Cancer cachexia-anorexia syndrome and skeletal muscle wasting
Background. Cachexia-anorexia syndrome is a common and important indicator of cancer. It occurs in 30% to 80% of cancer patients. Cachexia means "bad condition" and may be present in the early stages of tumor growth, before any signs of malignancy. Cancer cachexia is a syndrome of progressive body wasting, characterized by loss of adipose tissue and skeletal muscle mass. In most cancer patients, cachexia is characterized by anorexia, which implies a failure of food intake, regulated through a complex system of hormones and neuropeptides. A decline in food intake relative to energy expenditure is a fundamental physiologic derangement leading to cancer associated weight loss. The weight loss in patients with cachexia-anorexia syndrome differs from that in caloric starvation or anorexia nervosa. The pathophysiology of cancer cachexia is not fully understood; however, studies have shown that cytokines are important in the alteration of the carbohydrate, lipid and protein metabolism. Cancer, prolonged bed rest, HIV infection and aging are conditions in which muscle wasting is a common feature. An intervention that may potentially attenuate the progression of muscle wasting in cancer patients is resistance exercise training, defined as multiple repetitions of static or dynamic muscular contractions that increase muscle mass.
Conclusions. The main components of the pathological state of cachexia are anorexia and metabolic abnormalities such as fat depletion and muscle protein catabolism. Future developments may concentrate on the molecular abnormalities of cachexia and on examination of the functional benefit of resistance exercise training for cancer related muscle wasting.
Tisdale MJ. Pathogenesis of Cancer Cachexia. J Support Oncol 2003; 1: 159-68.
Inagaki J, Rodriguez V, Bodey GP. Proceedings: causes of death in cancer patients. Cancer 1974; 33: 568-73.
DeWys WD. Anorexia as a general effect of cancer. Cancer 1972; 45: 2013-19.
Perboni S, Inui A. Anorexia in cancer: role of feedeing-regulatory peptides. Phil Trans R Soc B 2006; 361: 1281-89.
Geels P, Eisenhauer E, Bezjak A, Zee B, Day A. Palliative effect of chemotherapy: objective tumor response is associated with symptom improvement in patients with metas tatic breast cancer. J Clin Oncol 2000; 18: 2395-405.
Tisdale MJ. Biology of cachexia. J Natl Cancer Inst 1997; 89: 1763-73.
Dahele M, Fearon KC. Research methodology: cancer cachexia syndrome. Palliative Medicine 2004; 18: 409-17.
Bossola M, Muscaritoli M, Costelli P, Bellantone R, Pacelli F, Busquets S, et al. Increased muscle ubiquitin mRNA levels in gastric cancer patients. Am J Physiol Regul Integr Comp Physiol 2001; 280: R1 518-23.
Rossi Fanelli F, Cangiano C, Ceci F, Cellerino R, Franchi F, Menichetti ET, et al. Plasma tryptophan and anorexia in human cancer. Eur J Cancer Clin Oncol 1986; 22: 89-95.
Padilla GV. Psychological aspects of nutrition and cancer. Surg Clin North Am 1986; 66: 1121-35.
Knoll J. Endogenous anorectic agents-satietins. Annu Rev Pharmacol Toxicol 1988; 28: 247-68.
Plata-Salaman CR. Immunoregulators in the nervous system. Neurosci Biobehav 1991; 5: 185-215.
Inui A. Cancer anorexia-cachexia syndrome: are neuropeptides the key? Cancer Res 1999; 59: 4493-501.
Inui A. Cancer Anorexia-Cachexia Syndrome: current issues in research and management. CA Cancer J Clin 2000; 52: 72-91.
Bosaeus I, Daneryd P, Lundholm K. Dietary intake, resting energy expenditure, weight loss and survival in cancer patients. J Nutr 2002; 132 (suppl): S 3465-S 3466.
Cohn SH, Gartenhaus W, Sawitsky A, Zanzi I, Vaswani A, Ellis KJ. Compartmental body composition of cancer patients by measurement of total body nitrogen, potassium, and water. Metabolism 1981; 30: 222-9.
