Skip to main content

Metabolic Changes During Cancer Cachexia Pathogenesis

  • Chapter
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1026))

Abstract

Wasting of adipose tissue and skeletal muscle is a hallmark of metastatic cancer and a major cause of death. Like patients with cachexia caused by other chronic infections or inflammatory diseases, the cancer subject manifests both malnutrition and metabolic stress. Both carbohydrate utilization and amino acid incorporation are decreased in the muscles of cancer cachexia patients. Cancer cells affect host metabolism in two ways: (a) their own metabolism of nutrients into other metabolites and (b) circulating factors they secrete or induce the host to secrete. Accelerated glycolysis and lactate production, i.e., the Warburg effect and the resultant increase in Cori cycle activity, are the most widely discussed metabolic effects. Meanwhile, although a large number of pro-cachexia circulating factors have been found, such as TNFa, IL-6, myostatin, and PTHrp, none have been shown to be a dominant factor that can be targeted singly to treat cancer cachexia in humans. It is possible that given the complex multifactorial nature of the cachexia secretome, and the personalized differences between cancer patients, targeting any single circulating factor would always be insufficient to treat cachexia for all patients. Here we review the metabolic changes that occur in response to tumor growth and tumor-secreted factors during cachexia.

This is a preview of subscription content, log in via an institution.

References

  1. Argiles JM, Busquets S, Stemmler B, Lopez-Soriano FJ (2014) Cancer cachexia: understanding the molecular basis. Nat Rev Cancer 14(11):754–762. doi:10.1038/nrc3829

    Article  CAS  PubMed  Google Scholar 

  2. Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331(6024):1559–1564. doi:10.1126/science.1203543

    Article  CAS  PubMed  Google Scholar 

  3. Massague J, Obenauf AC (2016) Metastatic colonization by circulating tumour cells. Nature 529(7586):298–306. doi:10.1038/nature17038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tisdale MJ (2009) Mechanisms of cancer cachexia. Physiol Rev 89(2):381–410. doi:10.1152/physrev.00016.2008

    Article  CAS  PubMed  Google Scholar 

  5. Spano D, Heck C, De Antonellis P, Christofori G, Zollo M (2012) Molecular networks that regulate cancer metastasis. Semin Cancer Biol 22(3):234–249. doi:10.1016/j.semcancer.2012.03.006

    Article  CAS  PubMed  Google Scholar 

  6. Fearon KC, Glass DJ, Guttridge DC (2012) Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab 16(2):153–166. doi:10.1016/j.cmet.2012.06.011

    Article  CAS  PubMed  Google Scholar 

  7. Waning DL, Guise TA (2014) Molecular mechanisms of bone metastasis and associated muscle weakness. Clin Cancer Res 20(12):3071–3077. doi:10.1158/1078-0432.CCR-13-1590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Guttridge DC (2015) A TGF-beta pathway associated with cancer cachexia. Nat Med 21(11):1248–1249. doi:10.1038/nm.3988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fox KM, Brooks JM, Gandra SR, Markus R, Chiou CF (2009) Estimation of cachexia among cancer patients based on four definitions. J Oncol 2009:693458. doi:10.1155/2009/693458

    Article  PubMed  PubMed Central  Google Scholar 

  10. Dewys WD, Begg C, Lavin PT, Band PR, Bennett JM, Bertino JR, Cohen MH, Douglass HO Jr, Engstrom PF, Ezdinli EZ, Horton J, Johnson GJ, Moertel CG, Oken MM, Perlia C, Rosenbaum C, Silverstein MN, Skeel RT, Sponzo RW, Tormey DC (1980) Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern cooperative oncology group. Am J Med 69(4):491–497

    Article  CAS  PubMed  Google Scholar 

  11. Warren S (1932) The immediate causes of death in cancer. Am J Med Sci 184:610–615

    Article  Google Scholar 

  12. Houten L, Reilley AA (1980) An investigation of the cause of death from cancer. J Surg Oncol 13(2):111–116

    Article  CAS  PubMed  Google Scholar 

  13. Harnett WL (1952) British empire cancer campaign: a survey of cancer in London. British Empire Cancer Campaign, London

    Google Scholar 

  14. Consul N, Guo X, Coker C, Lopez-Pintado S, Hibshoosh H, Zhao B, Kalinsky K, Acharyya S (2016) Monitoring metastasis and cachexia in a patient with breast cancer: a case study. Clin Med Insights Oncol 10:83–94. doi:10.4137/CMO.S40479

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kubo Y, Naito T, Mori K, Osawa G, Aruga E (2017) Skeletal muscle loss and prognosis of breast cancer patients. Support Care Cancer. doi:10.1007/s00520-017-3628-5

  16. Waning DL, Guise TA (2015) Cancer-associated muscle weakness: What's bone got to do with it? Bonekey Rep 4:691. doi:10.1038/bonekey.2015.59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Heymsfield SB HJ, Lawson DH (1980) Enteral hyperalimentation. In: JE B (ed) Developments in digestive diseases. Lea and Febiger, Philadelphia, pp 59–83

    Google Scholar 

  18. Clark CM, Goodlad GA (1971) Depletion of proteins of phasic and tonic muscles in tumour-bearing rats. Eur J Cancer 7(1):3–9

    Article  CAS  PubMed  Google Scholar 

  19. Lundholm K, Edstrom S, Ekman L, Karlberg I, Bylund AC, Schersten T (1978) A comparative study of the influence of malignant tumor on host metabolism in mice and man: evaluation of an experimental model. Cancer 42(2):453–461

    Article  CAS  PubMed  Google Scholar 

  20. Lundholm K, Bylund AC, Holm J, Schersten T (1976) Skeletal muscle metabolism in patients with malignant tumor. Eur J Cancer 12(6):465–473

    Article  CAS  PubMed  Google Scholar 

  21. Begg RW (1958) Tumor-host relations. Adv Cancer Res 5:1–54

    Article  CAS  PubMed  Google Scholar 

  22. Ramaswamy KLI, Baker N (1980) Dietary control of lipogenesis in vivo in host tissues and tumours of mice bearing Ehrlich ascites carcinoma. Cancer Res 40:4606–4611

    Google Scholar 

  23. Waterhouse C, Kemperman JH (1971) Carbohydrate metabolism in subjects with cancer. Cancer Res 31(9):1273–1278

    CAS  PubMed  Google Scholar 

  24. Warnold I, Lundholm K, Schersten T (1978) Energy balance and body composition in cancer patients. Cancer Res 38(6):1801–1807

