Development and progression of cancer cachexia: Perspectives from bench to bedside

Abstract

Cancer cachexia (CC) is a devastating syndrome characterized by weight loss, reduced fat mass and muscle mass that affects approximately 80% of cancer patients and is responsible for 22%-30% of cancer-associated deaths. Understanding underlying mechanisms for the development of CC are crucial to advance therapies to treat CC and improve cancer outcomes. CC is a multi-organ syndrome that results in extensive skeletal muscle and adipose tissue wasting; however, CC can impair other organs such as the liver, heart, brain, and bone as well. A considerable amount of CC research focuses on changes that occur within the muscle, but cancer-related impairments in other organ systems are understudied. Furthermore, metabolic changes in organ systems other than muscle may contribute to CC. Therefore, the purpose of this review is to address degenerative mechanisms which occur during CC from a whole-body perspective. Outlining the information known about metabolic changes that occur in response to cancer is necessary to develop and enhance therapies to treat CC. As much of the current evidences in CC are from pre-clinical models we should note the majority of the data reviewed here are from pre-clinical models.

Keywords

Muscle atrophy / Tumor-bearing mouse / Lewis lung carcinoma / Protein turnover / Mitochondrial dysfunction

Authors’ contribution

Seongkyun Lim and Jacob L. Brown wrote/edited the manuscript. Tyrone A. Washington and Nicholas P. Greene edited/revised/approved of manuscript.

Conflict of interest

The authors declare no financial or other conflicts of interest that could influence the interpretations of this work.

References

[1] J. Ferlay, I. Soerjomataram, R. Dikshit, et al.. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Canc, 136 (5) (Mar 1 2015), pp. E359-E386, DOI: 10.1002/ijc.29210

[2] F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, A. Jemal. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A Cancer J Clin, 68 (6) ( 2018), pp. 394-424, DOI: 10.3322/caac.21492

[3] C.H. Fearon Kenneth, J. Glass David, C. Guttridge Denis. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metabol, 16 (2) ( 8/8/2012), pp. 153-166, DOI: 10.1016/j.cmet.2012.06.011

[4] J.K. Onesti, D.C. Guttridge.Inflammation based regulation of cancer cachexia. BioMed Res Int, 2014 ( 2014), p. 168407, DOI: 10.1155/2014/16840710.1155/2014/168407

[5] B.D. Smith, G.L. Smith, A. Hurria, G.N. Hortobagyi, T.A. Buchholz. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol : Off. J. Am. Soc. Clin. Oncol., 27 (17) (Jun 10 2009), pp. 2758-2765, DOI: 10.1200/jco.2008.20.8983

[6] K. Fearon, F. Strasser, S.D. Anker, et al.. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol, 12 (5) (May 2011), pp. 489-495, DOI: 10.1016/S1470- 2045(10)70218-7

[7] T.W. Mattox. Cancer Cachexia: Cause, Diagnosis, and Treatment. Nutrition in Clinical Practice. vol. 32, official publication of the American Society for Parenteral and Enteral Nutrition (Oct 2017), pp. 599-606, DOI: 10.1177/0884533617722986. 5

[8] M.J. Tisdale. Cachexia in cancer patients. Nov. Nat Rev Canc, 2 (11) ( 2002), pp. 862-871. DOI: 10.1007/s00520-017-3902-6. DOI: 10.1038/nrc927

[9] E. Deluche, S. Leobon, J.C. Desport, L. Venat-Bouvet, J. Usseglio, N. Tubiana-Mathieu. Impact of body composition on outcome in patients with early breast cancer. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. Mar, 26 (3) ( 2018), pp. 861-868, DOI: 10.1007/s00520-017-3902-6

[10] P. Cormie, E.M. Zopf, X. Zhang, K.H. Schmitz. The impact of exercise on cancer mortality, recurrence, and treatment-related adverse effects. Jan. Epidemiol Rev, 39 (1) (1 2017), pp.71-92, DOI: 10.1093/epirev/mxx007

[11] G.R. Williams, H.N. Rier, A. McDonald, S.S. Shachar. Sarcopenia & aging in cancer. J Geriatr Oncol, 10 (3) (May 2019), pp.374-377, DOI: 10.1016/j.jgo.2018.10.009

[12] R.F. Dunne, B. Roussel, E. Culakova, et al.. Characterizing cancer cachexia in the geriatric oncology population. J Geriatr Oncol, 10 (3) (May 2019), pp.415-419, DOI: 10.1016/j.jgo.2018.08.008

[13] J.S. Temel, A.P. Abernethy, D.C. Currow, et al.. Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials. Lancet Oncol, 17 (4) ( 2016), pp. 519-531, DOI: 10.1016/S1470- 2045(15)00558-6. Apr

[14] T.S. Solheim, B.J.A. Laird, T.R. Balstad, et al.. A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancer. J Cachexia, Sarcopenia and Muscle, 8 (5) (Oct 2017), pp.778-788, DOI: 10.1002/jcsm.12201

[15] A. Maccio, C. Madeddu, G. Gramignano, et al.. A randomized phase III clinical trial of a combined treatment for cachexia in patients with gynecological cancers: evaluating the impact on metabolic and inflammatory profiles and quality of life. Gynecologic oncology, 124 (3) (Mar 2012), pp.417-425, DOI: 10.1016/j.ygyno.2011.12.435

[16] Y. Zhu, X. Shao, X. Wang, L. Liu, H. Liang. Sex disparities in cancer. Canc Lett, 466 ( 2019), pp. 35-38, DOI: 10.1016/j.canlet.2019.08.017

