1932

Abstract

Cancer is a life-threatening disease that has plagued humans for centuries. The vast majority of cancer-related mortality results from metastasis. Indeed, the invasive growth of metastatic cancer cells in vital organs causes fatal organ dysfunction, but metastasis-related deaths also result from cachexia, a debilitating wasting syndrome characterized by an involuntary loss of skeletal muscle mass and function. In fact, about 80% of metastatic cancer patients suffer from cachexia, which often renders them too weak to tolerate standard doses of anticancer therapies and makes them susceptible to death from cardiac and respiratory failure. The goals of this review are to highlight important findings that help explain how cancer-induced systemic changes drive the development of cachexia and to discuss unmet challenges and potential therapeutic strategies targeting cachexia to improve the quality of life and survival of cancer patients.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-030419-033642
2020-03-04
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/4/1/annurev-cancerbio-030419-033642.html?itemId=/content/journals/10.1146/annurev-cancerbio-030419-033642&mimeType=html&fmt=ahah

Literature Cited

  1. Acharyya S, Guttridge DC. 2007. Cancer cachexia signaling pathways continue to emerge yet much still points to the proteasome. Clin. Cancer Res. 13:1356–61
    [Google Scholar]
  2. Ali S, Garcia JM. 2014. Sarcopenia, cachexia and aging: diagnosis, mechanisms and therapeutic options—a mini-review. Gerontology 60:294–305
    [Google Scholar]
  3. Amthor H, Macharia R, Navarrete R, Schuelke M, Brown SC et al. 2007. Lack of myostatin results in excessive muscle growth but impaired force generation. PNAS 104:1835–40
    [Google Scholar]
  4. Anand BK, Brobeck JR. 1951. Localization of a “feeding center” in the hypothalamus of the rat. Proc. Soc. Exp. Biol. Med. 77:323–24
    [Google Scholar]
  5. Ando K, Takahashi F, Kato M, Kaneko N, Doi T et al. 2014. Tocilizumab, a proposed therapy for the cachexia of Interleukin6-expressing lung cancer. PLOS ONE 9:e102436
    [Google Scholar]
  6. Ando K, Takahashi F, Motojima S, Nakashima K, Kaneko N et al. 2013. Possible role for tocilizumab, an anti-interleukin-6 receptor antibody, in treating cancer cachexia. J. Clin. Oncol. 31:e69–72
    [Google Scholar]
  7. Argiles JM, Busquets S, Stemmler B, Lopez-Soriano FJ 2014. Cancer cachexia: understanding the molecular basis. Nat. Rev. Cancer 14:754–62
    [Google Scholar]
  8. Argiles JM, Busquets S, Toledo M, Lopez-Soriano FJ 2009. The role of cytokines in cancer cachexia. Curr. Opin. Support. Palliat. Care 3:263–68
    [Google Scholar]
  9. Argiles JM, Lopez-Soriano FJ, Stemmler B, Busquets S 2019. Therapeutic strategies against cancer cachexia. Eur. J. Transl. Myol. 29:7960
    [Google Scholar]
  10. Argiles JM, Stemmler B, Lopez-Soriano FJ, Busquets S 2018. Inter-tissue communication in cancer cachexia. Nat. Rev. Endocrinol. 15:9–20
    [Google Scholar]
  11. Armougom F, Henry M, Vialettes B, Raccah D, Raoult D 2009. Monitoring bacterial community of human gut microbiota reveals an increase in Lactobacillus in obese patients and Methanogens in anorexic patients. PLOS ONE 4:e7125
    [Google Scholar]
  12. Asp ML, Tian M, Kliewer KL, Belury MA 2011. Rosiglitazone delayed weight loss and anorexia while attenuating adipose depletion in mice with cancer cachexia. Cancer Biol. Ther. 12:957–65
    [Google Scholar]
  13. Asp ML, Tian M, Wendel AA, Belury MA 2010. Evidence for the contribution of insulin resistance to the development of cachexia in tumor-bearing mice. Int. J. Cancer 126:756–63
    [Google Scholar]
  14. Aversa Z, Costelli P, Muscaritoli M 2017. Cancer-induced muscle wasting: latest findings in prevention and treatment. Ther. Adv. Med. Oncol. 9:369–82
    [Google Scholar]
  15. Ballaro R, Penna F, Pin F, Gomez-Cabrera MC, Vina J, Costelli P 2019. Moderate exercise improves experimental cancer cachexia by modulating the redox homeostasis. Cancers 11:e285
    [Google Scholar]
  16. Baltgalvis KA, Berger FG, Pena MM, Davis JM, Muga SJ, Carson JA 2008. Interleukin-6 and cachexia in ApcMin/+ mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294:R393–401
    [Google Scholar]
  17. Baltgalvis KA, Berger FG, Pena MM, Davis JM, White JP, Carson JA 2009. Muscle wasting and interleukin-6-induced atrogin-I expression in the cachectic ApcMin/+ mouse. Pflugers Arch 457:989–1001