Knox CS, Crosby CO, Fuerer ID, Buzby GP, Cliffor MD, Mullen JL. Energy expenditure in malnourished cancer patients. Ann Surg 1983; 197: 152-62.
Nixon DW, Kutner M, Heymsfield S, Foltz AT, Carty C, Seitz S, et al. Resting energy expenditure in lung and colon cancer. Metabolism 1988; 37: 1059-64.
Fredrix, EW, Soeters PB, Wouters EF, Deerenberg IM, Von-Meyerfeldt MF, Saris WH. Effect of different tumor types on resting energy expenditure. Cancer Res 1991; 51: 6138-41.
Fredix EW, Saris WH, Soeters PB, Wouters EF, Kester AD, von Meyenfeldt MF, et al. Estimation of body composition by bioelectrical impedance in cancer patients. Eur J Clin Nutr 1990; 44: 749-52.
Falconer JS, Fearon KC, Plester CE, Ross JA, Carter DC. Cytokines, the acute-phase response, and resting energy expenditure in cachectic patients with pancreatic cancer. Ann Surg 1994; 219: 325-31.
Moley JF, Aamodt R, Rumble W, Kaye W, Norton JA. Body cell mass in cancer bearing and anorexia patients. J Parenter Enteral Nutr 1987; 11: 219-22.
Ohnuma T. Anorexia and cachexia. In: Kufe, Morton, Weichselbaum, editors. Cancer Medicine. Baltimore, MD: Williams & Wilkins; 1997. p. 3091-110.
Pedersen BK. Exercise immunology. New York: Chapman & Hall; 1997.
Adams GR, Haddad F. The relationship among IGF-1, DNA content, and protein accumulation during skeletal muscle hypertrophy. J Appl Physiol 1996; 81: 2509-16.
Richardson RA, Davidson HI. Nutritional demands in acute and chronic illness. Proc Nutr Soc 2003; 62: 777-81.
Van Miert AS, Kaya F, Van Duin CT. Changes in food intake and forestomach motility of dwarf goats by recombinant bovine cytokines IL-1beta, IL-2 and IFN-gamma. Physiol Behav 1992; 52: 859-64.
Montuschi P, Tringali G, Curro D, Ciabattoni G, Parente L, Preziosi P, et al. Evidence that IL-1beta and tumor necrosis factor inhibit gastric fundus motility via the 5-lipoxygense pathway. Eur J Pharmacol 1994; 252: 253-60.
Suto G, Kiraly A, Plourde V, Tache Y. Intravenous IL-1beta induced inhibition of gastric emptying: involvement of central corticotrophin-releasing factor and prostaglandin pathways in rats. Digest 1996; 57: 135-40.
Suto G, Kiraly A, Tache Y. IL-1b inhibits gastric emptying in rats: mediation through prostaglandin and corticotropin-releasing factor. Gastroenterol 1994; 106: 1568-75.
Sonti G, Ilyin SE, Plata-Salaman CR. Neuropeptide Y blocks and reverses IL-1b induced anorexia in rats. Peptides 1996; 17: 517-20.
Chrousos GP, Torpy DJ, Gold PW. Interactions between the hypothalamic- pituitary-adrenal axis and the female reproductive system: clinical implications. Ann Intern Med 1998; 129: 229-40.
Shimon I, Yan X, Ray DW, Melmed S. Cytokine dependent gp 130 receptor subunit regulates human fetal pituitary adrenocorticotropin hormone and growth hormone secretion. J Clin Invest 1997; 100: 357-63.
Argiles JM, Costelli P, Carbo N, Pallares-Trujillo J, Lopez-Soriano FJ. Tumor growth and nitrogen metabolism in the host. Int J Oncol 1999; 14: 479-86.
Moldawer LL, Andersson C, Gelin J, Lundholm KG. Regulation of food intake and hepatic protein synthesis by recombinant-derived cytokines. Am J Physiol 1988; 254: G 450-6.
Laviano A, Meguid MM, Yang ZJ, Gleason JR, Cangiano C, Rossi Fanelli F. Cracking the riddle of cancer anorexia. Nutrit 1996; 12: 706-10.