[17] M.E. Rosa-Caldwell, N.P. Greene. Muscle metabolism and atrophy: let's talk about sex. Biol Sex Differ, 10 (1) ( 2019), pp. 1-14, DOI: 10.1186/s13293-019-0257-3

[18] S. Rebecca, M.P.H. Siegel, D. Kimberly, M.P.H. Miller, D.V.M. Ahmedin Jemal. Cancer statistics. CA A Canc. J Clin., 67 (27) ( 2017), pp. 7-30, DOI: 10.3322/caac.21387

[19] M.B. Cook, S.M. Dawsey, N.D. Freedman, et al.. Sex disparities in cancer incidence by period and age. Canc Epidemiol Prevent Biomark, 18 (4) ( 2009), pp. 1174-1182, DOI: 10.1158/1055-9965.EPI-08-1118

[20] M.B. Cook, K.A. McGlynn, S.S. Devesa, N.D. Freedman, W.F. Anderson. Sex disparities in cancer mortality and survival. Cancer Epidemiol Biomark Prev, 20 (8) ( 2011), pp. 1629-1637, DOI: 10.1158/1055-9965.EPI-11-0246

[21] L.J. Anderson, H. Liu, J.M. Garcia. Sex Differences in Muscle Wasting. Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity. Springer ( 2017), pp. 153-197, DOI: 10.1007/978-3-319-70178-3_9

[22] O.M. Vagnildhaug, D. Blum, A. Wilcock, et al.. The applicability of a weight loss grading system in cancer cachexia: a longitudinal analysis. J Cachexia, Sarcopenia and Muscle, 8 (5) ( 2017), pp. 789-797, DOI: 10.1002/jcsm.12220

[23] V.E. Baracos, T. Reiman, M. Mourtzakis, I. Gioulbasanis, S. Antoun. Body composition in patients with non- small cell lung cancer: a contemporary view of cancer cachexia with the use of computed tomography image analysis. Am J Clin Nutr, 91 (4) ( 2010), pp. 1133S-1137S, DOI: 10.3945/ajcn.2010.28608C

[24] K. Amano, I. Maeda, T. Morita, et al.. C-reactive protein, symptoms and activity of daily living in patients with advanced cancer receiving palliative care. J Cachexia, Sarcopenia Muscle, 8 (3) ( 2017), pp. 457-465, DOI: 10.1002/jcsm.12184. Jun

[25] Z. Stojcev, K. Matysiak, M. Duszewski, T. Banasiewicz. The role of dietary nutrition in stomach cancer. Contemp Oncol, 17 (4) ( 2013), pp. 343-345, DOI: 10.5114/wo.2013.37213

[26] A. Laine, P. Iyengar, T.K. Pandita. The role of inflammatory pathways in cancer-associated cachexia and radiation resistance. Mol Canc Res, 11 (9) ( 2013), pp. 967-972, DOI: 10.1158/1541-7786.MCR-13-0189

[27] G.B. Stene, T.R. Balstad, A.S.M. Leer, et al.. Deterioration in muscle mass and physical function differs according to weight loss history in cancer cachexia. Cancers, 11 (12) (Dec 3 2019), DOI: 10.3390/cancers11121925

[28] A. Dolly, J.F. Dumas, S. Servais. Cancer cachexia and skeletal muscle atrophy in clinical studies: what do we really know?. J Cachexia, Sarcopenia and Muscle ( 2020), DOI: 10.1002/jcsm.12633

[29] M.E. Rosa-Caldwell, D.K. Fix, T.A. Washington, N.P. Greene. Muscle alterations in the development and progression of cancer-induced muscle atrophy: a review. J Appl Physiol, 128 (1) ( 2020), pp. 25-41, DOI: 10.1152/japplphysiol.00622.2019

[30] E.E. Talbert, M.C. Cuitiño, K.J. Ladner, et al.. Modeling human cancer-induced cachexia. Cell Rep, 28 (6) ( 2019), pp. 1612-1622, DOI: 10.1016/j.celrep.2019.07.016

[31] A. Loumaye, J.P. Thissen. Biomarkers of cancer cachexia. Clin Biochem, 50 (18) (Dec 2017), pp.1281-1288, DOI: 10.1016/j.clinbiochem.2017.07.011

[32] R.F. Dunne, K.M. Mustian, J.M. Garcia, et al.. Research priorities in cancer cachexia: the university of rochester cancer center NCI community oncology research Program (NCORP) research base symposium on cancer cachexia and sarcopenia. Curr Opin Support Palliat Care, 11 (4) ( 2017), p. 278, DOI: 10.1097/SPC.0000000000000301

[33] E.E. Talbert, H.L. Lewis, M.R. Farren, et al.. Circulating monocyte chemoattractant protein-1 (MCP-1) is associated with cachexia in treatment-naïve pancreatic cancer patients. J Cachexia, Sarcopenia and Muscle, 9 (2) ( 2018), pp. 358-368, DOI: 10.1097/SPC.0000000000000301

[34] J.M. Chakedis, M.E. Dillhoff, C.R. Schmidt, et al.. Plasma ceramides as a sexually dimorphic biomarker of pancreatic cancer-induced cachexia. medRxiv (2020), DOI: 10.1101/2020.06.01.20111492

[35] J.A. Carson, K.A. Baltgalvis. Interleukin 6 as a key regulator of muscle mass during cachexia. Exerc Sport Sci Rev, 38 (4) (Oct 2010), pp.168-176, DOI: 10.1097/JES.0b013e3181f44f11