    CAS  PubMed  Google Scholar 

  25. Bozzetti F, Pagnoni AM, Del Vecchio M (1980) Excessive caloric expenditure as a cause of malnutrition in patients with cancer. Surg Gynecol Obstet 150(2):229–234

    CAS  PubMed  Google Scholar 

  26. Emery PW, Edwards RH, Rennie MJ, Souhami RL, Halliday D (1984) Protein synthesis in muscle measured in vivo in cachectic patients with cancer. Br Med J (Clin Res Ed) 289(6445):584–586

    Article  CAS  Google Scholar 

  27. Lundholm K, Bennegard K, Eden E, Svaninger G, Emery PW, Rennie MJ (1982) Efflux of 3-methylhistidine from the leg in cancer patients who experience weight loss. Cancer Res 42(11):4807–4811

    CAS  PubMed  Google Scholar 

  28. O'Keefe SJ, Ogden J, Ramjee G, Rund J (1990) Contribution of elevated protein turnover and anorexia to cachexia in patients with hepatocellular carcinoma. Cancer Res 50(4):1226–1230

    PubMed  Google Scholar 

  29. Acharyya S, Ladner KJ, Nelsen LL, Damrauer J, Reiser PJ, Swoap S, Guttridge DC (2004) Cancer cachexia is regulated by selective targeting of skeletal muscle gene products. J Clin Invest 114(3):370–378. doi:10.1172/JCI20174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yu Z, Li P, Zhang M, Hannink M, Stamler JS, Yan Z (2008) Fiber type-specific nitric oxide protects oxidative myofibers against cachectic stimuli. PLoS One 3(5):e2086. doi:10.1371/journal.pone.0002086

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Diffee GM, Kalfas K, Al-Majid S, McCarthy DO (2002) Altered expression of skeletal muscle myosin isoforms in cancer cachexia. Am J Physiol Cell Physiol 283(5):C1376–C1382. doi:10.1152/ajpcell.00154.2002

    Article  CAS  PubMed  Google Scholar 

  32. Schmitt TL, Martignoni ME, Bachmann J, Fechtner K, Friess H, Kinscherf R, Hildebrandt W (2007) Activity of the Akt-dependent anabolic and catabolic pathways in muscle and liver samples in cancer-related cachexia. J Mol Med (Berl) 85(6):647–654. doi:10.1007/s00109-007-0177-2

    Article  CAS  Google Scholar 

  33. Eley HL, Skipworth RJ, Deans DA, Fearon KC, Tisdale MJ (2008) Increased expression of phosphorylated forms of RNA-dependent protein kinase and eukaryotic initiation factor 2alpha may signal skeletal muscle atrophy in weight-losing cancer patients. Br J Cancer 98(2):443–449. doi:10.1038/sj.bjc.6604150

    Article  CAS  PubMed  Google Scholar 

  34. Johns N, Hatakeyama S, Stephens NA, Degen M, Degen S, Frieauff W, Lambert C, Ross JA, Roubenoff R, Glass DJ, Jacobi C, Fearon KC (2014) Clinical classification of cancer cachexia: phenotypic correlates in human skeletal muscle. PLoS One 9(1):e83618. doi:10.1371/journal.pone.0083618

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Proud CG (2005) eIF2 and the control of cell physiology. Semin Cell Dev Biol 16(1):3–12. doi:10.1016/j.semcdb.2004.11.004

    Article  CAS  PubMed  Google Scholar 

  36. Proud CG (2007) Signalling to translation: how signal transduction pathways control the protein synthetic machinery. Biochem J 403(2):217–234. doi:10.1042/BJ20070024

    Article  CAS  PubMed  Google Scholar 

  37. Carlberg U, Nilsson A, Nygard O (1990) Functional properties of phosphorylated elongation factor 2. Eur J Biochem 191(3):639–645

    Article  CAS  PubMed  Google Scholar 

  38. Smith KL, Tisdale MJ (1993) Increased protein degradation and decreased protein synthesis in skeletal muscle during cancer cachexia. Br J Cancer 67(4):680–685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Eley HL, Tisdale MJ (2007) Skeletal muscle atrophy, a link between depression of protein synthesis and increase in degradation. J Biol Chem 282(10):7087–7097. doi:10.1074/jbc.M610378200

    Article  CAS  PubMed  Google Scholar 

  40. Eley HL, Russell ST, Tisdale MJ (2007) Effect of branched-chain amino acids on muscle atrophy in cancer cachexia. Biochem J 407(1):113–120. doi:10.1042/BJ20070651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Papageorgopoulos C, Caldwell K, Schweingrubber H, Neese RA, Shackleton CH, Hellerstein M (2002) Measuring synthesis rates of muscle creatine kinase and myosin with stable isotopes and mass spectrometry. Anal Biochem 309(1):1–10

    Article  CAS  PubMed  Google Scholar 

  42. Drexler HC, Ruhs A, Konzer A, Mendler L, Bruckskotten M, Looso M, Gunther S, Boettger T, Kruger M, Braun T (2012) On marathons and sprints: an integrated quantitative proteomics and transcriptomics analysis of differences between slow and fast muscle fibers. Mol Cell Proteomics 11(6):M111 010801. doi:10.1074/mcp.M111.010801

  43. Pallafacchina G, Calabria E, Serrano AL, Kalhovde JM, Schiaffino S (2002) A protein kinase B-dependent and rapamycin-sensitive pathway controls skeletal muscle growth but not fiber type specification. Proc Natl Acad Sci U S A 99(14):9213–9218. doi:10.1073/pnas.142166599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Raffaello A, Milan G, Masiero E, Carnio S, Lee D, Lanfranchi G, Goldberg AL, Sandri M (2010) JunB transcription factor maintains skeletal muscle mass and promotes hypertrophy. J Cell Biol 191(1):101–113. doi:10.1083/jcb.201001136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Glickman MH, Ciechanover A (2002) The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82(2):373–428. doi:10.1152/physrev.00027.2001

    Article  CAS  PubMed  Google Scholar 

  46. Hasselgren PO, Wray C, Mammen J (2002) Molecular regulation of muscle cachexia: it may be more than the proteasome. Biochem Biophys Res Commun 290(1):1–10. doi:10.1006/bbrc.2001.5849