    [Google Scholar]
  18. Baracos VE, Martin L, Korc M, Guttridge DC, Fearon KCH 2018. Cancer-associated cachexia. Nat. Rev. Dis. Primers 4:17105
    [Google Scholar]
  19. Barreto R, Mandili G, Witzmann FA, Novelli F, Zimmers TA, Bonetto A 2016. Cancer and chemotherapy contribute to muscle loss by activating common signaling pathways. Front. Physiol. 7:472
    [Google Scholar]
  20. Baud V, Karin M. 2001. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol 11:372–77
    [Google Scholar]
  21. Bennani-Baiti N, Walsh D. 2009. What is cancer anorexia-cachexia syndrome? A historical perspective. J. R. Coll. Physicians Edinb. 39:257–62
    [Google Scholar]
  22. Benny Klimek ME, Aydogdu T, Link MJ, Pons M, Koniaris LG, Zimmers TA 2010. Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia. Biochem. Biophys. Res. Commun. 391:1548–54
    [Google Scholar]
  23. Beutler B, Greenwald D, Hulmes JD, Chang M, Pan YC et al. 1985. Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature 316:552–54
    [Google Scholar]
  24. Bindels LB, Beck R, Schakman O, Martin JC, De Backer F et al. 2012. Restoring specific lactobacilli levels decreases inflammation and muscle atrophy markers in an acute leukemia mouse model. PLOS ONE 7:e37971
    [Google Scholar]
  25. Bindels LB, Delzenne NM. 2013. Muscle wasting: The gut microbiota as a new therapeutic target?. Int. J. Biochem. Cell Biol. 45:2186–90
    [Google Scholar]
  26. Bindels LB, Neyrinck AM, Loumaye A, Catry E, Walgrave H et al. 2018. Increased gut permeability in cancer cachexia: mechanisms and clinical relevance. Oncotarget 9:18224–38
    [Google Scholar]
  27. Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L et al. 2001a. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294:1704–8
    [Google Scholar]
  28. Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL et al. 2001b. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat. Cell Biol. 3:1014–19
    [Google Scholar]
  29. Bonetto A, Aydogdu T, Jin X, Zhang Z, Zhan R et al. 2012. JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia. Am. J. Physiol. Endocrinol. Metab. 303:E410–21
    [Google Scholar]
  30. Bonetto A, Aydogdu T, Kunzevitzky N, Guttridge DC, Khuri S et al. 2011. STAT3 activation in skeletal muscle links muscle wasting and the acute phase response in cancer cachexia. PLOS ONE 6:e22538
    [Google Scholar]
  31. Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L et al. 2012. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481:463–68
    [Google Scholar]
  32. Braun TP, Zhu X, Szumowski M, Scott GD, Grossberg AJ et al. 2011. Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic-pituitary-adrenal axis. J. Exp. Med. 208:2449–63
    [Google Scholar]
  33. Bren-Mattison Y, Hausburg M, Olwin BB 2011. Growth of limb muscle is dependent on skeletal-derived Indian hedgehog. Dev. Biol. 356:486–95
    [Google Scholar]
  34. Burfeind KG, Michaelis KA, Marks DL 2016. The central role of hypothalamic inflammation in the acute illness response and cachexia. Semin. Cell Dev. Biol. 54:42–52
    [Google Scholar]
  35. Busquets S, Toledo M, Marmonti E, Orpi M, Capdevila E et al. 2012. Formoterol treatment downregulates the myostatin system in skeletal muscle of cachectic tumour-bearing rats. Oncol. Lett. 3:185–89
    [Google Scholar]
  36. Carriere A, Jeanson Y, Berger-Muller S, Andre M, Chenouard V et al. 2014. Browning of white adipose cells by intermediate metabolites: an adaptive mechanism to alleviate redox pressure. Diabetes 63:3253–65
    [Google Scholar]
  37. Chen SE, Jin B, Li YP 2007. TNF-α regulates myogenesis and muscle regeneration by activating p38 MAPK. Am. J. Physiol. Cell Physiol. 292:C1660–71
    [Google Scholar]
  38. Cohen S, Nathan JA, Goldberg AL 2015. Muscle wasting in disease: molecular mechanisms and promising therapies. Nat. Rev. Drug Discov. 14:58–74
    [Google Scholar]
  39. Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S et al. 2001. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411:480–84
    [Google Scholar]
  40. Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N et al. 2003. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37:649–61
    [Google Scholar]
  41. Crawford AJ, Bhattacharya SK. 1987. Excessive intracellular zinc accumulation in cardiac and skeletal muscles of dystrophic hamsters. Exp. Neurol. 95:265–76
