Cancer Cachexia: Multilevel Metabolic Dysfunction

Overview

Journal Nat Metab

Publisher Springer Nature

Specialty Endocrinology

Date 2024 Nov 23

PMID 39578650

Authors

Mauricio Berriel Diaz

Maria Rohm

Stephan Herzig

Affiliations

Soon will be listed here.

Abstract

Cancer cachexia is a complex metabolic disorder marked by unintentional body weight loss or 'wasting' of body mass, driven by multiple aetiological factors operating at various levels. It is associated with many malignancies and significantly contributes to cancer-related morbidity and mortality. With emerging recognition of cancer as a systemic disease, there is increasing awareness that understanding and treatment of cancer cachexia may represent a crucial cornerstone for improved management of cancer. Here, we describe the metabolic changes contributing to body wasting in cachexia and explain how the entangled action of both tumour-derived and host-amplified processes induces these metabolic changes. We discuss energy homeostasis and possible ways that the presence of a tumour interferes with or hijacks physiological energy conservation pathways. In that context, we highlight the role played by metabolic cross-talk mechanisms in cachexia pathogenesis. Lastly, we elaborate on the challenges and opportunities in the treatment of this devastating paraneoplastic phenomenon that arise from the complex and multifaceted metabolic cross-talk mechanisms and provide a status on current and emerging therapeutic approaches.

Citing Articles

Metabolic Messengers: small extracellular vesicles.

Rohm T, Cunha E Rocha K, Olefsky J Nat Metab. 2025; 7(2):253-262.

PMID: 39920357 DOI: 10.1038/s42255-024-01214-5.

References

Evans W, Morley J, Argiles J, Bales C, Baracos V, Guttridge D . Cachexia: a new definition. Clin Nutr. 2008; 27(6):793-9. DOI: 10.1016/j.clnu.2008.06.013. View

Utech A, Tadros E, Hayes T, Garcia J . Predicting survival in cancer patients: the role of cachexia and hormonal, nutritional and inflammatory markers. J Cachexia Sarcopenia Muscle. 2012; 3(4):245-51. PMC: 3505579. DOI: 10.1007/s13539-012-0075-5. View

Fearon K, Glass D, Guttridge D . Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab. 2012; 16(2):153-66. DOI: 10.1016/j.cmet.2012.06.011. View

Han J, Harrison L, Patzelt L, Wu M, Junker D, Herzig S . Imaging modalities for diagnosis and monitoring of cancer cachexia. EJNMMI Res. 2021; 11(1):94. PMC: 8460705. DOI: 10.1186/s13550-021-00834-2. View

Babic A, Rosenthal M, Sundaresan T, Khalaf N, Lee V, Brais L . Adipose tissue and skeletal muscle wasting precede clinical diagnosis of pancreatic cancer. Nat Commun. 2023; 14(1):4317. PMC: 10354105. DOI: 10.1038/s41467-023-40024-3. View

Fearon K, Strasser F, Anker S, Bosaeus I, Bruera E, Fainsinger R . Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011; 12(5):489-95. DOI: 10.1016/S1470-2045(10)70218-7. View

Martin L, Senesse P, Gioulbasanis I, Antoun S, Bozzetti F, Deans C . Diagnostic criteria for the classification of cancer-associated weight loss. J Clin Oncol. 2014; 33(1):90-9. DOI: 10.1200/JCO.2014.56.1894. View

Chovsepian A, Prokopchuk O, Petrova G, Gjini T, Kuzi H, Heisz S . Diabetes increases mortality in patients with pancreatic and colorectal cancer by promoting cachexia and its associated inflammatory status. Mol Metab. 2023; 73:101729. PMC: 10192649. DOI: 10.1016/j.molmet.2023.101729. View

Talbert E, Cuitino M, Ladner K, Rajasekerea P, Siebert M, Shakya R . Modeling Human Cancer-induced Cachexia. Cell Rep. 2019; 28(6):1612-1622.e4. PMC: 6733019. DOI: 10.1016/j.celrep.2019.07.016. View

10.

Argiles J, Lopez-Soriano F, Toledo M, Betancourt A, Serpe R, Busquets S . The cachexia score (CASCO): a new tool for staging cachectic cancer patients. J Cachexia Sarcopenia Muscle. 2011; 2(2):87-93. PMC: 3117995. DOI: 10.1007/s13539-011-0027-5. View

11.

Morena da Silva F, Lim S, Cabrera A, Schrems E, Jones R, Rosa-Caldwell M . The time-course of cancer cachexia onset reveals biphasic transcriptional disruptions in female skeletal muscle distinct from males. BMC Genomics. 2023; 24(1):374. PMC: 10318789. DOI: 10.1186/s12864-023-09462-7. View

12.

Olaechea S, Sarver B, Liu A, Gilmore L, Alvarez C, Iyengar P . Race, Ethnicity, and Socioeconomic Factors as Determinants of Cachexia Incidence and Outcomes in a Retrospective Cohort of Patients With Gastrointestinal Tract Cancer. JCO Oncol Pract. 2023; 19(7):493-500. PMC: 10337717. DOI: 10.1200/OP.22.00674. View

13.

Martin L, Birdsell L, MacDonald N, Reiman T, Clandinin M, McCargar L . Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol. 2013; 31(12):1539-47. DOI: 10.1200/JCO.2012.45.2722. View

14.

Sandri M . Protein breakdown in cancer cachexia. Semin Cell Dev Biol. 2015; 54:11-9. DOI: 10.1016/j.semcdb.2015.11.002. View

15.

Lecker S, Jagoe R, Gilbert A, Gomes M, Baracos V, Bailey J . Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J. 2004; 18(1):39-51. DOI: 10.1096/fj.03-0610com. View

16.

Egerman M, Glass D . Signaling pathways controlling skeletal muscle mass. Crit Rev Biochem Mol Biol. 2013; 49(1):59-68. PMC: 3913083. DOI: 10.3109/10409238.2013.857291. View

17.

Neyroud D, Laitano O, Dasgupta A, Lopez C, Schmitt R, Schneider J . Blocking muscle wasting via deletion of the muscle-specific E3 ligase MuRF1 impedes pancreatic tumor growth. Commun Biol. 2023; 6(1):519. PMC: 10183033. DOI: 10.1038/s42003-023-04902-2. View

18.

Cai D, Frantz J, Tawa Jr N, Melendez P, Oh B, Lidov H . IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. Cell. 2004; 119(2):285-98. DOI: 10.1016/j.cell.2004.09.027. View

19.

Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A . Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 2004; 117(3):399-412. PMC: 3619734. DOI: 10.1016/s0092-8674(04)00400-3. View

20.

Zhao J, Brault J, 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(6):472-83. DOI: 10.1016/j.cmet.2007.11.004. View