[36] D.E. Lee, J.L. Brown, M.E. Rosa-Caldwell, et al.. Cancer cachexia-induced muscle atrophy: evidence for alterations in microRNAs important for muscle size. Physiol Genom, 49 (5) ( 2017), pp. 253-260, DOI: 10.1152/physiolgenomics.00006.2017

[37] M.J. Puppa, J.P. White, S. Sato, M. Cairns, J.W. Baynes, J.A. Carson. Gut barrier dysfunction in the Apc(Min/+) mouse model of colon cancer cachexia. Biochim Biophys Acta, 1812 (12) (Dec 2011), pp.1601-1606, DOI: 10.1016/j.bbadis.2011.08.010

[38] T.A. Zimmers, M.L. Fishel, A. Bonetto. STAT3 in the systemic inflammation of cancer cachexia. Semin Cell Dev Biol, 54 (Jun 2016), pp.28-41, DOI: 10.1016/j.semcdb.2016.02.009

[39] J.P. White, M.J. Puppa, S. Sato, et al.. IL-6 regulation on skeletal muscle mitochondrial remodeling during cancer cachexia in the ApcMin/+ mouse. Skeletal Muscle, 2 ( 2012), p. 14, DOI: 10.1186/2044-5040-2-14

[40] A.L. Serrano, B. Baeza-Raja, E. Perdiguero, M. Jardi, P. Munoz-Canoves. Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy. Cell Metabol, 7 (1) (Jan 2008), pp.33-44, DOI: 10.1152/ajpendo.00410.2012

[41] J.P. White, M.J. Puppa, S. Gao, S. Sato, S.L. Welle, J.A. Carson.Muscle mTORC1 suppression by IL-6 during cancer cachexia: a role for AMPK. Am J Physiol Endocrinol Metabol, 304 (10) ( 2013), pp. E1042-E1052, DOI: 10.1016/j. cmet.2007.11.011

[42] D.K. Fix, B.N. VanderVeen, B.R. Counts, J.A. Carson.Regulation of skeletal muscle DRP-1 and FIS-1 protein expression by IL-6 signaling. Oxid Med Cell Longev, 2019 ( 2019), p. 8908457, DOI: 10.1155/2019/8908457

[43] B.N. VanderVeen, D.K. Fix, J.A. Carson.Disrupted skeletal muscle mitochondrial dynamics, mitophagy, and biogenesis during cancer cachexia: a role for inflammation. Oxid Med Cell Longev ( 2017), p. 3292087, DOI: 10.1155/2017/3292087. 2017

[44] K.L. Hetzler, J.P. Hardee, M.J. Puppa, et al.. Sex differences in the relationship of IL-6 signaling to cancer cachexia progression. Biochim Biophys Acta, 1852 (5) (May 2015), pp.816-825, DOI: 10.1016/j.bbadis.2014.12.015

[45] S. Lim, K.R. Dunlap, M.E. Rosa-Caldwell, et al.. Comparative plasma proteomics in muscle atrophy during cancer-cachexia and disuse: the search for atrokines. Physiol Rep, 8 (19) ( 2020), Article e14608, DOI: 10.14814/phy2.14608

[46] M.L. Ramsey, E. Talbert, D. Ahn, et al.. Circulating interleukin-6 is associated with disease progression, but not cachexia in pancreatic cancer. Pancreatology : official journal of the International Association of Pancreatology (IAP), 19 (1) ( 2019), pp. 80-87, DOI: 10.1016/j.pan.2018.11.002. [et al.]. Jan

[47] M. Constantinou, J.Y. Tsai, H. Safran. Paclitaxel and concurrent radiation in upper gastrointestinal cancers. Canc Invest, 21 (6) ( 2003), pp. 887-896, DOI: 10.1081/CNV-120025092

[48] E.L. Beard Jr.. The american society of health system pharmacists. JONA's Healthc Law, Ethics, Regul, 3 (3) ( 2001), pp. 78-79

[49] J.M. Canada, C.R. Trankle, S. Carbone, et al.. Determinants of cardiorespiratory fitness following thoracic radiotherapy in lung or breast cancer survivors. Am J Cardiol (Dec 26 2019), DOI: 10.1016/j.amjcard.2019.12.019

[50] S. Sasaki, E. Oki, H. Saeki, et al.. Skeletal muscle loss during systemic chemotherapy for colorectal cancer indicates treatment response: a pooled analysis of a multicenter clinical trial (KSCC 1605-A). Int J Clin Oncol, 24 (10) (Oct 2019), pp.1204-1213, DOI: 10.1007/s10147-019-01460-8

[51] Z. Ghoreishi, A. Esfahani, A. Djazayeri, et al.. Omega-3 fatty acids are protective against paclitaxel-induced peripheral neuropathy: a randomized double-blind placebo controlled trial. BMC Canc, 12 (1) ( 2012), p. 355, DOI: 10.1186/1471-2407-12-355

[52] Y. Han, M.T. Smith.Pathobiology of cancer chemotherapy-induced peripheral neuropathy (CIPN). Front Pharmacol, 4 (Dec 18 2013), p. 156, DOI: 10.3389/fphar.2013.00156

[53] F.C. Howarth, S.C. Calaghan, M.R. Boyett, E. White.Effect of the microtubule polymerizing agent taxol on contraction, Ca2+ transient and L-type Ca2+ current in rat ventricular myocytes. J Physiol, 516 (Pt 2) ( 1999), p. 409, DOI: 10.1111/j.1469-7793.1999.0409v.x

[54] S. Konishi, S. Kishida. Studies on the morphological changes of skeletal muscle induced by vincristine, vinblastine and colchicine. Bull Osaka Med Sch, 30 (1) (Jul 1984), pp.19-40.