    [Google Scholar]
  42. Cypess AM, Lehman S, Williams G, Tal I, Rodman D et al. 2009. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360:1509–17
    [Google Scholar]
  43. Damrauer JS, Stadler ME, Acharyya S, Baldwin AS, Couch ME, Guttridge DC 2018. Chemotherapy-induced muscle wasting: association with NF-κB and cancer cachexia. Eur. J. Transl. Myol. 28:7590
    [Google Scholar]
  44. Danai LV, Babic A, Rosenthal MH, Dennstedt EA, Muir A et al. 2018. Altered exocrine function can drive adipose wasting in early pancreatic cancer. Nature 558:600–4
    [Google Scholar]
  45. Das SK, Eder S, Schauer S, Diwoky C, Temmel H et al. 2011. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 333:233–38
    [Google Scholar]
  46. de Aguiar Vallim TQ, Tarling EJ, Edwards PA 2013. Pleiotropic roles of bile acids in metabolism. Cell Metab 17:657–69
    [Google Scholar]
  47. DiGirolamo DJ, Kiel DP, Esser KA 2013. Bone and skeletal muscle: neighbors with close ties. J. Bone Miner. Res. 28:1509–18
    [Google Scholar]
  48. Doherty JR, Cleveland JL. 2013. Targeting lactate metabolism for cancer therapeutics. J. Clin. Investig. 123:3685–92
    [Google Scholar]
  49. Dwarkasing JT, Boekschoten MV, Argiles JM, van Dijk M, Busquets S et al. 2015. Differences in food intake of tumour-bearing cachectic mice are associated with hypothalamic serotonin signalling. J. Cachexia Sarcopenia Muscle 6:84–94
    [Google Scholar]
  50. Dwarkasing JT, van Dijk M, Dijk FJ, Boekschoten MV, Faber J et al. 2014. Hypothalamic food intake regulation in a cancer-cachectic mouse model. J. Cachexia Sarcopenia Muscle 5:159–69
    [Google Scholar]
  51. Dwarkasing JT, Witkamp RF, Boekschoten MV, Ter Laak MC, Heins MS, van Norren K 2016. Increased hypothalamic serotonin turnover in inflammation-induced anorexia. BMC Neurosci 17:26
    [Google Scholar]
  52. Egerman MA, Cadena SM, Gilbert JA, Meyer A, Nelson HN et al. 2015. GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab 22:164–74
    [Google Scholar]
  53. Egerman MA, Glass DJ. 2014. Signaling pathways controlling skeletal muscle mass. Crit. Rev. Biochem. Mol. Biol. 49:59–68
    [Google Scholar]
  54. Emmerson PJ, Wang F, Du Y, Liu Q, Pickard RT et al. 2017. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat. Med. 23:1215–19
    [Google Scholar]
  55. Esfandiari N, Ghosh S, Prado CM, Martin L, Mazurak V, Baracos VE 2014. Age, obesity, sarcopenia, and proximity to death explain reduced mean muscle attenuation in patients with advanced cancer. J. Frailty Aging 3:3–8
    [Google Scholar]
  56. Espat NJ, Auffenberg T, Rosenberg JJ, Rogy M, Martin D et al. 1996. Ciliary neurotrophic factor is catabolic and shares with IL-6 the capacity to induce an acute phase response. Am. J. Physiol. 271:R185–90
    [Google Scholar]
  57. Evans WJ. 1996. Reversing sarcopenia: how weight training can build strength and vitality. Geriatrics 51:46–53
    [Google Scholar]
  58. Faubert B, Li KY, Cai L, Hensley CT, Kim J et al. 2017. Lactate metabolism in human lung tumors. Cell 171:358–71.e9
    [Google Scholar]
  59. Fearon KCH, Arends J, Baracos V 2013. Understanding the mechanisms and treatment options in cancer cachexia. Nat. Rev. Clin. Oncol. 10:90–99
    [Google Scholar]
  60. Fearon KCH, Glass DJ, Guttridge DC 2012. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab 16:153–66
    [Google Scholar]
  61. Fearon KCH, Strasser F, Anker SD, Bosaeus I, Bruera E et al. 2011. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 12:489–95
    [Google Scholar]
  62. Fernandes LC, Machado UF, Nogueira CR, Carpinelli AR, Curi R 1990. Insulin secretion in Walker 256 tumor cachexia. Am. J. Physiol. 258:E1033–36
    [Google Scholar]
  63. Figueroa-Clarevega A, Bilder D. 2015. Malignant Drosophila tumors interrupt insulin signaling to induce cachexia-like wasting. Dev. Cell 33:47–55
    [Google Scholar]
  64. Fujita J, Tsujinaka T, Yano M, Ebisui C, Saito H 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 68:637–43
    [Google Scholar]
  65. Fukawa T, Yan-Jiang BC, Min-Wen JC, Jun-Hao ET, Huang D et al. 2016. Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia. Nat. Med. 22:666–71
    [Google Scholar]
  66. Gallot YS, Durieux AC, Castells J, Desgeorges MM, Vernus B et al. 2014. Myostatin gene inactivation prevents skeletal muscle wasting in cancer. Cancer Res 74:7344–56
