P, Svanberg E. et al . Dietary intake and resting energy expenditure in relation to weight loss in unselected cancer patients.  Int J Cancer. 2001;  93 380-383
    Google Scholar
  • 39 Wigmore S J, Falconer J S, Plester C E. et al . Ibuprofen reduces energy expenditure and acute-phase protein production compared with placebo in pancreatic cancer patients.  Br J Cancer. 1995;  72 185-188
    Google Scholar
  • 40 Harvie M N, Campbell I T. Energy balance, cancer and the sympathetic nervous system.  Eur J Cancer. 2000;  36 289-292
    Google Scholar
  • 41 Young V R. Energy metabolism and requirements in the cancer patient.  Cancer Res. 1977;  37 2336-2347
    Google Scholar
  • 42 Inui A. Neuropeptide Y: a key molecule in anorexia and cachexia in wasting disorders?.  Mol Med Today. 1999;  5 79-85
    Google Scholar
  • 43 Argiles J M, Busquets S, Lopez-Soriano F J. Cytokines in the pathogenesis of cancer cachexia.  Curr Opin Clin Nutr Metab Care. 2003;  6 401-406
    Google Scholar
  • 44 Palesty J A, Dudrick S J. What we have learned about cachexia in gastrointestinal cancer.  Dig Dis. 2003;  21 198-213
    Google Scholar
  • 45 Gordon J N, Green S R, Goggin P M. Cancer cachexia.  QJM. 2005;  98 779-788
    Google Scholar
  • 46 Barber M D. Cancer cachexia and its treatment with fish-oil-enriched nutritional supplementation.  Nutrition. 2001;  17 751-755
    Google Scholar
  • 47 Moldawer L L, Copeland III E M. Proinflammatory cytokines, nutritional support, and the cachexia syndrome: interactions and therapeutic options.  Cancer. 1997;  79 1828-1839
    Google Scholar
  • 48 Esper D H, Harb W A. The cancer cachexia syndrome: a review of metabolic and clinical manifestations.  Nutr Clin Pract. 2005;  20 369-376
    Google Scholar
  • 49 Mantovani G, Maccio A, Massa E. et al . Managing cancer-related anorexia/cachexia.  Drugs. 2001;  61 499-514
    Google Scholar
  • 50 Ebrahimi B, Tucker S L, Li D. et al . Cytokines in pancreatic carcinoma: correlation with phenotypic characteristics and prognosis.  Cancer. 2004;  101 2727-2736
    Google Scholar
  • 51 Martignoni M E, Kunze P, Hildebrandt W. et al . Role of mononuclear cells and inflammatory cytokines in pancreatic cancer-related cachexia.  Clin Cancer Res. 2005;  11 5802-5808
    Google Scholar
  • 52 Falconer J S, Fearon K C, Ross J A. et al . Acute-phase protein response and survival duration of patients with pancreatic cancer.  Cancer. 1995;  75 2077-2082
    Google Scholar
  • 53 Batterham R L, Cowley M A, Small C J. et al . Gut hormone PYY(3 – 36) physiologically inhibits food intake.  Nature. 2002;  418 650-654
    Google Scholar
  • 54 Tisdale M J. Biochemical mechanisms of cellular catabolism.  Curr Opin Clin Nutr Metab Care. 2002;  5 401-405
    Google Scholar
  • 55 Smith H J, Tisdale M J. Signal transduction pathways involved in proteolysis-inducing factor induced proteasome expression in murine myotubes.  Br J Cancer. 2003;  89 1783-1788
    Google Scholar
  • 56 Gomes-Marcondes M C, Smith H J, Cooper J C. et al . Development of an in-vitro model system to investigate the mechanism of muscle protein catabolism induced by proteolysis-inducing factor.  Br J Cancer. 2002;  86 1628-1633
    Google Scholar
  • 57 Tisdale M J. Metabolic abnormalities in cachexia and anorexia.  Nutrition. 2000;  16 1013-1014
    Google Scholar
  • 58 Cabal-Manzano R, Bhargava P, Torres-Duarte A. et al . Proteolysis-inducing factor is expressed in tumours of patients with gastrointestinal cancers and correlates with weight loss.  Br J Cancer. 2001;  84 1599-1601