[55] R. Barreto, G. Mandili, F.A. Witzmann, F. Novelli, T.A. Zimmers, A. Bonetto.Cancer and chemotherapy contribute to muscle loss by activating common signaling pathways. Front Physiol, 7 ( 2016), p. 472, DOI: 10.3389/fphys.2016.00472

[56] J.G. Le-Rademacher, J. Crawford, W.J. Evans, A. Jatoi. Overcoming obstacles in the design of cancer anorexia/weight loss trials. Crit Rev Oncol-Hematol, 117 ( 2017), pp. 30-37, DOI: 10.1016/j.critrevonc.2017.06.008

[57] F.S. Lira, J.C.R. Neto, M. Seelaender. Exercise training as treatment in cancer cachexia. Appl Physiol Nutr Metabol, 39 (6) ( 2014), pp. 679-686, DOI: 10.1139/apnm-2013-0554

[58] M. Halle, M.H. Schoenberg.Physical activity in the prevention and treatment of colorectal carcinoma. Deutsches Ärzteblatt Int, 106 (44) ( 2009), p. 722, DOI: 10.3238/arztebl.2009.0722

[59] A. Fanzani, V.M. Conraads, F. Penna, W. Martinet. Molecular and cellular mechanisms of skeletal muscle atrophy: an update. J Cachexia, Sarcopenia and Muscle, 3 (3) ( 2012), pp. 163-179, DOI: 10.1007/s13539-012-0074-6

[60] K.L. Smith, M.J. Tisdale. Increased protein degradation and decreased protein synthesis in skeletal muscle during cancer cachexia. Br J Canc, 67 (4) ( 1993), pp. 680-685, DOI: 10.1038/bjc.1993.126. Apr

[61] J.P. White, J.W. Baynes, S.L. Welle, et al.. The regulation of skeletal muscle protein turnover during the progression of cancer cachexia in the Apc Min/+ mouse. PloS One, 6 (9) ( 2011), Article e24650, DOI: 10.1371/journal.pone.0024650

[62] J.L. Brown, D.E. Lee, M.E. Rosa-Caldwell, et al.. Protein imbalance in the development of skeletal muscle wasting in tumour-bearing mice. J Cachexia, Sarcopenia and Muscle, 9 (5) (Oct 2018), pp.987-1002, DOI: 10.1002/jcsm.12354

[63] J.L. Brown, M.M. Lawrence, B. Ahn, et al.. Cancer cachexia in a mouse model of oxidative stress. J Cachexia, Sarcopenia and Muscle ( 2020/09/ 12 2020), DOI: 10.1002/jcsm.12615

[64] M. Sandri. Protein breakdown in muscle wasting: role of autophagy-lysosome and ubiquitin-proteasome. Int J Biochem Cell Biol, 45 (10) ( 2013), pp. 2121-2129, DOI: 10.1016/j.biocel.2013.04.023

[65] Y. Xie, A. Varshavsky. Physical association of ubiquitin ligases and the 26S proteasome. Proc Natl Acad Sci Unit States Am, 97 (6) ( 2000), pp. 2497-2502, DOI: 10.1073/pnas.060025497

[66] S.C. Bodine, E. Latres, S. Baumhueter, et al.. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science, 294 (5547) ( 2001), pp. 1704-1708, DOI: 10.1126/science.1065874

[67] M.D. Gomes, S.H. Lecker, R.T. Jagoe, A. Navon, A.L. Goldberg. Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci Unit States Am, 98 (25) ( 2001), pp. 14440-14445, DOI: 10.1073/pnas.251541198

[68] M.D. Petroski, R.J. Deshaies. Mechanism of lysine 48-linked ubiquitin-chain synthesis by the cullin-RING ubiquitin-ligase complex SCF-Cdc34. Cell, 123 (6) ( 2005), pp. 1107-1120, DOI: 10.1016/j.cell.2005.09.033

[69] F. Yamao. Ubiquitin system: selectivity and timing of protein destruction. J Biochem, 125 (2) ( 1999), pp. 223-229, DOI: 10.1093/oxfordjournals.jbchem.a022277

[70] J.T. Winston, D.M. Koepp, C. Zhu, S.J. Elledge, J.W. Harper. A family of mammalian F-box proteins. Curr Biol, 9 (20) ( 1999), DOI: 10.1016/S0960-9822(00)80021-4. 1180-S3

[71] R.A. Seaborne, D.C. Hughes, D.C. Turner, et al.. UBR5 is a novel E 3 ubiquitin ligase involved in skeletal muscle hypertrophy and recovery from atrophy. J Physiol, 597 (14) (Jul 2019), pp.3727-3749, DOI: 10.1113/JP278073

[72] S. Cohen, J.J. Brault, S.P. Gygi, et al.. During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation. JCB (J Cell Biol), 185 (6) ( 2009), pp. 1083-1095, DOI: 10.1083/jcb.200901052

[73] J. Zhao, Y. Zhang, W. Zhao, et al.. Effects of nandrolone on denervation atrophy depend upon time after nerve transection. Muscle Nerve: Off J Am Assoc Electrodiag Med, 37 (1) ( 2008), pp. 42-49, DOI: 10.1002/mus.20888