    Article  CAS  PubMed  Google Scholar 

  47. Khal J, Hine AV, Fearon KC, Dejong CH, Tisdale MJ (2005) Increased expression of proteasome subunits in skeletal muscle of cancer patients with weight loss. Int J Biochem Cell Biol 37(10):2196–2206. doi:10.1016/j.biocel.2004.10.017

    Article  CAS  PubMed  Google Scholar 

  48. Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, Burden SJ, Di Lisi R, Sandri C, Zhao J, Goldberg AL, Schiaffino S, Sandri M (2007) FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 6(6):458–471. doi:10.1016/j.cmet.2007.11.001

    Article  CAS  PubMed  Google Scholar 

  49. Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan ZQ, Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD, Glass DJ (2001) Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294(5547):1704–1708. doi:10.1126/science.1065874

    Article  CAS  PubMed  Google Scholar 

  50. Gomes MD, Lecker SH, Jagoe RT, Navon A, Goldberg AL (2001) Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci U S A 98(25):14440–14445. doi:10.1073/pnas.251541198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lecker SH, Jagoe RT, Gilbert A, Gomes M, Baracos V, Bailey J, Price SR, Mitch WE, Goldberg AL (2004) Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J 18(1):39–51. doi:10.1096/fj.03-0610com

    Article  CAS  PubMed  Google Scholar 

  52. Lokireddy S, Wijesoma IW, Sze SK, McFarlane C, Kambadur R, Sharma M (2012) Identification of atrogin-1-targeted proteins during the myostatin-induced skeletal muscle wasting. Am J Physiol Cell Physiol 303(5):C512–C529. doi:10.1152/ajpcell.00402.2011

    Article  CAS  PubMed  Google Scholar 

  53. Kedar V, McDonough H, Arya R, Li HH, Rockman HA, Patterson C (2004) Muscle-specific RING finger 1 is a bona fide ubiquitin ligase that degrades cardiac troponin I. Proc Natl Acad Sci U S A 101(52):18135–18140. doi:10.1073/pnas.0404341102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fielitz J, Kim MS, Shelton JM, Latif S, Spencer JA, Glass DJ, Richardson JA, Bassel-Duby R, Olson EN (2007) Myosin accumulation and striated muscle myopathy result from the loss of muscle RING finger 1 and 3. J Clin Invest 117(9):2486–2495. doi:10.1172/JCI32827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Clarke BA, Drujan D, Willis MS, Murphy LO, Corpina RA, Burova E, Rakhilin SV, Stitt TN, Patterson C, Latres E, Glass DJ (2007) The E3 ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle. Cell Metab 6(5):376–385. doi:10.1016/j.cmet.2007.09.009

    Article  CAS  PubMed  Google Scholar 

  56. Polge C, Heng AE, Jarzaguet M, Ventadour S, Claustre A, Combaret L, Bechet D, Matondo M, Uttenweiler-Joseph S, Monsarrat B, Attaix D, Taillandier D (2011) Muscle actin is polyubiquitinylated in vitro and in vivo and targeted for breakdown by the E3 ligase MuRF1. FASEB J 25(11):3790–3802. doi:10.1096/fj.11-180968

    Article  CAS  PubMed  Google Scholar 

  57. Cohen S, Brault JJ, Gygi SP, Glass DJ, Valenzuela DM, Gartner C, Latres E, Goldberg AL (2009) During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation. J Cell Biol 185(6):1083–1095. doi:10.1083/jcb.200901052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sandri M (2016) Protein breakdown in cancer cachexia. Semin Cell Dev Biol 54:11–19. doi:10.1016/j.semcdb.2015.11.002

    Article  CAS  PubMed  Google Scholar 

  59. Stephens NA, Gallagher IJ, Rooyackers O, Skipworth RJ, Tan BH, Marstrand T, Ross JA, Guttridge DC, Lundell L, Fearon KC, Timmons JA (2010) Using transcriptomics to identify and validate novel biomarkers of human skeletal muscle cancer cachexia. Genome Med 2(1):1. doi:10.1186/gm122

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. D'Orlando C, Marzetti E, Francois S, Lorenzi M, Conti V, di Stasio E, Rosa F, Brunelli S, Doglietto GB, Pacelli F, Bossola M (2014) Gastric cancer does not affect the expression of atrophy-related genes in human skeletal muscle. Muscle Nerve 49(4):528–533. doi:10.1002/mus.23945

    Article  PubMed  Google Scholar 

  61. Jagoe RT, Redfern CP, Roberts RG, Gibson GJ, Goodship TH (2002) Skeletal muscle mRNA levels for cathepsin B, but not components of the ubiquitin-proteasome pathway, are increased in patients with lung cancer referred for thoracotomy. Clin Sci (Lond) 102(3):353–361

    CAS  Google Scholar 

  62. Schersten T, Lundholm K (1972) Lysosomal enzyme activity in muscle tissue from patients with malignant tumor. Cancer 30(5):1246–1251

    Article  CAS  PubMed  Google Scholar 

  63. Lapierre LR, Kumsta C, Sandri M, Ballabio A, Hansen M (2015) Transcriptional and epigenetic regulation of autophagy in aging. Autophagy 11(6):867–880. doi:10.1080/15548627.2015.1034410

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Bechet D, Tassa A, Taillandier D, Combaret L, Attaix D (2005) Lysosomal proteolysis in skeletal muscle. Int J Biochem Cell Biol 37(10):2098–2114. doi:10.1016/j.biocel.2005.02.029

    Article  CAS  PubMed  Google Scholar 

  65. Deval C, Mordier S, Obled C, Bechet D, Combaret L, Attaix D, Ferrara M (2001) Identification of cathepsin L as a differentially expressed message associated with skeletal muscle wasting. Biochem J 360(Pt 1):143–150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Tassa A, Roux MP, Attaix D, Bechet DM (2003) Class III phosphoinositide 3-kinase--Beclin1 complex mediates the amino acid-dependent regulation of autophagy in C2C12 myotubes. Biochem J 376(Pt 3):577–586. doi:10.1042/BJ20030826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Penna F, Costamagna D, Pin F, Camperi A, Fanzani A, Chiarpotto EM, Cavallini G, Bonelli G, Baccino FM, Costelli P (2013) Autophagic degradation contributes to muscle wasting in cancer cachexia. Am J Pathol 182(4):1367–1378. doi:10.1016/j.ajpath.2012.12.023