Laviano A, Gleason JR, Meguid MM, Yang ZJ, Cangiano C, Rossi Fanelli F. Effects of intra-VMN mianserin and IL-1ra on meal number in anorectic tumor-bearing rats. J Investig Med 2000; 48: 40-8.
Otterness IG, Seymour PA, Golden HW, Reynolds JA, Daumy GO. The effects of continuous administration of murine interleukin-1alpha in the rat. Physiol Behav 1988; 43: 797-804.
Mrosovsky N, Molony LA, Conn CA, Kluger MJ. Anorexic effects of interleukin in the rat. Am J Physiol 1989; 257: R 1315-21.
Yasumoto K, Mukaida N, Harada A, Kuno K, Akiyama M, Nakashima E. Molecular analysis of the cytokine network involved in cachexia in colon 26 adenocarcinoma -bearing mice. Cancer Res 1995; 55: 921-7.
Bodnar RJ, Pasternak GW, Sha P, Stock MJ. Medication of anorexia by human recombinant tumor necrosis factor through a peripheral action in the rat. Cancer Res 1989; 49: 6280-84.
Kawakami M, Cerami A. Studies of endotoxin-induced decrease in lipoprotein lipase activity. J Exp Med 1981; 154: 631-7.
Feingold KR, Grunfeld C. Tumor necrosis factor-alpha stimulates hepatic lipogenesis in the rat in vitro. J Clin Invest 1987; 80: 184-90.
Pape ME, Kim KH. Effect of tumor necrosis factor on acetyl-coenzyme A carboxylase gene expression and pre-adipocyte differentiation. Mol Endocrinol 1988; 2: 395-403.
Semb H, Peterson J, Tavernier J, Olivecrona T. Multiple effects of tumor necrosis factor on lipoprotein lipase in vivo. J Biol Chem 1987; 262: 8390-4.
Strassmann G, Fong M, Kenny JS, Jacob CO. Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J Clin Invest 1992; 89: 1681-4.
Argiles JM, Garcia-Martinez C, Liovera M, Lopez-Soriano FJ. The role of cytokines in muscle wasting: its relation with cancer cachexia. Med Res Rev 1992; 12: 637-52.
Prelovsek O, Mars T, Jevsek M, Podbregar M, Grubic Z. High dexamethasone concentration prevents stimulatory effects of TNF-alpha and LPS on IL-6 secretion from the precursors of human muscle regeneration. Am J Physiol Regul Integr Comp Physiol. 2006; 291(6): 1651-6.
Steensberg A, Keller C, Starkie RL, Osada T, Febbraio MA, Pedersen BK. IL-6 and TNF-alpha expression in, and release from, contracting human skeletal muscle. Am J Physiol Endocrinol Metab 2000; 283(6): 1272-8.
Llovera M, Lopez-Soriano FJ, Argiles JM. Effects of tumor necrosis factor- on muscle protein turnover in female Wistars rats. J Natl Cancer Inst 1993; 85: 1334-9.
Darling G, Fraker DL, Jensen JC, Gorschboth CM, Norton JA. Cachectic effects of recombinant human tumor necrosis factor in rats. Cancer Res 1990; 50: 4008-13.
Argiles JM, Alvarez B, Lopez - Sorriano FJ. The metabolic basis of cancer cachexia. Med Res Rev 1997; 17: 477-98.
Bianchi A, Bruce J, Cooper AL, Childs C, Kohli M, Morris ID, et al. Increased brown adipose tissue activity in children with malignant disease. Horm Metab Res 1989; 21: 640-1.
Strassmann G, Jacob CO, Evans R. Mechanisms of experimental cancer cachexia. Interaction between mononuclear phagocytes and colon-26 carcinoma and its relevance to IL-6 mediated cancer cachexia. J Immunol 1992; 148: 3674-8.
Tsujinaka T, Fujita J, Ebisui C. Interleukin 6 receptor antibody inhibits muscle atrophy and modulates proteolytic systems in interleukin 6 transgenic mice. J Clin Invest 1996; 97: 244-9.