[74] J.P. White, M.J. Puppa, A. Narsale, J.A. Carson. Characterization of the male ApcMin/+ mouse as a hypogonadism model related to cancer cachexia. Biol Open, 2 (12) (Dec 15 2013), pp. 1346-1353, DOI: 10.1242/bio.20136544

[75] A.J. MacDonald, N. Johns, N. Stephens, et al.. Habitual myofibrillar protein synthesis is normal in patients with upper GI cancer cachexia. Clin Canc Res, 21 (7) (Apr 1 2015), pp. 1734-1740, DOI: 10.1158/1078-0432.CCR-14-2004

[76] S.C. Bodine, T.N. Stitt, M. Gonzalez, et al.. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol, 3 (11) ( 2001), pp. 1014-1019, DOI: 10.1038/ncb1101-1014

[77] S.C. Bodine. mTOR signaling and the molecular adaptation to resistance exercise. Med Sci Sports Exerc, 38 (11) ( 2006), pp. 1950-1957, DOI: 10.1249/01.mss.0000233797.24035.35

[78] T. Preiss,W. Hentze M. Starting the protein synthesis machine: eukaryotic translation initiation. Bioessays, 25 (12) ( 2003), pp. 1201-1211, DOI: 10.1002/bies.10362

[79] T.R. Peterson, M. Laplante, C.C. Thoreen, et al.. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell, 137 (5) ( 2009), pp. 873-886, DOI: 10.1016/j.cell.2009.03.046

[80] B.S. Gordon, J.L. Steiner, C.H. Lang, L.S. Jefferson, S.R. Kimball. Reduced REDD1 expression contributes to activation of mTORC1 following electrically induced muscle contraction. Am J Physiol Endocrinol Metabol, 307 (8) ( 2014), pp. E703-E711, DOI: 10.1152/ajpendo.00250.2014

[81] M. Bossola, E. Marzetti, F. Rosa, F. Pacelli. Skeletal muscle regeneration in cancer cachexia. Clin Exp Pharmacol Physiol, 43 (5) ( 2016), pp. 522-527, DOI: 10.1111/1440-1681.12559

[82] E.E. Talbert, D.C. Guttridge. Impaired regeneration: a role for the muscle microenvironment in cancer cachexia. Semin Cell Dev Biol, 54 (Jun 2016), pp.82-91, DOI: 10.1016/j.semcdb.2015.09.009

[83] W.A. He, E. Berardi, V.M. Cardillo, et al.. NF-κB-mediated Pax 7 dysregulation in the muscle microenvironment promotes cancer cachexia. J Clin Invest, 123 (11) ( 2013), pp. 4821-4835, DOI: 10.1172/JCI68523

[84] J.L. Brown, M.E. Rosa-Caldwell, D.E. Lee, et al.. Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing mice. J Cachexia, Sarcopenia and Muscle, 8 (6) ( 2017), pp. 926-938, DOI: 10.1002/jcsm.12232

[85] D.C. Wallace. Mitochondrial genetic medicine. Nat Genet, 50 (12) (Dec 2018), pp.1642-1649, DOI: 10.1038/s41588-018-0264-z

[86] J.M. Argilés, F.J. López-Soriano, S. Busquets. Muscle wasting in cancer: the role of mitochondria. Curr Opin Clin Nutr Metab Care, 18 (3) ( 2015), pp. 221-225, DOI: 10.1097/MCO.0000000000000164

[87] A.A. Tzika, C.C. Fontes-Oliveira, A.A. Shestov, et al.. Skeletal muscle mitochondrial uncoupling in a murine cancer cachexia model. Int J Oncol, 43 (3) ( 2013), pp. 886-894, DOI: 10.3892/ijo.2013.1998

[88] B.A. Guigni, D.M. Callahan, T.W. Tourville, et al.. Skeletal muscle atrophy and dysfunction in breast cancer patients: role for chemotherapy-derived oxidant stress. Am J Physiol Cell Physiol, 315 (5) ( 2018), pp. C744-C756, DOI: 10.1152/ajpcell.00002.2018

[89] G.K. Sakellariou, T. Pearson, A.P. Lightfoot, et al.. Mitochondrial ROS regulate oxidative damage and mitophagy but not age-related muscle fiber atrophy. Sci Rep, 6 ( 2016), p. 33944, DOI: 10.1038/srep33944

[90] J. Ježek, K.F. Cooper, R. Strich. Reactive oxygen species and mitochondrial dynamics: the yin and yang of mitochondrial dysfunction and cancer progression. Antioxidants, 7 (1) ( 2018), p. 13, DOI: 10.3390/antiox7010013

[91] G.S. de Castro, E. Simoes, J.D.C.C. Lima, et al.. Human cachexia induces changes in mitochondria, autophagy and apoptosis in the skeletal muscle. Cancers, 11 (9) ( 2019), p. 1264, DOI: 10.3390/cancers11091264

[92] S.T. Russell, H. Eley, M.J. Tisdale. Role of reactive oxygen species in protein degradation in murine myotubes induced by proteolysis-inducing factor and angiotensin II. Cell Signal, 19 (8) ( 2007), pp. 1797-1806, DOI: 10.1016/j.cellsig.2007.04.003

[93] R.D. Kilgour, A. Vigano, B. Trutschnigg, E. Lucar, M. Borod, J.A. Morais. Handgrip strength predicts survival and is associated with markers of clinical and functional outcomes in advanced cancer patients. Support Care Canc, 21 (12) ( 2013), pp. 3261-3270, DOI: 10.1007/s00520-013-1894-4