    Article  CAS  PubMed  Google Scholar 

  68. Chacon-Cabrera A, Fermoselle C, Urtreger AJ, Mateu-Jimenez M, Diament MJ, de Kier Joffe ED, Sandri M, Barreiro E (2014) Pharmacological strategies in lung cancer-induced cachexia: effects on muscle proteolysis, autophagy, structure, and weakness. J Cell Physiol 229(11):1660–1672. doi:10.1002/jcp.24611

    Article  CAS  PubMed  Google Scholar 

  69. Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y (2004) In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 15(3):1101–1111. doi:10.1091/mbc.E03-09-0704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Grumati P, Coletto L, Sabatelli P, Cescon M, Angelin A, Bertaggia E, Blaauw B, Urciuolo A, Tiepolo T, Merlini L, Maraldi NM, Bernardi P, Sandri M, Bonaldo P (2010) Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration. Nat Med 16(11):1313–1320. doi:10.1038/nm.2247

    Article  CAS  PubMed  Google Scholar 

  71. Wohlgemuth SE, Seo AY, Marzetti E, Lees HA, Leeuwenburgh C (2010) Skeletal muscle autophagy and apoptosis during aging: effects of calorie restriction and life-long exercise. Exp Gerontol 45(2):138–148. doi:10.1016/j.exger.2009.11.002

    Article  CAS  PubMed  Google Scholar 

  72. Mofarrahi M, Sigala I, Guo Y, Godin R, Davis EC, Petrof B, Sandri M, Burelle Y, Hussain SN (2012) Autophagy and skeletal muscles in sepsis. PLoS One 7(10):e47265. doi:10.1371/journal.pone.0047265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Derde S, Vanhorebeek I, Guiza F, Derese I, Gunst J, Fahrenkrog B, Martinet W, Vervenne H, Ververs EJ, Larsson L, Van den Berghe G (2012) Early parenteral nutrition evokes a phenotype of autophagy deficiency in liver and skeletal muscle of critically ill rabbits. Endocrinology 153(5):2267–2276. doi:10.1210/en.2011-2068

    Article  CAS  PubMed  Google Scholar 

  74. Qiu J, Tsien C, Thapalaya S, Narayanan A, Weihl CC, Ching JK, Eghtesad B, Singh K, Fu X, Dubyak G, McDonald C, Almasan A, Hazen SL, Naga Prasad SV, Dasarathy S (2012) Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis. Am J Physiol Endocrinol Metab 303(8):E983–E993. doi:10.1152/ajpendo.00183.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Smuder AJ, Kavazis AN, Min K (1985) Powers SK (2011) exercise protects against doxorubicin-induced oxidative stress and proteolysis in skeletal muscle. J Appl Physiol 110(4):935–942. doi:10.1152/japplphysiol.00677.2010

    Article  CAS  Google Scholar 

  76. Brocca L, Cannavino J, Coletto L, Biolo G, Sandri M, Bottinelli R, Pellegrino MA (2012) The time course of the adaptations of human muscle proteome to bed rest and the underlying mechanisms. J Physiol 590(20):5211–5230. doi:10.1113/jphysiol.2012.240267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. O'Leary MF, Vainshtein A, Carter HN, Zhang Y, Hood DA (2012) Denervation-induced mitochondrial dysfunction and autophagy in skeletal muscle of apoptosis-deficient animals. Am J Physiol Cell Physiol 303(4):C447–C454. doi:10.1152/ajpcell.00451.2011

    Article  PubMed  CAS  Google Scholar 

  78. Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S, Lecker SH, Goldberg AL (2007) FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab 6(6):472–483. doi:10.1016/j.cmet.2007.11.004

    Article  CAS  PubMed  Google Scholar 

  79. Nascimbeni AC, Fanin M, Masiero E, Angelini C, Sandri M (2012) The role of autophagy in the pathogenesis of glycogen storage disease type II (GSDII). Cell Death Differ 19(10):1698–1708. doi:10.1038/cdd.2012.52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. De Palma C, Morisi F, Cheli S, Pambianco S, Cappello V, Vezzoli M, Rovere-Querini P, Moggio M, Ripolone M, Francolini M, Sandri M, Clementi E (2012) Autophagy as a new therapeutic target in Duchenne muscular dystrophy. Cell Death Dis 3:e418. doi:10.1038/cddis.2012.159

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Sandri M, Coletto L, Grumati P, Bonaldo P (2013) Misregulation of autophagy and protein degradation systems in myopathies and muscular dystrophies. J Cell Sci 126(Pt 23):5325–5333. doi:10.1242/jcs.114041

    Article  CAS  PubMed  Google Scholar 

  82. Tardif N, Klaude M, Lundell L, Thorell A, Rooyackers O (2013) Autophagic-lysosomal pathway is the main proteolytic system modified in the skeletal muscle of esophageal cancer patients. Am J Clin Nutr 98(6):1485–1492. doi:10.3945/ajcn.113.063859

    Article  CAS  PubMed  Google Scholar 

  83. Wang H, Sun HQ, Zhu X, Zhang L, Albanesi J, Levine B, Yin H (2015) GABARAPs regulate PI4P-dependent autophagosome:lysosome fusion. Proc Natl Acad Sci U S A 112(22):7015–7020. doi:10.1073/pnas.1507263112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Stephens NA, Skipworth RJ, Gallagher IJ, Greig CA, Guttridge DC, Ross JA, Fearon KC (2015) Evaluating potential biomarkers of cachexia and survival in skeletal muscle of upper gastrointestinal cancer patients. J Cachexia Sarcopenia Muscle 6(1):53–61. doi:10.1002/jcsm.12005

    Article  PubMed  PubMed Central  Google Scholar 

  85. Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT (2009) Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proc Natl Acad Sci U S A 106(48):20405–20410. doi:10.1073/pnas.0911570106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Carnio S, LoVerso F, Baraibar MA, Longa E, Khan MM, Maffei M, Reischl M, Canepari M, Loefler S, Kern H, Blaauw B, Friguet B, Bottinelli R, Rudolf R, Sandri M (2014) Autophagy impairment in muscle induces neuromuscular junction degeneration and precocious aging. Cell Rep 8(5):1509–1521. doi:10.1016/j.celrep.2014.07.061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Karsli-Uzunbas G, Guo JY, Price S, Teng X, Laddha SV, Khor S, Kalaany NY, Jacks T, Chan CS, Rabinowitz JD, White E (2014) Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discov 4(8):914–927. doi:10.1158/2159-8290.CD-14-0363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M, Metzger D, Reggiani C, Schiaffino S, Sandri M (2009) Autophagy is required to maintain muscle mass. Cell Metab 10(6):507–515. doi:10.1016/j.cmet.2009.10.008