Tamura S, Fujimoto-Ouchi K, Mori K, Endo M, Matsumoto T, Eden H, et al. Involvement of human interleukin 6 in experimental cachexia induced by a human uterine carcinoma xenograft. Clin Cancer Res 1995; 1: 1353-8.
Fearon KC, McMillan DC, Preston T, Winstanley P, Cruickshank AM, Shenkin A. Elevated circulating interleukin-6 is associated with an acute phase response but reduced fixed hepatic protein synthesis in patients with cancer. Ann Surg 1991; 213: 26-31.
Goodman MN. Interleukin-6 induces skeletal muscle protein breakdown in rats. Proc Soc Exp Biol Med 1994; 205: 182-5.
Pedersen BK, Febbraio MA. Muscle as an Endocrine Organ: Focus on Muscle-Derived Interleukin-6. Physiol Rev 2007; 88: 1379-1406.
Matthys P, Heremans H, Opdenakker G, Billiau A. Anti-interferon-gamma antibody treatment growth of Lewis lung tumors in mice and tumor-associated cachexia. Eur J Cancer. 1991; 27: 182-7.
Langstain HN, Doherty GM, Fraker DL, Buresh C, Norton JA. The roles of -interferon and tumor necrosis factor in an experimental rat model of cancer cachexia. Cancer Res 1991; 51: 2302-6.
Mori M, Yamaguchi K, Honda S, Nagasaki K, Ueda M, Abe O, et al. Cancer Cachexia Syndrome Developed in Nude Mice Bearing Melanoma Cells Producing Leukemia-inhibitory Factor. Cancer Res 1991; 51: 6656-9.
Lorite MJ, Cariuk P, Tisdale MJ. Induction of muscle protein degradation by a tumor factor. Br J Cancer 1997; 76: 1035-40.
Todorov PT, McDevitt TM, Cariuk P, Coles B, Deacon M, Tisdale MJ. Induction of muscle protein degradation and weight loss by a tumor product. Cancer Res 1996; 56: 1256-61.
Hussey HJ, Todorov PT, Field WN, Inagaki N, Tanaka Y, Ishitsuka H, et al. Effect of a fluorinated pyrimidine on cachexia and tumor growth in murine cachexia models: relationship with a proteolysis inducing factor. Br J Cancer 2000; 83: 56-62.
Cohn SH, Gartenhaus W, Sawitsky A, Rai K, Zani I, Vaswani A, et al. Compartmental body composition of cancer patients by measurement of total body nitrogen, potassium, andwater. Metabolism 1981; 30: 222-9.
Argiles JM, Moore-Carrasco R, Fuster G, Busquets S, Lopez Soriano FJ. Cancer cachexia: the molecular mechanisms. Int J Biochem Cell Biol 2003; 35: 405-9.
Mitch WE, Goldberg AL. Mechanisms of skeletal muscle wasting: The role of the ubiquitin-proteasome pathway. N Engl J Med 1996; 335: 1897-1905.
Guttridge DC, Mayo MW, Madrid LV, Wang C, Baldwin AS. NF- B-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science 2000; 298: 2363-7.
Tisdale MJ. Biomedicine: protein loss in cancer cachexia. Science 2000; 289: 2293-4.
Spina RJ, Chi MMY, Hopkins MG, Nemeth PM, Lowry OH, Holloszy JO. Mitochondrial enzymes increase in muscle in response to 7-10 days of cycle exercise. J Appl Physiol 1996; 80: 2250-4.
Al-Majid S, McCarthy DO. Cancer-induced fatigue and skeletal muscle wasting: the role of exercise. Biol Res Nurs 2001; 2: 186-97.
Diffee GM, Kalfas K, Al-Majid S, McCarthy DO. Altered expression of skeletal muscle myosin isoforms in cancer cachexia. Am J Physiol Cell Physiol 2002; 283: C 1376-82.
Tisdale MJ. Cachexia in cancer patients. Nat Rev Cancer 2002; 2: 862-71.
Jurdana M. Radiation effects on skeletal muscle. Radiol Oncol 2008; 42: 15-22.