    [Google Scholar]
  67. Gilliam LA, Moylan JS, Callahan LA, Sumandea MP, Reid MB 2011. Doxorubicin causes diaphragm weakness in murine models of cancer chemotherapy. Muscle Nerve 43:94–102
    [Google Scholar]
  68. Gilliam LA, St. Clair DK 2011. Chemotherapy-induced weakness and fatigue in skeletal muscle: the role of oxidative stress. Antioxid. Redox Signal. 15:2543–63
    [Google Scholar]
  69. Go KL, Delitto D, Judge SM, Gerber MH, George TJ Jr et al. 2017. Orthotopic patient-derived pancreatic cancer xenografts engraft into the pancreatic parenchyma, metastasize, and induce muscle wasting to recapitulate the human disease. Pancreas 46:813–19
    [Google Scholar]
  70. Gomes MD, Lecker SH, Jagoe RT, Navon A, Goldberg AL 2001. Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. PNAS 98:14440–45
    [Google Scholar]
  71. Goncalves MD, Hwang SK, Pauli C, Murphy CJ, Cheng Z et al. 2018. Fenofibrate prevents skeletal muscle loss in mice with lung cancer. PNAS 115:E743–52
    [Google Scholar]
  72. Greco SH, Tomkotter L, Vahle AK, Rokosh R, Avanzi A et al. 2015. TGF-β blockade reduces mortality and metabolic changes in a validated murine model of pancreatic cancer cachexia. PLOS ONE 10:e0132786
    [Google Scholar]
  73. Guise TA, Mundy GR. 1998. Cancer and bone. Endocr. Rev. 19:18–54
    [Google Scholar]
  74. Guttridge DC, Mayo MW, Madrid LV, Wang CY, Baldwin AS Jr 2000. NF-κB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science 289:2363–66
    [Google Scholar]
  75. Heber D, Byerly LO, Chlebowski RT 1985. Metabolic abnormalities in the cancer patient. Cancer 55:225–29
    [Google Scholar]
  76. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F 2003. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem. J. 374:1–20
    [Google Scholar]
  77. Henderson JT, Seniuk NA, Richardson PM, Gauldie J, Roder JC 1994. Systemic administration of ciliary neurotrophic factor induces cachexia in rodents. J. Clin. Investig. 93:2632–38
    [Google Scholar]
  78. Holroyde CP, Gabuzda TG, Putnam RC, Paul P, Reichard GA 1975. Altered glucose metabolism in metastatic carcinoma. Cancer Res 35:3710–14
    [Google Scholar]
  79. Holroyde CP, Reichard GA. 1981. Carbohydrate metabolism in cancer cachexia. Cancer Treat. Rep. 65:Suppl. 555–59
    [Google Scholar]
  80. Holroyde CP, Skutches CL, Boden G, Reichard GA 1984. Glucose metabolism in cachectic patients with colorectal cancer. Cancer Res 44:5910–13
    [Google Scholar]
  81. Honors MA, Kinzig KP. 2012. The role of insulin resistance in the development of muscle wasting during cancer cachexia. J. Cachexia Sarcopenia Muscle 3:5–11
    [Google Scholar]
  82. Hsu JY, Crawley S, Chen M, Ayupova DA, Lindhout DA et al. 2017. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature 550:255–59
    [Google Scholar]
  83. Hui S, Ghergurovich JM, Morscher RJ, Jang C, Teng X et al. 2017. Glucose feeds the TCA cycle via circulating lactate. Nature 551:115–18
    [Google Scholar]
  84. Jatoi A, Ritter HL, Dueck A, Nguyen PL, Nikcevich DA et al. 2010. A placebo-controlled, double-blind trial of infliximab for cancer-associated weight loss in elderly and/or poor performance non-small cell lung cancer patients (N01C9). Lung Cancer 68:234–39
    [Google Scholar]
  85. Johnen H, Lin S, Kuffner T, Brown DA, Tsai VW et al. 2007. Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1. Nat. Med. 13:1333–40
    [Google Scholar]
  86. Jones A, Friedrich K, Rohm M, Schafer M, Algire C et al. 2013. TSC22D4 is a molecular output of hepatic wasting metabolism. EMBO Mol. Med. 5:294–308
    [Google Scholar]
  87. Jones JE, Cadena SM, Gong C, Wang X, Chen Z et al. 2018. Supraphysiologic administration of GDF11 induces cachexia in part by upregulating GDF15. Cell Rep 22:1522–30
    [Google Scholar]
  88. Kalyani RR, Corriere M, Ferrucci L 2014. Age-related and disease-related muscle loss: the effect of diabetes, obesity, and other diseases. Lancet Diabetes Endocrinol 2:819–29
    [Google Scholar]
  89. Kandarian SC, Nosacka RL, Delitto AE, Judge AR, Judge SM et al. 2018. Tumour-derived leukaemia inhibitory factor is a major driver of cancer cachexia and morbidity in C26 tumour-bearing mice. J. Cachexia Sarcopenia Muscle 9:1109–20
    [Google Scholar]