[94] S. Al-Majid, D.O. McCarthy. Resistance exercise training attenuates wasting of the extensor digitorum longus muscle in mice bearing the colon-26 adenocarcinoma. Biol Res Nurs, 2 (3) ( 2001), pp. 155-166, DOI: 10.1177/109980040100200301

[95] B.N. VanderVeen, J.P. Hardee, D.K. Fix, J.A. Carson. Skeletal muscle function during the progression of cancer cachexia in the male ApcMin/+ mouse. J Appl Physiol, 124 (3) ( 2018), pp. 684-695, DOI: 10.1152/japplphysiol.00897.2017

[96] K.T. Murphy, A. Chee, J. Trieu, T. Naim, G.S. Lynch. Importance of functional and metabolic impairments in the characterization of the C-26 murine model of cancer cachexia. Dis Models & Mechan, 5 (4) ( 2012), pp. 533-545, DOI: 10.1242/dmm.008839

[97] R.I. Close. Dynamic properties of mammalian skeletal muscles. Physiol Rev, 52 (1) ( 1972), pp. 129-197, DOI: 10.1152/physrev.1972.52.1.129

[98] T. Van Eijden, S.J.J. Turkawski. Morphology and physiology of masticatory muscle motor units. Crit Rev Oral Biol Med, 12 (1) ( 2001), pp. 76-91, DOI: 10.1177/10454411010120010601

[99] S.T. Isaac, T.C. Tan, P. Polly. Endoplasmic reticulum stress, calcium dysregulation and altered protein translation: intersection of processes that contribute to cancer cachexia induced skeletal muscle wasting. Curr Drug Targets, 17 (10) ( 2016), pp. 1140-1146, DOI: 10.2174/1389450116666150416115721

[100] A.G. Szent-Györgyi. Calcium regulation of muscle contraction. Biophys J, 15 (7) ( 1975), pp. 707-723, DOI: 10.1016/S0006-3495(75)85849-8. Jul

[101] E.J. Griffiths, G.A. Rutter. Mitochondrial calcium as a key regulator of mitochondrial ATP production in mammalian cells. Biochim Biophys Acta Bioenerg, 1787 (11) ( 2009), pp. 1324-1333, DOI: 10.1016/j.bbabio.2009.01.019

[102] T.J. Patel, R.L. Lieber. Force transmission in skeletal muscle: from actomyosin to external tendons. Exerc Sport Sci Rev, 25 ( 1997), pp. 321-363.

[103] R.J. Bloch, H. Gonzalez-Serratos. Lateral force transmission across costameres in skeletal muscle. Exerc Sport Sci Rev, 31 (2) ( 2003), pp. 73-78, DOI: 10.1097/00003677-200304000-00004

[104] J.P. Hardee, J.E. Mangum, S. Gao, et al.. Eccentric contraction-induced myofiber growth in tumor-bearing mice. J Appl Physiol, 120 (1) ( 2016), pp. 29-37, DOI: 10.1152/japplphysiol.00416.2015

[105] M. Egeblad, Z. Werb. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Canc, 2 (3) ( 2002), pp. 161-174, DOI: 10.1038/nrc745. Mar

[106] R.D. Devine, S. Bicer, P.J. Reiser, M. Velten, L.E. Wold.Metalloproteinase expression is altered in cardiac and skeletal muscle in cancer cachexia. Am J Physiol Heart Circ Physiol, 309 (4) ( Aug 15 2015), pp. H685-H691, DOI: 10.1152/ajpheart.00106.2015

[107] S.M. Judge, R.L. Nosacka, D. Delitto, et al.. Skeletal muscle fibrosis in pancreatic cancer patients with respect to survival. JNCI Cancer Spectr, 2 (3) ( 2018), p. pky043, DOI: 10.1093/jncics/pky043

[108] R.N. Montalvo, B.R. Counts, J.A. Carson. Understanding sex differences in the regulation of cancer-induced muscle wasting. Curr Opin Support Palliat Care, 12 (4) (Dec 2018), pp.394-403, DOI: 10.1097/SPC.0000000000000380

[109] S. Oliván, A.C. Calvo, R. Manzano, P. Zaragoza, R. Osta. Sex differences in constitutive autophagy. BioMed Res Int, 2014 ( 2014), DOI: 10.1155/2014/652817

[110] M. Ogawa, T. Kitano, N. Kawata, et al.. Daidzein down-regulates ubiquitin-specific protease 19 expression through estrogen receptor β and increases skeletal muscle mass in young female mice. J Nutr Biochem, 49 ( 2017), pp. 63-70, DOI: 10.1016/j.jnutbio.2017.07.017

[111] M. Picard, D. Ritchie, M.M. Thomas, K.J. Wright, R.T. Hepple. Alterations in intrinsic mitochondrial function with aging are fiber type-specific and do not explain differential atrophy between muscles. Aging Cell, 10 (6) ( 2011), pp. 1047-1055, DOI: 10.1111/j.1474-9726.2011.00745.x

[112] Y. Itoh, R. Mackie, K. Kampf, et al.. Four core genotypes mouse model: localization of the Sry transgene and bioassay for testicular hormone levels. BMC Res Notes, 8 ( 2015), DOI: 10.1186/s13104-015-0986-2. 69-69

[113] B.N. VanderVeen, E.A. Murphy, J.A. Carson. The impact of immune cells on the skeletal muscle microenvironment during cancer cachexia. Review. Front Physiol, 11 (1037) (2020-August-31 2020), DOI: 10.3389/fphys.2020.01037

