Obesity, Dietary Fats, and Gastrointestinal Cancer Risk-Potential Mechanisms Relating to Lipid Metabolism and Inflammation

Abstract

Obesity is a major driving factor in the incidence, progression, and poor treatment response in gastrointestinal cancers. Herein, we conducted a comprehensive analysis of the impact of obesity and its resulting metabolic perturbations across four gastrointestinal cancer types, namely, oesophageal, gastric, liver, and colorectal cancer. Importantly, not all obese phenotypes are equal. Obese adipose tissue heterogeneity depends on the location, structure, cellular profile (including resident immune cell populations), and dietary fatty acid intake. We discuss whether adipose heterogeneity impacts the tumorigenic environment. Dietary fat quality, in particular saturated fatty acids, promotes a hypertrophic, pro-inflammatory adipose profile, in contrast to monounsaturated fatty acids, resulting in a hyperplastic, less inflammatory adipose phenotype. The purpose of this review is to examine the impact of obesity, including dietary fat quality, on adipose tissue biology and oncogenesis, specifically focusing on lipid metabolism and inflammatory mechanisms. This is achieved with a particular focus on gastrointestinal cancers as exemplar models of obesity-associated cancers.

Keywords: adipose; diet; gastrointestinal cancer; inflammation; metabolism; monounsaturated fatty acids; obesity; saturated fatty acids.

Figure 1

Obesity alters the immunometabolic landscape to support gastrointestinal cancer. Obese adipose tissue secretes metabolites that have been proven to show oncogenic potential. These include insulin, insulin-like growth factor (IGF-1), glucose, cholesterol, reactive oxygen species (ROS), and pro-inflammatory cytokines. These metabolites and cytokines then enter the circulation to neighbouring gastrointestinal organs where they drive normal cells to cancer cells and ultimately to metastatic cancer cells. IL, interleukin; MAPK, mitogen-activated protein kinase; mTOR, mechanistic target of rapamycin; PI3K, phosphoinositide-3-kinase; RAS, rat sarcoma; TNFα, tumour necrosis factor alpha. This figure was created using Biorender.com (accessed on 7 August 2023).

Figure 2

Fatty acids affect adipose distribution morphology and immune cell behaviour. Saturated and monounsaturated fatty acids can dictate adipose tissue distribution and adipocyte size (hypertrophy versus hyperplastic) [41]. Additionally, fatty acids can differentially regulate immune cell behaviour including macrophages, neutrophils, B cells, T cells, and dendritic cells. ATP, adenosine triphosphate; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; IFN-γ, interferon-gamma; IL, interleukin; IRS-1, insulin receptor substrate 1; JNK, c-Jun N-terminal kinase; MCP-1, monocyte chemoattractant protein-1, MKK, mitogen-activated protein kinase kinase; mTOR, mechanistic target of rapamycin; NF-κB, nuclear factor kappa B; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; NK, natural killer; NO, nitric oxide; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PI3K, phosphoinositide-3-kinase; PPARγ, peroxisome proliferator-activated receptor gamma; ROS, reactive oxygen species; Th, helper T cell; TLR, toll-life receptor; TNFα, tumour necrosis factor alpha; Treg, regulatory T cell; ↑, increase; ↓, decrease. This figure was created using Biorender.com (accessed on 7 August 2023).

Figure 3

Adipose structure and function drive tumorigenesis. Overconsumption results in lean adipose tissue expansion to either hypertrophic metabolically unhealthy adipose tissue or hyperplastic metabolically healthy adipose tissue. The metabolically unhealthy adipose creates a pro-tumorigenic environment with increased immune cell infiltration, pro-inflammatory cytokine secretion, and increased free fatty acid release, which drive progression from a benign epithelium toward tumour growth and ultimately metastasis to a greater extent than metabolically healthy adipose. EMT, epithelial–mesenchymal transition; Th, helper T cells; NK, natural killer; Treg, regulatory T cells; ↑, increase; ↓, decrease. This figure was created using Biorender.com (accessed on 7 August 2023).

Figure 4

Obese adipose and fatty acid effects on gastrointestinal cancers. Obese adipose increases immune cell infiltration, which then creates a tumorigenic environment on neighbouring gastrointestinal organs including the oesophagus, stomach, liver, and colon. Effects seen are an increase in inflammation, angiogenesis, proliferation, and cell differentiation, which can differ based on the specific organ. Palmitate and oleate have differential effects on oesophageal, gastric, liver, and colorectal cancer. Generally, saturated fatty acid palmitate drives cellular behaviours which may increase a tumorigenic environment to a greater extent than monounsaturated fatty acid oleate. CPT1A, carnitine palmitoyltransferase 1A; CXCL, chemokine (C-X-C motif) ligand; FABP1, fatty-acid binding protein 1; IL, interleukin; MCP-1, monocyte chemoattractant protein-1, MDC, macrophage-derived chemokine; TNFα, tumour necrosis factor alpha; VEGF, vascular endothelial growth factor; ↑, increase; ↓, decrease. This figure was created using Biorender.com (accessed on 7 August 2023).