  90. Kaplan RN, Psaila B, Lyden D 2006. Bone marrow cells in the ‘pre-metastatic niche’: within bone and beyond. Cancer Metastasis Rev 25:521–29
    [Google Scholar]
  91. Kawakami M, Pekala PH, Lane MD, Cerami A 1982. Lipoprotein lipase suppression in 3T3-L1 cells by an endotoxin-induced mediator from exudate cells. PNAS 79:912–16
    [Google Scholar]
  92. Kawamata Y, Fujii R, Hosoya M, Harada M, Yoshida H et al. 2003. A G protein-coupled receptor responsive to bile acids. J. Biol. Chem. 278:9435–40
    [Google Scholar]
  93. Kir S, Komaba H, Garcia AP, Economopoulos KP, Liu W et al. 2016. PTH/PTHrP receptor mediates cachexia in models of kidney failure and cancer. Cell Metab 23:315–23
    [Google Scholar]
  94. Kir S, White JP, Kleiner S, Kazak L, Cohen P et al. 2014. Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature 513:100–4
    [Google Scholar]
  95. Kliewer KL, Ke JY, Tian M, Cole RM, Andridge RR, Belury MA 2015. Adipose tissue lipolysis and energy metabolism in early cancer cachexia in mice. Cancer Biol. Ther. 16:886–97
    [Google Scholar]
  96. Kopf M, Baumann H, Freer G, Freudenberg M, Lamers M et al. 1994. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 368:339–42
    [Google Scholar]
  97. Kwon Y, Song W, Droujinine IA, Hu Y, Asara JM, Perrimon N 2015. Systemic organ wasting induced by localized expression of the secreted insulin/IGF antagonist ImpL2. Dev. Cell 33:36–46
    [Google Scholar]
  98. Lach-Trifilieff E, Minetti GC, Sheppard K, Ibebunjo C, Feige JN et al. 2014. An antibody blocking activin type II receptors induces strong skeletal muscle hypertrophy and protects from atrophy. Mol. Cell Biol. 34:606–18
    [Google Scholar]
  99. Latres E, Mastaitis J, Fury W, Miloscio L, Trejos J et al. 2017. Activin A more prominently regulates muscle mass in primates than does GDF8. Nat. Commun. 8:15153
    [Google Scholar]
  100. Laurence J. 1858. The Diagnosis of Surgical Cancer London: John Churchill
  101. Lee SJ, Reed LA, Davies MV, Girgenrath S, Goad ME et al. 2005. Regulation of muscle growth by multiple ligands signaling through activin type II receptors. PNAS 102:18117–22
    [Google Scholar]
  102. Lerner L, Tao J, Liu Q, Nicoletti R, Feng B et al. 2016. MAP3K11/GDF15 axis is a critical driver of cancer cachexia. J. Cachexia Sarcopenia Muscle 7:467–82
    [Google Scholar]
  103. Li YP, Chen Y, John J, Moylan J, Jin B et al. 2005. TNF-α acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1/MAFbx in skeletal muscle. FASEB J 19:362–70
    [Google Scholar]
  104. Li YP, 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 alpha. FASEB J 12:871–80
    [Google Scholar]
  105. Liang H, Pun S, Wronski TJ 1999. Bone anabolic effects of basic fibroblast growth factor in ovariectomized rats. Endocrinology 140:5780–88
    [Google Scholar]
  106. Liu M, Yang J, Zhang Y, Zhou Z, Cui X et al. 2018. ZIP4 promotes pancreatic cancer progression by repressing ZO-1 and Claudin-1 through a ZEB1-dependent transcriptional mechanism. Clin. Cancer Res. 24:3186–96
    [Google Scholar]
  107. Llovera M, Garcia-Martinez C, Lopez-Soriano J, Agell N, Lopez-Soriano FJ et al. 1998a. Protein turnover in skeletal muscle of tumour-bearing transgenic mice overexpressing the soluble TNF receptor-1. Cancer Lett 130:19–27
    [Google Scholar]
  108. Llovera M, Garcia-Martinez C, Lopez-Soriano J, Carbo N, Agell N et al. 1998b. Role of TNF receptor 1 in protein turnover during cancer cachexia using gene knockout mice. Mol. Cell Endocrinol. 142:183–89
    [Google Scholar]
  109. Loffredo FS, Steinhauser ML, Jay SM, Gannon J, Pancoast JR et al. 2013. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153:828–39
    [Google Scholar]
  110. Lonbro S, Dalgas U, Primdahl H, Johansen J, Nielsen JL et al. 2013. Progressive resistance training rebuilds lean body mass in head and neck cancer patients after radiotherapy—results from the randomized DAHANCA 25B trial. Radiother. Oncol. 108:314–19
    [Google Scholar]
  111. Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E et al. 2009. Autophagy is required to maintain muscle mass. Cell Metab 10:507–15
    [Google Scholar]
  112. McAllister SS, Weinberg RA. 2010. Tumor-host interactions: a far-reaching relationship. J. Clin. Oncol. 28:4022–28
    [Google Scholar]
  113. McCart AE, Vickaryous NK, Silver A 2008. Apc mice: models, modifiers and mutants. Pathol. Res. Pract. 204:479–90
    [Google Scholar]
