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Cancer cachexia: multilevel metabolic dysfunction

Nature Metabolism volume 6, pages 2222–2245 (2024)Cite this article

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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.

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Fig. 1: Three mechanistic levels of cancer cachexia pathogenesis.
Fig. 2: Intracellular processes contributing to muscle wasting in cancer cachexia.
Fig. 3: Intracellular processes contributing to adipose tissue wasting in cancer cachexia.
Fig. 4: Tumour-derived and host-derived cachexia mediators induce wasting-related processes in various organs.
Fig. 5: Metabolite and energy substrate exchange in cancer cachexia tissue cross-talk networks.
Fig. 6: Circular plot summarizing tissue cross-talk connections in cancer cachexia.

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Acknowledgements

We thank L. Harrison for proofreading the manuscript and preparing the figures. This work was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (949017) to M.R. and a grant from the Else-Kröner-Fresenius-Stiftung (2020 EKSE.23), as well as the Edith-Haberland-Wagner Stiftung to S.H.

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  1. These authors contributed equally: Mauricio Berriel Diaz, Maria Rohm, Stephan Herzig.

Authors and Affiliations

  1. Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany

    Mauricio Berriel Diaz, Maria Rohm & Stephan Herzig

  2. Joint Heidelberg-IDC Translational Diabetes Program, Department of Inner Medicine, Heidelberg University Hospital, Heidelberg, Germany

    Mauricio Berriel Diaz, Maria Rohm & Stephan Herzig

  3. German Center for Diabetes Research (DZD), Neuherberg, Germany

    Mauricio Berriel Diaz, Maria Rohm & Stephan Herzig

  4. Chair Molecular Metabolic Control, Technical University of Munich, Munich, Germany

    Stephan Herzig

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M.B.D., M.R. and S.H. elaborated the concept and contributed equally to writing and revising the manuscript.

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S.H. serves on the Scientific Advisory Board of Actimed Therapeutics (United Kingdom). The remaining authors declare no competing interests.

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Berriel Diaz, M., Rohm, M. & Herzig, S. Cancer cachexia: multilevel metabolic dysfunction. Nat Metab 6, 2222–2245 (2024). https://doi.org/10.1038/s42255-024-01167-9

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