    Article  CAS  PubMed  Google Scholar 

  89. Lucke B, Berwick M, Zeckwer I (1952) Liver catalase activity in parabiotic rats with one partner tumor-bearing. J Natl Cancer Inst 13(3):681–686

    CAS  PubMed  Google Scholar 

  90. Beutler B, Mahoney J, Le Trang N, Pekala P, Cerami A (1985) Purification of cachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin-induced RAW 264.7 cells. J Exp Med 161(5):984–995

    Article  CAS  PubMed  Google Scholar 

  91. Garcia-Martinez C, Agell N, Llovera M, Lopez-Soriano FJ, Argiles JM (1993) Tumour necrosis factor-alpha increases the ubiquitinization of rat skeletal muscle proteins. FEBS Lett 323(3):211–214

    Article  CAS  PubMed  Google Scholar 

  92. Garcia-Martinez C, Llovera M, Agell N, Lopez-Soriano FJ, Argiles JM (1994) Ubiquitin gene expression in skeletal muscle is increased by tumour necrosis factor-alpha. Biochem Biophys Res Commun 201(2):682–686

    Article  CAS  PubMed  Google Scholar 

  93. Llovera M, Carbo N, Lopez-Soriano J, Garcia-Martinez C, Busquets S, Alvarez B, Agell N, Costelli P, Lopez-Soriano FJ, Celada A, Argiles JM (1998) Different cytokines modulate ubiquitin gene expression in rat skeletal muscle. Cancer Lett 133(1):83–87

    Article  CAS  PubMed  Google Scholar 

  94. Llovera M, Garcia-Martinez C, Agell N, Lopez-Soriano FJ, Argiles JM (1997) TNF can directly induce the expression of ubiquitin-dependent proteolytic system in rat soleus muscles. Biochem Biophys Res Commun 230(2):238–241

    Article  CAS  PubMed  Google Scholar 

  95. van Hall G (2012) Cytokines: muscle protein and amino acid metabolism. Curr Opin Clin Nutr Metab Care 15(1):85–91. doi:10.1097/MCO.0b013e32834e6ea2

    Article  PubMed  CAS  Google Scholar 

  96. Tisdale MJ (1997) Biology of cachexia. J Natl Cancer Inst 89(23):1763–1773

    Article  CAS  PubMed  Google Scholar 

  97. Chen SE, Gerken E, Zhang Y, Zhan M, Mohan RK, Li AS, Reid MB, Li YP (2005) Role of TNF-{alpha} signaling in regeneration of cardiotoxin-injured muscle. Am J Physiol Cell Physiol 289(5):C1179–C1187. doi:10.1152/ajpcell.00062.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Chen SE, Jin B, Li YP (2007) TNF-alpha regulates myogenesis and muscle regeneration by activating p38 MAPK. Am J Physiol Cell Physiol 292(5):C1660–C1671. doi:10.1152/ajpcell.00486.2006

    Article  CAS  PubMed  Google Scholar 

  99. Miller SC, Ito H, Blau HM, Torti FM (1988) Tumor necrosis factor inhibits human myogenesis in vitro. Mol Cell Biol 8(6):2295–2301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Oliff A, Defeo-Jones D, Boyer M, Martinez D, Kiefer D, Vuocolo G, Wolfe A, Socher SH (1987) Tumors secreting human TNF/cachectin induce cachexia in mice. Cell 50(4):555–563

    Article  CAS  PubMed  Google Scholar 

  101. Garcia-Martinez C, Lopez-Soriano FJ, Argiles JM (1993) Acute treatment with tumour necrosis factor-alpha induces changes in protein metabolism in rat skeletal muscle. Mol Cell Biochem 125(1):11–18

    Article  CAS  PubMed  Google Scholar 

  102. Li YP, Reid MB (2000) NF-kappaB mediates the protein loss induced by TNF-alpha in differentiated skeletal muscle myotubes. Am J Physiol Regul Integr Comp Physiol 279(4):R1165–R1170

    Article  CAS  PubMed  Google Scholar 

  103. Keren A, Tamir Y, Bengal E (2006) The p38 MAPK signaling pathway: a major regulator of skeletal muscle development. Mol Cell Endocrinol 252(1–2):224–230. doi:10.1016/j.mce.2006.03.017

    Article  CAS  PubMed  Google Scholar 

  104. Bernet JD, Doles JD, Hall JK, Kelly Tanaka K, Carter TA, Olwin BB (2014) p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat Med 20(3):265–271. doi:10.1038/nm.3465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Cosgrove BD, Gilbert PM, Porpiglia E, Mourkioti F, Lee SP, Corbel SY, Llewellyn ME, Delp SL, Blau HM (2014) Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat Med 20(3):255–264. doi:10.1038/nm.3464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Fukawa T, Yan-Jiang BC, Min-Wen JC, Jun-Hao ET, Huang D, Qian CN, Ong P, Li Z, Chen S, Mak SY, Lim WJ, Kanayama HO, Mohan RE, Wang RR, Lai JH, Chua C, Ong HS, Tan KK, Ho YS, Tan IB, Teh BT, Shyh-Chang N (2016) Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia. Nat Med 22(6):666–671. doi:10.1038/nm.4093

    Article  CAS  PubMed  Google Scholar 

  107. Maltoni M, Fabbri L, Nanni O, Scarpi E, Pezzi L, Flamini E, Riccobon A, Derni S, Pallotti G, Amadori D (1997) Serum levels of tumour necrosis factor alpha and other cytokines do not correlate with weight loss and anorexia in cancer patients. Support Care Cancer 5(2):130–135

    Article  CAS  PubMed  Google Scholar 

  108. Jatoi A, Ritter HL, Dueck A, Nguyen PL, Nikcevich DA, Luyun RF, Mattar BI, Loprinzi CL (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(2):234–239. doi:10.1016/j.lungcan.2009.06.020

    Article  PubMed  Google Scholar 

  109. Scott HR, McMillan DC, Crilly A, McArdle CS, Milroy R (1996) The relationship between weight loss and interleukin 6 in non-small-cell lung cancer. Br J Cancer 73(12):1560–1562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Moses AG, Maingay J, Sangster K, Fearon KC, Ross JA (2009) Pro-inflammatory cytokine release by peripheral blood mononuclear cells from patients with advanced pancreatic cancer: relationship to acute phase response and survival. Oncol Rep 21(4):1091–1095

