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

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.

Fig. 1 |. Mechanisms underlying the association between energy balance and obesity-related gastrointestinal cancers.

Line thickness corresponds to the current evidence for the strength of the effect or association. Black lines represent positive or enhancing effects, and red lines represent negative or inhibiting effects. IGF, insulin-like growth factor.

Fig. 2 |. Adipokines and cytokines secreted by adipose tissue and their effects on cancer-related processes.

The increased secretion of adipokines (leptin and adiponectin) and cytokines (C-reactive protein, TNF, IL-6, IL-8 and serum amyloid A protein (SAA)) driven by adipose tissue in obesity can alter the expression and secretion of factors positioned by the primary tumour (vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), angiopoietin-related protein 4 (ANGPTL4) and fibroblast growth factor (FGF)) to promote tumour proliferation, invasion, angiogenesis and metastasis.

Fig. 3 |. The insulin-insulin-like growth factor axis and adipose tissue-derived adipokine signalling in cancer.

Excess energy balance promotes cell proliferation, angiogenesis and an anti-apoptotic environment by increasing circulating levels of insulin and bioavailable insulin-like growth factor (IGF) (via the mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) signalling pathways) and dysregulating adipokine expression (via nuclear factor-κB (NF-κB) signalling). AKT, RAC serine/threonine-protein kinase; EGF, epidermal growth factor; IGF1R, insulin-like growth factor 1 receptor; IR, insulin receptor; IRS, insulin receptor substrate; JAK, Janus kinase; MAPKK, dual specificity mitogen-activated protein kinase kinase; MAPKKK, mitogen-activated protein kinase kinase kinase; PI3K, phosphoinositide 3-kinase; RAS, GTPase RAS; STAT, signal transducer and activator of transcription.