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Energy balance and gastrointestinal cancer: risk, interventions, outcomes and mechanisms

Nature Reviews Gastroenterology & Hepatology volume 15, pages 683–698 (2018)Cite this article

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Abstract

Obesity increases the risk of multiple gastrointestinal cancers and worsens disease outcomes. Conversely, strong inverse associations have emerged between physical activity and colon cancer and possibly other gastrointestinal malignancies. The effect of weight loss interventions — such as modifications of diet and/or physical activity or bariatric surgery — remains unclear in patients who are obese and have gastrointestinal cancer, although large clinical trials are underway. Human intervention studies have already shed light on potential mechanisms underlying the energy balance–cancer relationship, with preclinical models supporting emerging pathway effects. Central to interventions that reduce obesity or increase physical activity are pluripotent cancer-preventive effects (including reduced systemic and adipose tissue inflammation and angiogenesis, altered adipokine levels and improved insulin resistance) that directly interface with the hallmarks of cancer. Other mechanisms, such as DNA repair, oxidative stress and telomere length, immune function, effects on cancer stem cells and the microbiome, could also contribute to energy balance effects on gastrointestinal cancers. Although some mechanisms are well understood (for instance, systemic effects on inflammation and insulin signalling), other areas remain unclear. The current state of knowledge supports the need to better integrate mechanistic approaches with preclinical and human studies to develop effective, personalized diet and exercise interventions to reduce the burden of obesity on gastrointestinal cancer.

Key points

  • Energy balance interventions, such as physical activity and caloric restriction, can reduce individual cancer risk and prevent gastrointestinal carcinogenesis.

  • Intervention trials are instrumental in fully understanding the effects of energy balance on cancer risk, clinical outcomes and underlying biological mechanisms.

  • The main mechanistic pathways underlying the obesity–gastrointestinal cancer link include systemic inflammation, metabolic reprogramming and adipose tissue-dependent effects.

  • Additional pathways that might have a role are oxidative stress and DNA repair, proliferation, apoptosis and angiogenesis, the gut microbiome and immune function.

  • Preclinical studies using both diet-induced and genetically induced obesity models provide supporting evidence to clinical findings.

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Fig. 1: Mechanisms underlying the association between energy balance and obesity-related gastrointestinal cancers.
Fig. 2: Adipokines and cytokines secreted by adipose tissue and their effects on cancer-related processes.
Fig. 3: The insulin–insulin-like growth factor axis and adipose tissue-derived adipokine signalling in cancer.

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Acknowledgements

C.M.U. was supported by grants from the US National Institutes of Health (NIH)–US National Cancer Institute (NCI) (R01 CA189184, R01 CA207371 and U01 CA206110). C.M.U. and C.H. were also supported by NIH–NCI grant R01 CA211705. A.N.H. was supported by the NIH under Ruth L. Kirschstein National Research Service Award T32 HG008962 from the US National Human Genome Research Institute. S.D.H. was supported by NIH–NCI grant R35 CA197627.

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  1. Huntsman Cancer Institute, Salt Lake City, UT, USA

    Cornelia M. Ulrich, Caroline Himbert & Andreana N. Holowatyj

  2. Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA

    Cornelia M. Ulrich, Caroline Himbert & Andreana N. Holowatyj

  3. Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA

    Stephen D. Hursting

  4. UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA

    Stephen D. Hursting

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Ulrich, C.M., Himbert, C., Holowatyj, A.N. et al. Energy balance and gastrointestinal cancer: risk, interventions, outcomes and mechanisms. Nat Rev Gastroenterol Hepatol 15, 683–698 (2018). https://doi.org/10.1038/s41575-018-0053-2

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