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Metabolic rearrangements in primary liver cancers: cause and consequences

Nature Reviews Gastroenterology & Hepatology volume 16, pages 748–766 (2019)Cite this article

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Abstract

Primary liver cancer (PLC) is the fourth most frequent cause of cancer-related death. The high mortality rates arise from late diagnosis and the limited accuracy of diagnostic and prognostic biomarkers. The liver is a major regulator, orchestrating the clearance of toxins, balancing glucose, lipid and amino acid uptake, managing whole-body metabolism and maintaining metabolic homeostasis. Tumour onset and progression is frequently accompanied by rearrangements of metabolic pathways, leading to dysregulation of metabolism. The limitation of current therapies targeting PLCs, such as hepatocellular carcinoma and cholangiocarcinoma, points towards the importance of deciphering this metabolic complexity. In this Review, we discuss the role of metabolic liver disruptions and the implications of these processes in PLCs, emphasizing their clinical relevance and value in early diagnosis and prognosis and as putative therapeutic targets. We also describe system biology approaches able to reconstruct the metabolic complexity of liver diseases. We also discuss whether metabolic rearrangements are a cause or consequence of PLCs, emphasizing the opportunity to clinically exploit the rewired metabolism. In line with this idea, we discuss circulating metabolites as promising biomarkers for PLCs.

Key points

  • The heterogeneous mutational landscape of primary liver cancers (PLCs) is associated with unique metabolic dysregulations.

  • Substantial metabolic rearrangements are present in chronic liver diseases and contribute to the development of PLCs.

  • Genome-wide metabolic models are useful tools to tackle the complexity of PLC metabolism.

  • Metabolomics in different biological fluids (liquid biopsy samples) have excellent translational potential for the diagnosis of liver diseases and PLCs.

  • Targeting metabolic rearrangements in chronic liver diseases and PLCs offers unexploited preventative and therapeutic opportunities.

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Fig. 1: Dysregulated pathways in PLC.
Fig. 2: Pathways branching from glycolysis.
Fig. 3: Intersecting glycolysis and PPP and nucleotide synthesis.
Fig. 4: Connection between TCA and urea cycles, amino acids and de novo lipogenesis.
Fig. 5: Schematic overview of the genome scale metabolic model development.

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Acknowledgements

The laboratory of J.B.A. is supported by the Novo Nordisk Foundation (14040), Danish Cancer Society (R167-A10784) and the Danish Medical Research Council (4183–00118A). The work of J.M.B. is supported by funds from the Spanish Carlos III Health Institute (ISCIII; FIS PI15/01132, PI18/01075 and Miguel Servet Program CON14/00129) co-financed by: “Fondo Europeo de Desarrollo Regional” (FEDER); “Instituto de Salud Carlos III” (CIBERehd), Spain; BIOEF (Basque Foundation for Innovation and Health Research; EiTB Maratoia BIO15/CA/016/BD); La Caixa Scientific Foundation (HR17-00601); and “Fundación Científica de la Asociación Española Contra el Cáncer” (AECC Scientific Foundation).

Reviewer information

Nature Reviews Gastroenterology & Hepatology thanks Amedeo Columbano, Carmen Wong and the other, anonymous, reviewer(s) for their contribution to the peer review of this work

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Authors and Affiliations

  1. Biotech Research and Innovation Centre (BRIC) Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Letizia Satriano, Monika Lewinska & Jesper B. Andersen

  2. Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain

    Pedro M. Rodrigues & Jesus M. Banales

  3. National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain

    Jesus M. Banales

  4. IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

    Jesus M. Banales

Authors
  1. Letizia Satriano
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  2. Monika Lewinska
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  3. Pedro M. Rodrigues
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  4. Jesus M. Banales
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  5. Jesper B. Andersen
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Contributions

J.B.A., L.S. and M.L. researched data for the article, made a substantial contribution to discussions of content, and wrote and reviewed/edited the manuscript before submission. P.M.R. and J.M.B. wrote and reviewed/edited the manuscript before submission. L.S. and M.L. contributed equally.

Corresponding author

Correspondence to Jesper B. Andersen.

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Satriano, L., Lewinska, M., Rodrigues, P.M. et al. Metabolic rearrangements in primary liver cancers: cause and consequences. Nat Rev Gastroenterol Hepatol 16, 748–766 (2019). https://doi.org/10.1038/s41575-019-0217-8

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  • DOI: https://doi.org/10.1038/s41575-019-0217-8

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