  114. McPherron AC, Lawler AM, Lee SJ 1997. Regulation of skeletal muscle mass in mice by a new TGF-β superfamily member. Nature 387:83–90
    [Google Scholar]
  115. Milan G, Romanello V, Pescatore F, Armani A, Paik JH et al. 2015. Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy. Nat. Commun. 6:6670
    [Google Scholar]
  116. Mitch WE, Goldberg AL. 1996. Mechanisms of muscle wasting: the role of the ubiquitin-proteasome pathway. N. Engl. J. Med. 335:1897–905
    [Google Scholar]
  117. Morley JE, Thomas DR, Wilson MM 2006. Cachexia: pathophysiology and clinical relevance. Am. J. Clin. Nutr. 83:735–43
    [Google Scholar]
  118. Mourtzakis M, Prado CM, Lieffers JR, Reiman T, McCargar LJ, Baracos VE 2008. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care. Appl. Physiol. Nutr. Metab. 33:997–1006
    [Google Scholar]
  119. Murphy KT. 2016. The pathogenesis and treatment of cardiac atrophy in cancer cachexia. Am. J. Physiol. Heart Circ. Physiol. 310:H466–77
    [Google Scholar]
  120. Muscaritoli M, Molfino A, Lucia S, Rossi Fanelli F 2015. Cachexia: a preventable comorbidity of cancer. A T.A.R.G.E.T. approach. Crit. Rev. Oncol. Hematol. 94:251–59
    [Google Scholar]
  121. Narsale AA, Carson JA. 2014. Role of interleukin-6 in cachexia: therapeutic implications. Curr. Opin. Support. Palliat. Care 8:321–27
    [Google Scholar]
  122. Nedergaard J, Cannon B. 2014. The browning of white adipose tissue: some burning issues. Cell Metab 20:396–407
    [Google Scholar]
  123. Nissinen TA, Hentila J, Penna F, Lampinen A, Lautaoja JH et al. 2018. Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses. J. Cachexia Sarcopenia Muscle 9:514–29
    [Google Scholar]
  124. Norton JA, Moley JF, Green MV, Carson RE, Morrison SD 1985. Parabiotic transfer of cancer anorexia/cachexia in male rats. Cancer Res 45:5547–52
    [Google Scholar]
  125. Ohe Y, Podack ER, Olsen KJ, Miyahara Y, Miura K et al. 1993. Interleukin-6 cDNA transfected Lewis lung carcinoma cells show unaltered net tumour growth rate but cause weight loss and shortened survival in syngeneic mice. Br. J. Cancer 67:939–44
    [Google Scholar]
  126. Oliff A, Defeo-Jones D, Boyer M, Martinez D, Kiefer D et al. 1987. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell 50:555–63
    [Google Scholar]
  127. Paul PK, Gupta SK, Bhatnagar S, Panguluri SK, Darnay BG et al. 2010. Targeted ablation of TRAF6 inhibits skeletal muscle wasting in mice. J. Cell. Biol. 191:1395–411
    [Google Scholar]
  128. Peddle-McIntyre CJ, Bell G, Fenton D, McCargar L, Courneya KS 2012. Feasibility and preliminary efficacy of progressive resistance exercise training in lung cancer survivors. Lung Cancer 75:126–32
    [Google Scholar]
  129. Pedersen L, Idorn M, Olofsson GH, Lauenborg B, Nookaew I et al. 2016. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metab 23:554–62
    [Google Scholar]
  130. Penna F, Ballaro R, Martinez-Cristobal P, Sala D, Sebastian D et al. 2019. Autophagy exacerbates muscle wasting in cancer cachexia and impairs mitochondrial function. J. Mol. Biol. 431:2674–86
    [Google Scholar]
  131. Penna F, Busquets S, Argiles JM 2016. Experimental cancer cachexia: evolving strategies for getting closer to the human scenario. Semin. Cell Dev. Biol 54:20–27
    [Google Scholar]
  132. Petruzzelli M, Schweiger M, Schreiber R, Campos-Olivas R, Tsoli M et al. 2014. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab 20:433–47
    [Google Scholar]
  133. Petruzzelli M, Wagner EF. 2016. Mechanisms of metabolic dysfunction in cancer-associated cachexia. Genes Dev 30:489–501
    [Google Scholar]
  134. Pigna E, Berardi E, Aulino P, Rizzuto E, Zampieri S et al. 2016. Aerobic exercise and pharmacological treatments counteract cachexia by modulating autophagy in colon cancer. Sci. Rep. 6:26991
    [Google Scholar]
  135. Polge C, Heng AE, Jarzaguet M, Ventadour S, Claustre A et al. 2011. Muscle actin is polyubiquitinylated in vitro and in vivo and targeted for breakdown by the E3 ligase MuRF1. FASEB J 25:3790–802
    [Google Scholar]
  136. Power RA, Iwaniec UT, Magee KA, Mitova-Caneva NG, Wronski TJ 2004. Basic fibroblast growth factor has rapid bone anabolic effects in ovariectomized rats. Osteoporos. Int. 15:716–23
    [Google Scholar]
  137. Prado BL, Qian Y. 2019. Anti-cytokines in the treatment of cancer cachexia. Ann. Palliat. Med. 8:67–79
    [Google Scholar]
