Review Article | Published:

Cancer metabolism: a therapeutic perspective

Nature Reviews Clinical Oncology volume 14, pages 1131 (2017) | Download Citation

  • An Erratum to this article was published on 17 January 2017

This article has been updated

Abstract

Awareness that the metabolic phenotype of cells within tumours is heterogeneous — and distinct from that of their normal counterparts — is growing. In general, tumour cells metabolize glucose, lactate, pyruvate, hydroxybutyrate, acetate, glutamine, and fatty acids at much higher rates than their nontumour equivalents; however, the metabolic ecology of tumours is complex because they contain multiple metabolic compartments, which are linked by the transfer of these catabolites. This metabolic variability and flexibility enables tumour cells to generate ATP as an energy source, while maintaining the reduction–oxidation (redox) balance and committing resources to biosynthesis — processes that are essential for cell survival, growth, and proliferation. Importantly, experimental evidence indicates that metabolic coupling between cell populations with different, complementary metabolic profiles can induce cancer progression. Thus, targeting the metabolic differences between tumour and normal cells holds promise as a novel anticancer strategy. In this Review, we discuss how cancer cells reprogramme their metabolism and that of other cells within the tumour microenvironment in order to survive and propagate, thus driving disease progression; in particular, we highlight potential metabolic vulnerabilities that might be targeted therapeutically.

Key points

  • The metabolic ecology of tumours enables component cells to generate ATP, maintain redox balance, and undertake biosynthesis, which in turn support tumour progression

  • Tumours share features of complex ecosystems, with cancer cells inducing nutrient enrichment; however, the requirement for a tight nutrient balance might be a vulnerability of tumours that can be exploited therapeutically

  • Compared with their normal counterparts, tumour cells require higher rates of catabolite uptake, transfer, and utilization; hence, catabolite-deprivation might be a selective and effective anticancer treatment strategy

  • Targeting glycolysis and mitochondrial metabolism with drug combinations holds promise as another strategy to disrupt the diverse metabolic compartments within tumours

  • Measuring glucose, lactate, pyruvate, β-hydroxybutyrate, and glutamine levels in different tumour compartments and their intercompartmental transfer is needed in clinical trials that examine the efficacy of drugs targeting tumour metabolism

  • Normal tissues frequently have activation of metabolic pathways that are upregulated in cancer and, therefore, dose-limiting toxicity is a challenge in the development of drugs targeting these pathways

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Change history

  • 17 January 2017

    Owing to a typesetting error, the final line of text in Box 3, and the abbreviation lists for Tables 2 and 3 were omitted from the print and the online pdf versions of this article; for Table 3, the abbrevation list was also omitted from the online html version. These errors have now been corrected in the online pdf and html versions of the manuscript.

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Acknowledgements

The Sotgia and Lisanti laboratories in the UK have been supported, in part, by funding from the EU (European Research Council Advanced Grant), Breast Cancer Now, The Healthy Life Foundation, and the Manchester Cancer Research Centre (MCRC). The work of Ubaldo E. Martinez-Outschoorn has been supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH), under Award Number K08-CA175193. Richard G. Pestell's laboratory receives funding from the NIH and the NCI, as well as the Breast Cancer Research Foundation and the Ralph and Marian C. Falk Medical Research Trust.

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Author notes

    • Ubaldo E. Martinez-Outschoorn
    • , Maria Peiris-Pagés
    • , Federica Sotgia
    •  & Michael P. Lisanti

    U.E.M.-O. and M.P.-P. should be considered as co-first authors, and F.S. and M.P.L. should be considered as co-last authors.

Affiliations

  1. The Sidney Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, Pennsylvania 19107, USA.

    • Ubaldo E. Martinez-Outschoorn
    •  & Richard G. Pestell
  2. The Breast Cancer Now Manchester Research Unit, Institute of Cancer Sciences, Cancer Research UK Manchester Institute, University of Manchester, Paterson Building, Wilmslow Road, Manchester M20 4BX, UK.

    • Maria Peiris-Pagés
    • , Federica Sotgia
    •  & Michael P. Lisanti
  3. The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, Cancer Research UK Manchester Institute, University of Manchester, Paterson Building, Wilmslow Road, Manchester M20 4BX, UK.

    • Maria Peiris-Pagés
    • , Federica Sotgia
    •  & Michael P. Lisanti
  4. School of Environment and Life Sciences, University of Salford, Cockcroft Building, Salford M5 4WT, UK.

    • Federica Sotgia

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Contributions

U.E.M.-O. and M.P.-P. researched the data for the article and wrote the manuscript. U.E.M.-O., M.P.-P., F.S., and M.P.L. contributed substantially to discussions of content, and U.E.M.-O., R.G.P., F.S., and M.P.L. reviewed and edited the manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Federica Sotgia or Michael P. Lisanti.

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https://doi.org/10.1038/nrclinonc.2016.60

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