CoChat
Sign Up
Cited by 111Muscle Physiology and DisordersNutrition and Health in AgingMuscle metabolism and nutrition

Molecular pathways: cachexia signaling-A targeted approach to cancer treatment

Open access
Miyamoto, Yuji, Hanna, Diana L., Zhang, Wu, Baba, Hideo, Lenz, Heinz-Josef·2016·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-16-0495PMC PMC4987228
Open this paper in CoChat — free account

Abstract

Cancer cachexia is a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass, which negatively affects quality of life and portends a poor prognosis. Numerous molecular substrates and mechanisms underlie the dysregulation of skeletal muscle synthesis and degradation observed in cancer cachexia, including proinflammatory cytokines (TNFα, IL1, and IL6), and the NF-κB, IGF1/AKT/mTOR, and myostatin/activin–SMAD pathways. Recent preclinical and clinical studies have demonstrated that anti-cachexia drugs (such as MABp1 and soluble receptor antagonist of myostatin/activin) not only prevent muscle wasting but also may prolong overall survival. In this review, we focus on the significance of cachexia signaling in patients with cancer and highlight promising drugs targeting tumor cachexia in clinical development. Clin Cancer Res; 22(16); 3999–4004. ©2016 AACR.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1158/1078-0432.ccr-16-0495

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Proinflammatory cytokines TNF-α, IL-6, and IFN-γ drive catabolic signaling associated with cachexia.

    “Proinflammatory cytokines, such as TNF-α, IL-6, and IFN-γ, drive catabolic signaling associated with cachexia”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Miyamoto et al., 2016

    The Background sections on cachexia pathways and cytokine-driven protein degradation link TNF-α and IL-6 to muscle-wasting signaling. They name IL-1, rather than IFN-γ, alongside those cytokines; a search for IFN-γ found no passage supporting that part of the claim. The indexed passages provide no page numbers. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 44