  138. Prado CM, Birdsell LA, Baracos VE 2009. The emerging role of computerized tomography in assessing cancer cachexia. Curr. Opin. Support. Palliat. Care 3:269–75
    [Google Scholar]
  139. Qi J, Gong J, Zhao T, Zhao J, Lam P et al. 2008. Downregulation of AMP-activated protein kinase by Cidea-mediated ubiquitination and degradation in brown adipose tissue. EMBO J 27:1537–48
    [Google Scholar]
  140. Rohm M, Schafer M, Laurent V, Ustunel BE, Niopek K et al. 2016. An AMP-activated protein kinase-stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice. Nat. Med. 22:1120–30
    [Google Scholar]
  141. Rommel C, Bodine SC, Clarke BA, Rossman R, Nunez L et al. 2001. Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nat. Cell Biol. 3:1009–13
    [Google Scholar]
  142. Ropelle ER, Pauli JR, Zecchin KG, Ueno M, de Souza CT et al. 2007. A central role for neuronal adenosine 5′-monophosphate-activated protein kinase in cancer-induced anorexia. Endocrinology 148:5220–29
    [Google Scholar]
  143. Ruan H, Hacohen N, Golub TR, Van Parijs L, Lodish HF 2002. Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-alpha is obligatory. Diabetes 51:1319–36
    [Google Scholar]
  144. Sandri M. 2016. Protein breakdown in cancer cachexia. Semin. Cell Dev. Biol. 54:11–19
    [Google Scholar]
  145. Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E et al. 2004. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117:399–412
    [Google Scholar]
  146. Sartori R, Schirwis E, Blaauw B, Bortolanza S, Zhao J et al. 2013. BMP signaling controls muscle mass. Nat. Genet. 45:1309–18
    [Google Scholar]
  147. Schieber AM, Lee YM, Chang MW, Leblanc M, Collins B et al. 2015. Disease tolerance mediated by microbiome E. coli involves inflammasome and IGF-1 signaling. Science 350:558–63
    [Google Scholar]
  148. Schuelke M, Wagner KR, Stolz LE, Hubner C, Riebel T et al. 2004. Myostatin mutation associated with gross muscle hypertrophy in a child. N. Engl. J. Med. 350:2682–88
    [Google Scholar]
  149. Short KR, Vittone JL, Bigelow ML, Proctor DN, Nair KS 2004. Age and aerobic exercise training effects on whole body and muscle protein metabolism. Am. J. Physiol. Endocrinol. Metab. 286:E92–101
    [Google Scholar]
  150. Sidossis LS, Porter C, Saraf MK, Borsheim E, Radhakrishnan RS et al. 2015. Browning of subcutaneous white adipose tissue in humans after severe adrenergic stress. Cell Metab 22:219–27
    [Google Scholar]
  151. Sinha M, Jang YC, Oh J, Khong D, Wu EY et al. 2014. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344:649–52
    [Google Scholar]
  152. Sohn JW. 2015. Network of hypothalamic neurons that control appetite. BMB Rep 48:229–33
    [Google Scholar]
  153. Solheim TS, Laird BJA, Balstad TR, Bye A, Stene G et al. 2018. Cancer cachexia: rationale for the MENAC (Multimodal-Exercise, Nutrition and Anti-inflammatory medication for Cachexia) trial. BMJ Support. Palliat. Care 8:258–65
    [Google Scholar]
  154. Strassmann G, Fong M, Kenney JS, Jacob CO 1992. Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J. Clin. Investig. 89:1681–84
    [Google Scholar]
  155. Summermatter S, Bouzan A, Pierrel E, Melly S, Stauffer D et al. 2017. Blockade of metallothioneins 1 and 2 increases skeletal muscle mass and strength. Mol. Cell Biol. 37:e00305
    [Google Scholar]
  156. Swann JR, Want EJ, Geier FM, Spagou K, Wilson ID et al. 2011. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. PNAS 108:Suppl. 14523–30
    [Google Scholar]
  157. Tintignac LA, Lagirand J, Batonnet S, Sirri V, Leibovitch MP, Leibovitch SA 2005. Degradation of MyoD mediated by the SCF (MAFbx) ubiquitin ligase. J. Biol. Chem. 280:2847–56
    [Google Scholar]
  158. Tsai VW, Macia L, Johnen H, Kuffner T, Manadhar R et al. 2013. TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator. PLOS ONE 8:e55174
    [Google Scholar]
  159. Tsujinaka T, Fujita J, Ebisui C, Yano M, Kominami E et al. 1996. Interleukin 6 receptor antibody inhibits muscle atrophy and modulates proteolytic systems in interleukin 6 transgenic mice. J. Clin. Investig. 97:244–49
    [Google Scholar]
  160. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI 2006. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444:1027–31
    [Google Scholar]
  161. Varian BJ, Goureshetti S, Poutahidis T, Lakritz JR, Levkovich T et al. 2016. Beneficial bacteria inhibit cachexia. Oncotarget 7:11803–16