[114] J.K. Kays, S. Shahda, M. Stanley, et al.. Three cachexia phenotypes and the impact of fat-only loss on survival in FOLFIRINOX therapy for pancreatic cancer. J Cachexia, Sarcopenia and Muscle, 9 (4) ( 2018), pp. 673-684, DOI: 10.1002/jcsm.12307

[115] C. Drott, H. Persson, K. Lundholm. Cardiovascular and metabolic response to adrenaline infusion in weight-losing patients with and without cancer. Clin Physiol, 9 (5) (Oct 1989), pp.427-439, DOI: 10.1111/j.1475-097X.1989.tb00997.x

[116] C.R. Santos, A. Schulze. Lipid metabolism in cancer. FEBS J, 279 (15) (Aug 2012), pp.2610-2623, DOI: 10.1111/j.1742-4658.2012.08644.x

[117] F.G. Shellock, M.S. Riedinger, M.C. Fishbein. Brown adipose tissue in cancer patients: possible cause of cancer-induced cachexia. J Canc Res Clin Oncol, 111 (1) ( 1986), pp. 82-85, DOI: 10.1007/BF00402783

[118] S.L. Brooks, A.M. Neville, N.J. Rothwell, M.J. Stock, S. Wilson. Sympathetic activation of brown-adipose-tissue thermogenesis in cachexia. Biosci Rep, 1 (6) ( 1981), pp. 509-517, DOI: 10.1007/BF01121584

[119] C. Bing, M. Brown, P. King, P. Collins, M.J. Tisdale, G. Williams. Increased gene expression of brown fat uncoupling protein (UCP) 1 and skeletal muscle UCP2 and UCP3 in MAC16-induced cancer cachexia. Canc Res, 60 (9) ( 2000), pp. 2405-2410.

[120] S. Kir, J.P. White, S. Kleiner, et al.. Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature, 513 (7516) ( 2014), pp. 100-104, DOI: 10.1038/nature13528. Sep 4

[121] M. Petruzzelli, M. Schweiger, R. Schreiber, et al.. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metabol, 20 (3) ( Sep 2 2014), pp. 433-447, DOI: 10.1016/j.cmet.2014.06.011

[122] M. Tsoli, M. Moore, D. Burg, et al.. Activation of thermogenesis in brown adipose tissue and dysregulated lipid metabolism associated with cancer cachexia in mice. Canc Res, 72 (17) ( Sep 1 2012), pp. 4372-4382, DOI: 10.1158/0008-5472.CAN-11-3536

[123] P. Cohen, J.D. Levy, Y. Zhang, et al.. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell, 156 (1-2) ( 2014), pp. 304-316, DOI: 10.1016/j.cell.2013.12.021. Jan 16

[124] A.M. Ryan, D.G. Power, L. Daly, S.J. Cushen, Ní Bhuachalla Ē, C.M. Prado. Cancer-associated malnutrition, cachexia and sarcopenia: the skeleton in the hospital closet 40 years later. Proc Nutr Soc, 75 (2) (May 2016), pp.199-211, DOI: 10.1017/S002966511500419X

[125] M. Petruzzelli, E.F. Wagner. Mechanisms of metabolic dysfunction in cancer-associated cachexia. Genes Dev, 30 (5) ( 2016), pp. 489-501, DOI: 10.1101/gad.276733.115. Mar 1

[126] A.A. Narsale, R.T. Enos, M.J. Puppa, et al.. Liver inflammation and metabolic signaling in ApcMin/+ mice: the role of cachexia progression. PloS One, 10 (3) ( 2015), Article e0119888, DOI: 10.1371/journal.pone.0119888

[127] A.A. Narsale, M.J. Puppa, J.P. Hardee, et al.. Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in ApcMin/+ mice. Oncotarget, 7 (37) ( 2016), p. 59482, DOI: 10.18632/oncotarget.10699

[128] J.M. Argilés, B. Stemmler, F.J. López-Soriano, S. Busquets.Nonmuscle tissues contribution to cancer cachexia. Mediat Inflamm, 2015 ( 2015), p. 182872, DOI: 10.1155/2015/182872

[129] K. Hirai, O. Ishiko, M. Tisdale. Mechanism of depletion of liver glycogen in cancer cachexia. Biochem Biophys Res Commun, 241 (1) (Dec 8 1997), pp. 49-52, DOI: 10.1006/bbrc.1997.7732

[130] M.E. Rosa-Caldwell, J.L. Brown, D.E. Lee, et al.. Hepatic alterations during the development and progression of cancer cachexia. Appl Physiol Nutr Metabol ( 2019), DOI: 10.1139/apnm-2019-0407. (ja)

[131] A.A. Narsale, J.A. Carson.Role of IL-6 in cachexia-therapeutic implications. Curr Opin Support Palliat Care, 8 (4) ( 2014), p. 321, DOI: 10.1097/SPC.0000000000000091

[132] J.F. Dumas, C. Goupille, C.M. Julienne, et al.. Efficiency of oxidative phosphorylation in liver mitochondria is decreased in a rat model of peritoneal carcinosis. J Hepatol, 54 (2) ( 2011), pp. 320-327, DOI: 10.1016/j.jhep.2010.08.012. Feb

[133] G. Grasmann, E. Smolle, H. Olschewski, K. Leithner. Gluconeogenesis in cancer cells - repurposing of a starvation-induced metabolic pathway?. Biochim Biophys Acta Rev Canc, 1872 (1) (Aug 2019), pp.24-36, DOI: 10.1016/j.bbcan.2019.05.006