    CAS  PubMed  Google Scholar 

  111. Black K, Garrett IR, Mundy GR (1991) Chinese hamster ovarian cells transfected with the murine interleukin-6 gene cause hypercalcemia as well as cachexia, leukocytosis and thrombocytosis in tumor-bearing nude mice. Endocrinology 128(5):2657–2659. doi:10.1210/endo-128-5-2657

    Article  CAS  PubMed  Google Scholar 

  112. Strassmann G, Fong M, Kenney JS, Jacob CO (1992) Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J Clin Invest 89(5):1681–1684. doi:10.1172/JCI115767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Strassmann G, Fong M, Freter CE, Windsor S, D'Alessandro F, Nordan RP (1993) Suramin interferes with interleukin-6 receptor binding in vitro and inhibits colon-26-mediated experimental cancer cachexia in vivo. J Clin Invest 92(5):2152–2159. doi:10.1172/JCI116816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Goodman MN (1994) Interleukin-6 induces skeletal muscle protein breakdown in rats. Proc Soc Exp Biol Med 205(2):182–185

    Article  CAS  PubMed  Google Scholar 

  115. 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(2):R393–R401. doi:10.1152/ajpregu.00716.2007

    Article  CAS  PubMed  Google Scholar 

  116. Espat NJ, Auffenberg T, Rosenberg JJ, Rogy M, Martin D, Fang CH, Hasselgren PO, 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 Phys 271(1 Pt 2):R185–R190

    CAS  Google Scholar 

  117. Bayliss TJ, Smith JT, Schuster M, Dragnev KH, Rigas JR (2011) A humanized anti-IL-6 antibody (ALD518) in non-small cell lung cancer. Expert Opin Biol Ther 11(12):1663–1668. doi:10.1517/14712598.2011.627850

    Article  CAS  PubMed  Google Scholar 

  118. Reardon KA, Davis J, Kapsa RM, Choong P, Byrne E (2001) Myostatin, insulin-like growth factor-1, and leukemia inhibitory factor mRNAs are upregulated in chronic human disuse muscle atrophy. Muscle Nerve 24(7):893–899

    Article  CAS  PubMed  Google Scholar 

  119. Carlson CJ, Booth FW, Gordon SE (1999) Skeletal muscle myostatin mRNA expression is fiber-type specific and increases during hindlimb unloading. Am J Phys 277(2 Pt 2):R601–R606

    CAS  Google Scholar 

  120. Zachwieja JJ, Smith SR, Sinha-Hikim I, Gonzalez-Cadavid N, Bhasin S (1999) Plasma myostatin-immunoreactive protein is increased after prolonged bed rest with low-dose T3 administration. J Gravit Physiol 6(2):11–15

    CAS  PubMed  Google Scholar 

  121. Gustafsson T, Osterlund T, Flanagan JN, von Walden F, Trappe TA, Linnehan RM (1985) Tesch PA (2010) effects of 3 days unloading on molecular regulators of muscle size in humans. J Appl Physiol 109(3):721–727. doi:10.1152/japplphysiol.00110.2009

    Article  CAS  Google Scholar 

  122. Shao C, Liu M, Wu X, Ding F (2007) Time-dependent expression of myostatin RNA transcript and protein in gastrocnemius muscle of mice after sciatic nerve resection. Microsurgery 27(5):487–493. doi:10.1002/micr.20392

    Article  PubMed  Google Scholar 

  123. Elkina Y, von Haehling S, Anker SD, Springer J (2011) The role of myostatin in muscle wasting: an overview. J Cachexia Sarcopenia Muscle 2(3):143–151. doi:10.1007/s13539-011-0035-5

    Article  PubMed  PubMed Central  Google Scholar 

  124. Zimmers TA, Davies MV, Koniaris LG, Haynes P, Esquela AF, Tomkinson KN, McPherron AC, Wolfman NM, Lee SJ (2002) Induction of cachexia in mice by systemically administered myostatin. Science 296(5572):1486–1488. doi:10.1126/science.1069525

    Article  CAS  PubMed  Google Scholar 

  125. Langley B, Thomas M, Bishop A, Sharma M, Gilmour S, Kambadur R (2002) Myostatin inhibits myoblast differentiation by down-regulating MyoD expression. J Biol Chem 277(51):49831–49840. doi:10.1074/jbc.M204291200

    Article  CAS  PubMed  Google Scholar 

  126. Aversa Z, Bonetto A, Penna F, Costelli P, Di Rienzo G, Lacitignola A, Baccino FM, Ziparo V, Mercantini P, Rossi Fanelli F, Muscaritoli M (2012) Changes in myostatin signaling in non-weight-losing cancer patients. Ann Surg Oncol 19(4):1350–1356. doi:10.1245/s10434-011-1720-5

    Article  PubMed  Google Scholar 

  127. George I, Bish LT, Kamalakkannan G, Petrilli CM, Oz MC, Naka Y, Sweeney HL, Maybaum S (2010) Myostatin activation in patients with advanced heart failure and after mechanical unloading. Eur J Heart Fail 12(5):444–453. doi:10.1093/eurjhf/hfq039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Elliott B, Renshaw D, Getting S, Mackenzie R (2012) The central role of myostatin in skeletal muscle and whole body homeostasis. Acta Physiol (Oxf) 205(3):324–340. doi:10.1111/j.1748-1716.2012.02423.x

    Article  CAS  Google Scholar 

  129. Loumaye A, de Barsy M, Nachit M, Lause P, Frateur L, van Maanen A, Trefois P, Gruson D, Thissen JP (2015) Role of Activin a and myostatin in human cancer cachexia. J Clin Endocrinol Metab 100(5):2030–2038. doi:10.1210/jc.2014-4318

    Article  CAS  PubMed  Google Scholar 

  130. Sinha M, Jang YC, Oh J, Khong D, Wu EY, Manohar R, Miller C, Regalado SG, Loffredo FS, Pancoast JR, Hirshman MF, Lebowitz J, Shadrach JL, Cerletti M, Kim MJ, Serwold T, Goodyear LJ, Rosner B, Lee RT, Wagers AJ (2014) Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344(6184):649–652. doi:10.1126/science.1251152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Egerman MA, Cadena SM, Gilbert JA, Meyer A, Nelson HN, Swalley SE, Mallozzi C, Jacobi C, Jennings LL, Clay I, Laurent G, Ma S, Brachat S, Lach-Trifilieff E, Shavlakadze T, Trendelenburg AU, Brack AS, Glass DJ (2015) GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab 22(1):164–174. doi:10.1016/j.cmet.2015.05.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Zhou Y, Sharma N, Dukes D, Myzithras MB, Gupta P, Khalil A, Kahn J, Ahlberg JS, Hayes DB, Franti M, Criswell T (2017) GDF11 treatment attenuates the recovery of skeletal muscle function after injury in older rats. AAPS J 19(2):431–437. doi:10.1208/s12248-016-0024-x