  1. [1]Fearon K Strasser F Anker SD Bosaeus I Bruera E Fainsinger RL Definition and classification of cancer cachexia: an international consensus Lancet Oncol 2011 12 489 95 21296615
  2. [2]Bruera E ABC of palliative care Anorexia, cachexia, and nutrition BMJ 1997 315 1219 22 9393230 PMC2127742
  3. [3]Wigmore SJ Plester CE Richardson RA Fearon KC Changes in nutritional status associated with unresectable pancreatic cancer Br J Cancer 1997 75 106 9 9000606 PMC2222706
  4. [4]Andreyev HJ Norman AR Oates J Cunningham D Why do patients with weight loss have a worse outcome when undergoing chemotherapy for gastrointestinal malignancies? Eur J Cancer 1998 34 503 9 9713300
  5. [5]Biolo G Cederholm T Muscaritoli M Muscle contractile and metabolic dysfunction is a common feature of sarcopenia of aging and chronic diseases: from sarcopenic obesity to cachexia Clin Nutr 2014 33 737 48 24785098
  6. [6]Tisdale MJ Reversing cachexia Cell 2010 142 511 2 20723750
  7. [8]Fearon KC Glass DJ Guttridge DC Cancer cachexia: mediators, signaling, and metabolic pathways Cell Metab 2012 16 153 66 22795476
  8. [9]Glickman MH Ciechanover A The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction Physiol Rev 2002 82 373 428 11917093
  9. [10]Zhao J Brault JJ Schild A Cao P Sandri M Schiaffino S FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells Cell Metab 2007 6 472 83 18054316
  10. [11]Hasselgren PO Wray C Mammen J Molecular regulation of muscle cachexia: it may be more than the proteasome Biochem Biophys Res Commun 2002 290 1 10 11779124
  11. [12]Narsale AA Carson JA Role of interleukin-6 in cachexia: therapeutic implications Curr Opin Support Palliat Care 2014 8 321 7 25319274 PMC4323347
  12. [13]Li YP Reid MB NF-kappaB mediates the protein loss induced by TNF-alpha in differentiated skeletal muscle myotubes Am J Physiol Regul Integr Comp Physiol 2000 279 R1165 70 11003979
  13. [14]Garcia-Martinez C Lopez-Soriano FJ Argiles JM Acute treatment with tumour necrosis factor-alpha induces changes in protein metabolism in rat skeletal muscle Mol Cell Biochem 1993 125 11 8 8264567
  14. [15]Fong Y Moldawer LL Marano M Wei H Barber A Manogue K Cachectin/TNF or IL-1 alpha induces cachexia with redistribution of body proteins Am J Physiol 1989 256 R659 65 2784290
  15. [16]Li YP Schwartz RJ Waddell ID Holloway BR Reid MB Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-kappaB activation in response to tumor necrosis factor alpha FASEB J 1998 12 871 80 9657527
  16. [17]Hunter RB Stevenson E Koncarevic A Mitchell-Felton H Essig DA Kandarian SC Activation of an alternative NF-kappaB pathway in skeletal muscle during disuse atrophy FASEB J 2002 16 529 38 11919155
  17. [19]Bonetto A Aydogdu T Jin X Zhang Z Zhan R Puzis L JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia Am J Physiol Endocrinol Metab 2012 303 E410 21 22669242 PMC3423125
  18. [21]Schuelke M Wagner KR Stolz LE Hubner C Riebel T Komen W Myostatin mutation associated with gross muscle hypertrophy in a child N Engl J Med 2004 350 2682 8 15215484
  19. [22]Chen YG Lui HM Lin SL Lee JM Ying SY Regulation of cell proliferation, apoptosis, and carcinogenesis by activin Exp Biol Med (Maywood) 2002 227 75 87 11815670
  20. [23]Chen YG Wang Q Lin SL Chang CD Chuang J Ying SY Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis Exp Biol Med (Maywood) 2006 231 534 44 16636301
  21. [24]Sartori R Milan G Patron M Mammucari C Blaauw B Abraham R Smad2 and 3 transcription factors control muscle mass in adulthood Am J Physiol Cell Physiol 2009 296 C1248 57 19357234
  22. [25]Sacheck JM Ohtsuka A McLary SC Goldberg AL IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1 Am J Physiol Endocrinol Metab 2004 287 E591 601 15100091
  23. [26]Rommel C Bodine SC Clarke BA Rossman R Nunez L Stitt TN Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways Nat Cell Biol 2001 3 1009 13 11715022
  24. [28]Calnan DR Brunet A The FoxO code Oncogene 2008 27 2276 88 18391970
  25. [29]Sartori R Gregorevic P Sandri M TGFbeta and BMP signaling in skeletal muscle: potential significance for muscle-related disease Trends Endocrinol Metab 2014 25 464 71 25042839
  26. [31]Lok C Cachexia: the last illness Nature 2015 528 182 3 26659165
  27. [32]Argiles JM Lopez-Soriano FJ Catabolic proinflammatory cytokines Curr Opin Clin Nutr Metab Care 1998 1 245 51 10565356