    Google Scholar
  • 59 Watchorn T M, Waddell I, Dowidar N. et al . Proteolysis-inducing factor regulates hepatic gene expression via the transcription factors NF-(kappa)B and STAT3.  FASEB J. 2001;  15 562-564
    Google Scholar
  • 60 Watchorn T M, Waddell I, Ross J A. Proteolysis-inducing factor differentially influences transcriptional regulation in endothelial subtypes.  Am J Physiol Endocrinol Metab. 2002;  282 E763-E769
    Google Scholar
  • 61 Whitehouse A S, Tisdale M J. Increased expression of the ubiquitin-proteasome pathway in murine myotubes by proteolysis-inducing factor (PIF) is associated with activation of the transcription factor NF-kappaB.  Br J Cancer. 2003;  89 1116-1122
    Google Scholar
  • 62 Lecker S H, Solomon V, Mitch W E. et al . Muscle protein breakdown and the critical role of the ubiquitin-proteasome pathway in normal and disease states.  J Nutr. 1999;  129 227S-237S
    Google Scholar
  • 63 Khal J, Wyke S M, Russell S T. et al . Expression of the ubiquitin-proteasome pathway and muscle loss in experimental cancer cachexia.  Br J Cancer. 2005;  1-7
    Google Scholar
  • 64 Voisin L, Breuille D, Combaret L. et al . Muscle wasting in a rat model of long-lasting sepsis results from the activation of lysosomal, Ca2 +-activated, and ubiquitin-proteasome proteolytic pathways.  J Clin Invest. 1996;  97 1610-1617
    Google Scholar
  • 65 O’Riordain M G, Falconer J S, Maingay J. et al . Peripheral blood cells from weight-losing cancer patients control the hepatic acute phase response by a primarily interleukin-6 dependent mechanism.  Int J Oncol. 1999;  15 823-827
    Google Scholar
  • 66 Wigmore S J, Ross J A, Falconer J S. et al . The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer.  Nutrition. 1996;  12 S27-S30
    Google Scholar
  • 67 Wigmore S J, Todorov P T, Barber M D. et al . Characteristics of patients with pancreatic cancer expressing a novel cancer cachectic factor.  Br J Surg. 2000;  87 53-58
    Google Scholar
  • 68 Bauer J, Capra S, Battistuta D. et al . Compliance with nutrition prescription improves outcomes in patients with unresectable pancreatic cancer.  Clin Nutr. 2008;  24 998-1004
    Google Scholar
  • 69 Willox J C, Corr J, Shaw J. et al . Prednisolone as an appetite stimulant in patients with cancer.  Br Med J (Clin Res Ed). 1984;  288 27
    Google Scholar
  • 70 Bruera E, Ernst S, Hagen N. et al . Effectiveness of megestrol acetate in patients with advanced cancer: a randomized, double-blind, crossover study.  Cancer Prev Control. 1998;  2 74-78
    Google Scholar
  • 71 Vadell C, Segui M A, Gimenez-Arnau J M. et al . Anticachectic efficacy of megestrol acetate at different doses and versus placebo in patients with neoplastic cachexia.  Am J Clin Oncol. 1998;  21 347-351
    Google Scholar
  • 72 Loprinzi C L, Schaid D J, Dose A M. et al . Body-composition changes in patients who gain weight while receiving megestrol acetate.  J Clin Oncol. 1993;  11 152-154
    Google Scholar
  • 73 Strasser F, Luftner D, Possinger K. et al . Comparison of orally administered cannabis extract and delta-9-tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: a multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group.  J Clin Oncol. 2006;  24 3394-3400
    Google Scholar
  • 74 Stephens T W, Basinski M, Bristow P K. et al . The role of neuropeptide Y in the antiobesity action of the obese gene product.  Nature. 1995;  377 530-532
    Google Scholar