    Article  CAS  PubMed  Google Scholar 

  133. Zhou X, Wang JL, Lu J, Song Y, Kwak KS, Jiao Q, Rosenfeld R, Chen Q, Boone T, Simonet WS, Lacey DL, Goldberg AL, Han HQ (2010) Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142(4):531–543. doi:10.1016/j.cell.2010.07.011

    Article  CAS  PubMed  Google Scholar 

  134. Busquets S, Toledo M, Orpi M, Massa D, Porta M, Capdevila E, Padilla N, Frailis V, Lopez-Soriano FJ, Han HQ, Argiles JM (2012) Myostatin blockage using actRIIB antagonism in mice bearing the Lewis lung carcinoma results in the improvement of muscle wasting and physical performance. J Cachexia Sarcopenia Muscle 3(1):37–43. doi:10.1007/s13539-011-0049-z

    Article  PubMed  Google Scholar 

  135. Murphy KT, Chee A, Gleeson BG, Naim T, Swiderski K, Koopman R, Lynch GS (2011) Antibody-directed myostatin inhibition enhances muscle mass and function in tumor-bearing mice. Am J Physiol Regul Integr Comp Physiol 301(3):R716–R726. doi:10.1152/ajpregu.00121.2011

    Article  CAS  PubMed  Google Scholar 

  136. 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(3):1548–1554. doi:10.1016/j.bbrc.2009.12.123

    Article  CAS  PubMed  Google Scholar 

  137. Gallot YS, Durieux AC, Castells J, Desgeorges MM, Vernus B, Plantureux L, Remond D, Jahnke VE, Lefai E, Dardevet D, Nemoz G, Schaeffer L, Bonnieu A, Freyssenet DG (2014) Myostatin gene inactivation prevents skeletal muscle wasting in cancer. Cancer Res 74(24):7344–7356. doi:10.1158/0008-5472.CAN-14-0057

    Article  CAS  PubMed  Google Scholar 

  138. Carroll J (2016) Novartis’ ‘breakthrough’ muscle drug bimagrumab flunks a late-stage trial. http://www.fiercebiotech.com/biotech/novartis-breakthrough-muscle-drug-bimagrumab-flunks-a-late-stage-trial. Accessed 21 Apr 2016

  139. Todorov P, Cariuk P, McDevitt T, Coles B, Fearon K, Tisdale M (1996) Characterization of a cancer cachectic factor. Nature 379(6567):739–742. doi:10.1038/379739a0

    Article  CAS  PubMed  Google Scholar 

  140. Hussey HJ, Todorov PT, Field WN, Inagaki N, Tanaka Y, Ishitsuka H, Tisdale MJ (2000) Effect of a fluorinated pyrimidine on cachexia and tumour growth in murine cachexia models: relationship with a proteolysis inducing factor. Br J Cancer 83(1):56–62. doi:10.1054/bjoc.2000.1278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Lorite MJ, Thompson MG, Drake JL, Carling G, Tisdale MJ (1998) Mechanism of muscle protein degradation induced by a cancer cachectic factor. Br J Cancer 78(7):850–856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Wyke SM, Tisdale MJ (2005) NF-kappaB mediates proteolysis-inducing factor induced protein degradation and expression of the ubiquitin-proteasome system in skeletal muscle. Br J Cancer 92(4):711–721. doi:10.1038/sj.bjc.6602402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Todorov PT, Field WN, Tisdale MJ (1999) Role of a proteolysis-inducing factor (PIF) in cachexia induced by a human melanoma (G361). Br J Cancer 80(11):1734–1737. doi:10.1038/sj.bjc.6690590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Tisdale MJ (2008) Re: Wieland BM et al. is there a human homologue to the murine proteolysis-inducing factor? Clin Cancer Res 14(7):2245; author reply 2245–2246. doi:10.1158/1078-0432.CCR-07-4769

  145. Wieland BM, Stewart GD, Skipworth RJ, Sangster K, Fearon KC, Ross JA, Reiman TJ, Easaw J, Mourtzakis M, Kumar V, Pak BJ, Calder K, Filippatos G, Kremastinos DT, Palcic M, Baracos VE (2007) Is there a human homologue to the murine proteolysis-inducing factor? Clin Cancer Res 13(17):4984–4992. doi:10.1158/1078-0432.CCR-07-0946

    Article  CAS  PubMed  Google Scholar 

  146. Case 27461 (1941) New Engl J Med 225:789–791

    Google Scholar 

  147. Moseley JM, Kubota M, Diefenbach-Jagger H, Wettenhall RE, Kemp BE, Suva LJ, Rodda CP, Ebeling PR, Hudson PJ, Zajac JD et al (1987) Parathyroid hormone-related protein purified from a human lung cancer cell line. Proc Natl Acad Sci U S A 84(14):5048–5052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Juppner H, Abou-Samra AB, Uneno S, Gu WX, Potts JT Jr, Segre GV (1988) The parathyroid hormone-like peptide associated with humoral hypercalcemia of malignancy and parathyroid hormone bind to the same receptor on the plasma membrane of ROS 17/2.8 cells. J Biol Chem 263(18):8557–8560

    CAS  PubMed  Google Scholar 

  149. Strewler GJ, Stern PH, Jacobs JW, Eveloff J, Klein RF, Leung SC, Rosenblatt M, Nissenson RA (1987) Parathyroid hormone like protein from human renal carcinoma cells. Structural and functional homology with parathyroid hormone. J Clin Invest 80(6):1803–1807. doi:10.1172/JCI113275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Orland SM, Stewart AF, Livolsi VA, Wein AJ (1986) Detection of the hypercalcemic hormone of malignancy in an adrenal cortical carcinoma. J Urol 136(5):1000–1002