[134] G.P. Bongaerts, H.K. van Halteren, C.A. Verhagen, D.J. Wagener. Cancer cachexia demonstrates the energetic impact of gluconeogenesis in human metabolism. Med Hypotheses, 67 (5) ( 2006), pp. 1213-1222, DOI: 10.1016/j.mehy.2006.04.048

[135] H.S. Lai, J.C. Lee, P.H. Lee, S.T. Wang, W.J. Chen. Plasma free amino acid profile in cancer patients. Semin Canc Biol, 15 (4) (Aug 2005), pp.267-276, DOI: 10.1016/j.semcancer.2005.04.003

[136] P.E. Porporato. Understanding cachexia as a cancer metabolism syndrome. Oncogenesis, 5 (2) (Feb 22 2016), Article e200, DOI: 10.1038/oncsis.2016.3

[137] Centers for Disease Control and P. Leading causes of death 2012. Im Internet:.

[138] C.E. Hamo, M.W. Bloom.Cancer and heart failure: understanding the intersection. Card Fail Rev, 3 (1) ( 2017), p. 66, DOI: 10.15420/cfr. 2016:24:2

[139] C. de Miguel Sánchez, S.G. Elustondo, A. Estirado, et al.. Palliative performance status, heart rate and respiratory rate as predictive factors of survival time in terminally ill cancer patients. J Pain Symptom Manag, 31 (6) ( 2006), pp. 485-492, DOI: 10.1016/j.jpainsymman.2005.10.007

[140] N.D. Manne, M. Lima, R.T. Enos, P. Wehner, J.A. Carson, E. Blough. Altered cardiac muscle mTOR regulation during the progression of cancer cachexia in the ApcMin/+ mouse. Int J Oncol, 42 (6) (Jun 2013), pp.2134-2140, DOI: 10.3892/ijo.2013.1893

[141] M. Tian, Y. Nishijima, M.L. Asp, M.B. Stout, P.J. Reiser, M.A. Belury. Cardiac alterations in cancer-induced cachexia in mice. Int J Oncol, 37 (2) ( 2010), pp. 347-353, DOI: 10.3892/ijo_00000683

[142] P.F. Cosper, L.A. Leinwand. Cancer causes cardiac atrophy and autophagy in a sexually dimorphic manner. Canc Res, 71 (5) (Mar 1 2011), pp. 1710-1720, DOI: 10.1158/0008-5472.CAN-10-3145

[143] Lee DE, Brown JL, Rosa-Caldwell ME, et al. Cancer-induced cardiac atrophy adversely affects myocardial redox state and mitochondrial oxidative characteristics. JCSM Rapid Commun. DOI: 10.1002/rco2.18.

[144] S.F. Leibowitz, J.T. Alexander. Hypothalamic serotonin in control of eating behavior, meal size, and body weight. Biol Psychiatr, 44 (9) ( 1998), pp. 851-864, DOI: 10.1016/S0006-3223(98)00186-3

[145] M.M. Meguid, S.O. Fetissov, M. Varma, et al.. Hypothalamic dopamine and serotonin in the regulation of food intake. Nutrition, 16 (10) ( 2000), pp. 843-857, DOI: 10.1016/S0899-9007(00)00449-4

[146] M.J. Tisdale. Cancer anorexia and cachexia. Nutrition, 17 (5) ( 2001), pp. 438-442, DOI: 10.1016/S0899-9007(01)00506-8

[147] K. Fearon, J. Arends, V. Baracos. Understanding the mechanisms and treatment options in cancer cachexia. Nat Rev Clin Oncol, 10 (2) ( 2013), pp. 90-99, DOI: 10.1038/nrclinonc.2012.209

[148] C. Granda-Cameron, D. DeMille, M.P. Lynch, et al.. An interdisciplinary approach to manage cancer cachexia. Clin J Oncol Nurs, 14 (1) ( 2010), DOI: 10.1188/10.CJON.72-80

[149] A. Molfino, F. Rossi-Fanelli, A. Laviano. The interaction between pro-inflammatory cytokines and the nervous system. Nat Rev Canc, 3 (224) ( 2009), DOI: 10.1038/nrc2507-c1

[150] M. Coma, R. Vicente, S. Busquets, et al.. Impaired voltage-gated K+ channel expression in brain during experimental cancer cachexia. FEBS (Fed Eur Biochem Soc) Lett, 536 (1-3) (Feb 11 2003), pp. 45-50, DOI: 10.1016/S0014-5793(03)00009-7

[151] G.J. Bennett, T. Doyle, D. Salvemini. Mitotoxicity in distal symmetrical sensory peripheral neuropathies. Nat Rev Neurol, 10 (6) (Jun 2014), pp.326-336, DOI: 10.1038/nrneurol.2014.77

[152] T.A. Blackwell, I. Cervenka, B. Khatri, et al.. Transcriptomic analysis of the development of skeletal muscle atrophy in cancer-cachexia in tumor-bearing mice. Physiol Genom, 50 (12) (Dec 1 2018), pp. 1071-1082, DOI: 10.1152/physiolgenomics.00061.2018

[153] R.N. Montalvo, B.R. Counts, J.A. Carson. Understanding sex differences in the regulation of cancer-induced muscle wasting. Curr Opin Support Palliat Care, 12 (4) ( 2018), pp. 394-403, DOI: 10.1097/SPC.0000000000000380