  28. [33]Torelli GF Meguid MM Moldawer LL Edwards CK 3rd Kim HJ Carter JL Use of recombinant human soluble TNF receptor in anorectic tumor-bearing rats Am J Physiol 1999 277 R850 5 10484503
  29. [34]Jatoi A Dakhil SR Nguyen PL Sloan JA Kugler JW Rowland KM Jr A placebo-controlled double blind trial of etanercept for the cancer anorexia/weight loss syndrome: results from N00C1 from the North Central Cancer Treatment Group Cancer 2007 110 1396 403 17674351
  30. [35]Jatoi A Ritter HL Dueck A Nguyen PL Nikcevich DA Luyun RF 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 2010 68 234 9 19665818 PMC5951722
  31. [36]Wiedenmann B Malfertheiner P Friess H Ritch P Arseneau J Mantovani G A multicenter, phase II study of infliximab plus gemcitabine in pancreatic cancer cachexia J Support Oncol 2008 6 18 25 18257397
  32. [37]Johnston AJ Murphy KT Jenkinson L Laine D Emmrich K Faou P Targeting of Fn14 prevents cancer-induced cachexia and prolongs survival Cell 2015 162 1365 78 26359988
  33. [38]Hong DS Hui D Bruera E Janku F Naing A Falchook GS MABp1, a first-in-class true human antibody targeting interleukin-1alpha in refractory cancers: an open-label, phase 1 dose-escalation and expansion study Lancet Oncol 2014 15 656 66 24746841
  34. [43]Padrao AI Oliveira P Vitorino R Colaco B Pires MJ Marquez M Bladder cancer-induced skeletal muscle wasting: disclosing the role of mitochondria plasticity Int J Biochem Cell Biol 2013 45 1399 409 23608519
  35. [44]Loumaye A de Barsy M Nachit M Lause P Frateur L van Maanen A Role of Activin A and myostatin in human cancer cachexia J Clin Endocrinol Metab 2015 100 2030 8 25751105
  36. [45]Busquets S Toledo M Orpi M Massa D Porta M Capdevila E 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 2012 3 37 43 22450815 PMC3302990
  37. [46]Benny Klimek ME Aydogdu T Link MJ Pons M Koniaris LG Zimmers TA Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia Biochem Biophys Res Commun 2010 391 1548 1554 20036643
  38. [47]Zhou X Wang JL Lu J Song Y Kwak KS Jiao Q Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival Cell 2010 142 531 43 20723755
  39. [48]Murphy KT Chee A Gleeson BG Naim T Swiderski K Koopman R Antibody-directed myostatin inhibition enhances muscle mass and function in tumor-bearing mice Am J Physiol Regul Integr Comp Physiol 2011 301 R716 26 21677277
  40. [50]Amato AA Sivakumar K Goyal N David WS Salajegheh M Praestgaard J Treatment of sporadic inclusion body myositis with bimagrumab Neurology 2014 83 2239 46 25381300 PMC4277670
  41. [51]Aversa Z Bonetto A Penna F Costelli P Di Rienzo G Lacitignola A Changes in myostatin signaling in non-weight-losing cancer patients Ann Surg Oncol 2012 19 1350 6 21519918
  42. [52]Gallot YS Durieux AC Castells J Desgeorges MM Vernus B Plantureux L Myostatin gene inactivation prevents skeletal muscle wasting in cancer Cancer Res 2014 74 7344 56 25336187
  43. [53]Toledo M Busquets S Penna F Zhou X Marmonti E Betancourt A Complete reversal of muscle wasting in experimental cancer cachexia: additive effects of activin type II receptor inhibition and beta-2 agonist Int J Cancer 2016 138 2021 9 26595367
  44. [54]Mori S Matsuzaki K Yoshida K Furukawa F Tahashi Y Yamagata H TGF-beta and HGF transmit the signals through JNK-dependent Smad2/3 phosphorylation at the linker regions Oncogene 2004 23 7416 29 15326485

Cited by

Sorted by citations

Authors
Miyamoto, Y., Hanna, D. L., Zhang, W., Baba, H., & Lenz, H.-J.
Affiliations
  • University of Southern California (US)
  • Kumamoto University (JP)
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2016-08-14
Volume
22
Issue
16
Pages
3999-4004
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-16-0495
PMC
PMC4987228
OpenAlex
W2470158267
Cited by
111
References
5
Citations by year
2026: 8 · 2025: 7 · 2024: 8 · 2023: 12 · 2022: 16 · 2021: 10 · 2020: 18 · 2019: 7 · 2018: 14 · 2017: 8 · 2016: 2
FWCI
0.94
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (R01CA166161, P30CA014089)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
Keywords
cancer cachexia, skeletal muscle atrophy, inflammatory cytokines, NF-κB signaling, Smad signaling
MeSH terms
Animals, Antineoplastic Agents, Cachexia, Clinical Trials as Topic, Humans, Muscular Atrophy, Neoplasms, Signal Transduction, Biomarkers, Cytokines, Muscle, Skeletal, Muscle Development, Translational Research, Biomedical, Molecular Targeted Therapy, Proteolysis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review