  • 75 Pascual L A, Figuls M, Urrutia C G. et al . Systematic review of megestrol acetate in the treatment of anorexia-cachexia syndrome.  J Pain Symptom Manage. 2004;  27 360-369
    Google Scholar
  • 76 Endres S, Ghorbani R, Kelley V E. et al . 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. 1989;  320 265-271
    Google Scholar
  • 77 Wigmore S J, Fearon K C, Maingay J P. et al . Down-regulation of the acute-phase response in patients with pancreatic cancer cachexia receiving oral eicosapentaenoic acid is mediated via suppression of interleukin-6.  Clin Sci. 1997;  92 215-221
    Google Scholar
  • 78 Jho D H, Cole S M, Lee E M. et al . Role of omega-3 fatty acid supplementation in inflammation and malignancy.  Integr Cancer Ther. 2004;  3 98-111
    Google Scholar
  • 79 Fearon K C, Barber M D, Moses A G. et al . Double-blind, placebo-controlled, randomized study of eicosapentaenoic acid diester in patients with cancer cachexia.  J Clin Oncol. 2006;  24 3401-3407
    Google Scholar
  • 80 Gordon J N, Trebble T M, Ellis R D. et al . Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial.  Gut. 2005;  54 540-545
    Google Scholar
  • 81 Goldberg R M, Loprinzi C L, Mailliard J A. et al . Pentoxifylline for treatment of cancer anorexia and cachexia? A randomized, double-blind, placebo-controlled trial.  J Clin Oncol. 1995;  13 2856-2859
    Google Scholar
  • 82 McMillan D C, Wigmore S J, Fearon K C. et al . A prospective randomized study of megestrol acetate and ibuprofen in gastrointestinal cancer patients with weight loss.  Br J Cancer. 1999;  79 495-500
    Google Scholar
  • 83 McMillan D C, O’Gorman P, Fearon K C. et al . A pilot study of megestrol acetate and ibuprofen in the treatment of cachexia in gastrointestinal cancer patients.  Br J Cancer. 1997;  76 788-790
    Google Scholar
  • 84 Neoptolemos J, Dunn J, Stocken D. et al . Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial.  Lancet. 2001;  358 1576-1585
    Google Scholar
  • 85 Park J, Ryu J, Lee J. et al . Gemcitabine chemotherapy versus 5-fluorouracil-based concurrent chemoradiotherapy in locally advanced unresectable pancreatic cancer.  Pancreas. 2006;  33 397-402
    Google Scholar
  • 86 Park J, Yoon Y, Kim Y. et al . Survival and prognostic factors of unresectable pancreatic cancer.  J Clin Gastroenterol. 2008;  42 86-91
    Google Scholar
  • 87 Oettle H, Neuhaus P. Adjuvant therapy in pancreatic cancer: a critical appraisal.  Drugs. 2007;  67 2293-2310
    Google Scholar
  • 88 Fisher B, Perera F, Kocha W. et al . Analysis of the clinical benefit of 5-fluorouracil and radiation treatment in locally advanced pancreatic cancer.  Int J Radiat Oncol Biol Phys. 2008;  45 291-295
    Google Scholar
  • 89 Michalski C, Kleeff J, Jaeger D. et al . Adjuvant treatment of pancreatic cancer.  Dtsch med Wochenschr. 2007;  132 803-807
    Google Scholar
  • 90 Melstrom L, Melstrom K J, Ding X. et al . Mechanisms of skeletal muscle degradation and its therapy in cancer cachexia.  Histology and Histopathology. 2007;  22 805-814
    Google Scholar
  • 91 Smith H J, Lorite M J, Tisdale M J. Effect of a cancer cachectic factor on protein synthesis/degradation in murine C 2C12 myoblasts: modulation by eicosapentaenoic acid.  Cancer research. 1999;  59 5507-5513
    Google Scholar
  • 92 Tisdale M J. Wasting in cancer.  The Journal of Nutrition. 1999;  129 243S-246S
    Google Scholar

PD Dr. M. E. Martignoni

Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München

Ismaninger Straße 22

81675 München

Phone: ++ 49/89/41 40 50 93

Email: me.martignoni@chir.med.tu-muenchen.de

      >