    [Google Scholar]
  162. von Haehling S, Anker MS, Anker SD 2016. Prevalence and clinical impact of cachexia in chronic illness in Europe, USA, and Japan: facts and numbers update 2016. J. Cachexia Sarcopenia Muscle 7:507–9
    [Google Scholar]
  163. Vujasinovic M, Valente R, Del Chiaro M, Permert J, Lohr JM 2017. Pancreatic exocrine insufficiency in pancreatic cancer. Nutrients 9:183
    [Google Scholar]
  164. Wahlstrom A, Sayin SI, Marschall HU, Backhed F 2016. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab 24:41–50
    [Google Scholar]
  165. Wang G, Biswas AK, Ma W, Kandpal M, Coker C et al. 2018. Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle. Nat. Med. 24:770–81
    [Google Scholar]
  166. Waning DL, Guise TA. 2014. Molecular mechanisms of bone metastasis and associated muscle weakness. Clin. Cancer Res. 20:3071–77
    [Google Scholar]
  167. Waning DL, Guise TA. 2015. Cancer-associated muscle weakness: What's bone got to do with it. ? BoneKEy Rep 4:691
    [Google Scholar]
  168. Waning DL, Mohammad KS, Reiken S, Xie W, Andersson DC et al. 2015. Excess TGF-β mediates muscle weakness associated with bone metastases in mice. Nat. Med. 21:1262–71
    [Google Scholar]
  169. Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW et al. 2006. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 439:484–89
    [Google Scholar]
  170. White JP, Baynes JW, Welle SL, Kostek MC, Matesic LE et al. 2011. The regulation of skeletal muscle protein turnover during the progression of cancer cachexia in the ApcMin/+ mouse. PLOS ONE 6:e24650
    [Google Scholar]
  171. Wiedenmann B, Malfertheiner P, Friess H, Ritch P, Arseneau J et al. 2008. A multicenter, phase II study of infliximab plus gemcitabine in pancreatic cancer cachexia. J. Support. Oncol. 6:18–25
    [Google Scholar]
  172. Wigmore SJ, Plester CE, Richardson RA, Fearon KC 1997. Changes in nutritional status associated with unresectable pancreatic cancer. Br. J. Cancer 75:106–9
    [Google Scholar]
  173. Wilcox G. 2005. Insulin and insulin resistance. Clin. Biochem. Rev. 26:19–39
    [Google Scholar]
  174. Yakar S, Rosen CJ, Beamer WG, Ackert-Bicknell CL, Wu Y et al. 2002. Circulating levels of IGF-1 directly regulate bone growth and density. J. Clin. Investig. 110:771–81
    [Google Scholar]
  175. Yakovenko A, Cameron M, Trevino JG 2018. Molecular therapeutic strategies targeting pancreatic cancer induced cachexia. World J. Gastrointest. Surg. 10:95–106
    [Google Scholar]
  176. Yang J, Zhang Z, Zhang Y, Ni X, Zhang G et al. 2019. ZIP4 promotes muscle wasting and cachexia in mice with orthotopic pancreatic tumors by stimulating RAB27B-regulated release of extracellular vesicles from cancer cells. Gastroenterology 156:722–34.e6
    [Google Scholar]
  177. Yang L, Chang CC, Sun Z, Madsen D, Zhu H et al. 2017. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat. Med. 23:1158–66
    [Google Scholar]
  178. Zaki MH, Nemeth JA, Trikha M 2004. CNTO 328, a monoclonal antibody to IL-6, inhibits human tumor-induced cachexia in nude mice. Int. J. Cancer 111:592–95
    [Google Scholar]
  179. Zhang Y, Xie C, Wang H, Foss RM, Clare M et al. 2016. Irisin exerts dual effects on browning and adipogenesis of human white adipocytes. Am. J. Physiol. Endocrinol. Metab. 311:E530–41
    [Google Scholar]
  180. Zhao J, Brault JJ, Schild A, Cao P, Sandri M et al. 2007. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab 6:472–83
    [Google Scholar]
  181. Zhou X, Wang JL, Lu J, Song Y, Kwak KS et al. 2010. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142:531–43
    [Google Scholar]
  182. Zimmers TA, Davies MV, Koniaris LG, Haynes P, Esquela AF et al. 2002. Induction of cachexia in mice by systemically administered myostatin. Science 296:1486–88
    [Google Scholar]
  183. Zimmers TA, Fishel ML, Bonetto A 2016. STAT3 in the systemic inflammation of cancer cachexia. Semin. Cell Dev. Biol. 54:28–41
    [Google Scholar]
  184. Zimmers TA, Jiang Y, Wang M, Liang TW, Rupert JE et al. 2017. Exogenous GDF11 induces cardiac and skeletal muscle dysfunction and wasting. Basic Res. Cardiol. 112:48
    [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-030419-033642
Loading
/content/journals/10.1146/annurev-cancerbio-030419-033642
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error