Abstract
Increasing recognition of an association between obesity and many cancer types exists, but how the myriad of local and systemic effects of obesity affect key cellular and non-cellular processes within the tumour microenvironment (TME) relevant to carcinogenesis, tumour progression and response to therapies remains poorly understood. The TME is a complex cellular environment in which the tumour exists along with blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, signalling molecules and the extracellular matrix. Obesity, in particular visceral obesity, might fuel the dysregulation of key pathways relevant to both the adipose microenvironment and the TME, which interact to promote carcinogenesis in at-risk epithelium. The tumour-promoting effects of obesity can occur at the local level as well as systemically via circulating inflammatory, growth factor and metabolic mediators associated with adipose tissue inflammation, as well as paracrine and autocrine effects. This Review explores key pathways linking visceral obesity and gastrointestinal cancer, including inflammation, hypoxia, altered stromal and immune cell function, energy metabolism and angiogenesis.
Key points
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Epidemiological evidence implicates obesity as a risk factor for the development of cancers at multiple sites in the gastrointestinal tract, including the oesophagus, liver, colon, gastric cardia and pancreas.
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Immune, metabolic and inflammation-associated properties of excess adiposity are increasingly understood, but how they influence the tumour microenvironment (TME), which comprises tumour cells, blood vessels, immune cells, fibroblasts and the extracellular matrix, remains unclear.
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Adipocyte stem cells are increased in adipose tissue of individuals with obesity; in mouse models, these cells migrate to tumour sites and differentiate into cell types that might affect the TME.
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Interstitial fibrosis within the TME can influence cytokine signalling, epithelial cell morphology and stem cell differentiation. Adipocyte stem cells might be a source of cancer-associated fibroblasts, and obesity might play a part in fibrosis-associated mechanosignalling within tumours.
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Metabolic reprogramming in the TME is associated with obesity, hypoxia and angiogenesis. These processes are tightly interconnected and represent a potential target affecting not only tumours but also immune or inflammatory cells within the TME.
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Bariatric or metabolic surgery is associated with an improvement in the metabolic profile of patients with obesity and a marked decrease in the incidence of cancer development.
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O’Sullivan, J., Lysaght, J., Donohoe, C.L. et al. Obesity and gastrointestinal cancer: the interrelationship of adipose and tumour microenvironments. Nat Rev Gastroenterol Hepatol 15, 699–714 (2018). https://doi.org/10.1038/s41575-018-0069-7
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DOI: https://doi.org/10.1038/s41575-018-0069-7
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