    Article  CAS  PubMed  Google Scholar 

  151. Iguchi H, Onuma E, Sato K, Sato K, Ogata E (2001) Involvement of parathyroid hormone-related protein in experimental cachexia induced by a human lung cancer-derived cell line established from a bone metastasis specimen. Int J Cancer 94(1):24–27. doi:10.1002/ijc.1425

    Article  CAS  PubMed  Google Scholar 

  152. Petruzzelli M, Schweiger M, Schreiber R, Campos-Olivas R, Tsoli M, Allen J, Swarbrick M, Rose-John S, Rincon M, Robertson G, Zechner R, Wagner EF (2014) A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab 20(3):433–447. doi:10.1016/j.cmet.2014.06.011

    Article  CAS  PubMed  Google Scholar 

  153. Kir S, White JP, Kleiner S, Kazak L, Cohen P, Baracos VE, Spiegelman BM (2014) Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature 513(7516):100–104. doi:10.1038/nature13528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Bosaeus I, Daneryd P, Svanberg E, Lundholm K (2001) Dietary intake and resting energy expenditure in relation to weight loss in unselected cancer patients. Int J Cancer 93(3):380–383

    Article  CAS  PubMed  Google Scholar 

  155. Falconer JS, Fearon KC, Plester CE, Ross JA, Carter DC (1994) Cytokines, the acute-phase response, and resting energy expenditure in cachectic patients with pancreatic cancer. Ann Surg 219(4):325–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Fredrix EW, Soeters PB, Wouters EF, Deerenberg IM, von Meyenfeldt MF, Saris WH (1991) Effect of different tumor types on resting energy expenditure. Cancer Res 51(22):6138–6141

    CAS  PubMed  Google Scholar 

  157. Rigaud D, Hassid J, Meulemans A, Poupard AT, Boulier A (2000) A paradoxical increase in resting energy expenditure in malnourished patients near death: the king penguin syndrome. Am J Clin Nutr 72(2):355–360

    CAS  PubMed  Google Scholar 

  158. Zylicz Z, Schwantje O, Wagener DJ, Folgering HT (1990) Metabolic response to enteral food in different phases of cancer cachexia in rats. Oncology 47(1):87–91

    Article  CAS  PubMed  Google Scholar 

  159. Bennani-Baiti N, Walsh D (2011) Animal models of the cancer anorexia-cachexia syndrome. Support Care Cancer 19(9):1451–1463. doi:10.1007/s00520-010-0972-0

    Article  PubMed  Google Scholar 

  160. Hyltander A, Drott C, Korner U, Sandstrom R, Lundholm K (1991) Elevated energy expenditure in cancer patients with solid tumours. Eur J Cancer 27(1):9–15

    Article  CAS  PubMed  Google Scholar 

  161. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324(5930):1029–1033. doi:10.1126/science.1160809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Holroyde CP, Gabuzda TG, Putnam RC, Paul P, Reichard GA (1975) Altered glucose metabolism in metastatic carcinoma. Cancer Res 35(12):3710–3714

    CAS  PubMed  Google Scholar 

  163. Holroyde CP, Axelrod RS, Skutches CL, Haff AC, Paul P, Reichard GA (1979) Lactate metabolism in patients with metastatic colorectal cancer. Cancer Res 39(12):4900–4904

    CAS  PubMed  Google Scholar 

  164. Shellock FG, Riedinger MS, Fishbein MC (1986) Brown adipose tissue in cancer patients: possible cause of cancer-induced cachexia. J Cancer Res Clin Oncol 111(1):82–85

    Article  CAS  PubMed  Google Scholar 

  165. van Hall G, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjerling P, Hiscock N, Moller K, Saltin B, Febbraio MA, Pedersen BK (2003) Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 88(7):3005–3010. doi:10.1210/jc.2002-021687

    Article  PubMed  CAS  Google Scholar 

  166. Kawakami M, Murase T, Ogawa H, Ishibashi S, Mori N, Takaku F, Shibata S (1987) Human recombinant TNF suppresses lipoprotein lipase activity and stimulates lipolysis in 3T3-L1 cells. J Biochem 101(2):331–338

    Article  CAS  PubMed  Google Scholar 

  167. Green A, Dobias SB, Walters DJ, Brasier AR (1994) Tumor necrosis factor increases the rate of lipolysis in primary cultures of adipocytes without altering levels of hormone-sensitive lipase. Endocrinology 134(6):2581–2588. doi:10.1210/endo.134.6.8194485

    Article  CAS  PubMed  Google Scholar 

  168. Das SK, Eder S, Schauer S, Diwoky C, Temmel H, Guertl B, Gorkiewicz G, Tamilarasan KP, Kumari P, Trauner M, Zimmermann R, Vesely P, Haemmerle G, Zechner R, Hoefler G (2011) Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 333(6039):233–238. doi:10.1126/science.1198973

    Article  CAS  PubMed  Google Scholar 

  169. Son Y, Kim S, Chung HT, Pae HO (2013) Reactive oxygen species in the activation of MAP kinases. Methods Enzymol 528:27–48. doi:10.1016/B978-0-12-405881-1.00002-1

    Article  CAS  PubMed  Google Scholar 

  170. Muller FL, Song W, Liu Y, Chaudhuri A, Pieke-Dahl S, Strong R, Huang TT, Epstein CJ, Roberts LJ 2nd, Csete M, Faulkner JA, Van Remmen H (2006) Absence of CuZn superoxide dismutase leads to elevated oxidative stress and acceleration of age-dependent skeletal muscle atrophy. Free Radic Biol Med 40(11):1993–2004. doi:10.1016/j.freeradbiomed.2006.01.036

    Article  CAS  PubMed  Google Scholar 

  171. Gomes-Marcondes MC, Tisdale MJ (2002) Induction of protein catabolism and the ubiquitin-proteasome pathway by mild oxidative stress. Cancer Lett 180(1):69–74

    Article  CAS  PubMed  Google Scholar 

  172. Solheim TS, Fearon KC, Blum D, Kaasa S (2013) Non-steroidal anti-inflammatory treatment in cancer cachexia: a systematic literature review. Acta Oncol 52(1):6–17. doi:10.3109/0284186X.2012.724536

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ng Shyh-Chang .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Shyh-Chang, N. (2017). Metabolic Changes During Cancer Cachexia Pathogenesis. In: Song, E., Hu, H. (eds) Translational Research in Breast Cancer. Advances in Experimental Medicine and Biology, vol 1026. Springer, Singapore. https://doi.org/10.1007/978-981-10-6020-5_11

Download citation

Publish with us

Policies and ethics