Mechanisms of obesity-induced gastrointestinal neoplasia

Abstract

Obesity is among the fastest growing diseases worldwide; treatment is inadequate, and associated disorders, including gastrointestinal cancers, have high morbidity and mortality. An increased understanding of the mechanisms of obesity-induced carcinogenesis is required to develop methods to prevent or treat these cancers. In this report, we review the mechanisms of obesity-associated colorectal, esophageal, gastric, and pancreatic cancers and potential treatment strategies.

Keywords: BE; BMI; Barrett's esophagus; CRC; Colorectal Cancer; EAC; Esophageal Cancer; GCA; GI; Gastric Cancer; IGF; IGFBP; IGFR; IL; IR; LPS; MAPK; MCP-1; MSI; PAC; Pancreatic Cancer; RR; TNF; body mass index; colorectal cancer; esophageal adenocarcinoma; gastric adenocarcinoma; gastrointestinal; insulin receptor; insulin-like growth factor; insulin-like growth factor binding protein; insulin-like growth factor receptor; interleukin; lipopolysaccharides; mTOR; mammalian target of rapamycin; microsatellite instability; mitogen-activated protein kinase; monocyte chemoattractant protein 1; pancreatic adenocarcinoma; relative risk; sTNFR2; soluble tumor necrosis factor receptor 2; tumor necrosis factor.

Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Relative Risks of GI Cancers in Obese Men and Women

Obesity confers increased risk of several malignancies. Reductions in obesity rates should result in decreased cancer incidence and potentially mortality. In men, obesity-associated cancers include esophageal, colon, liver, pancreas and prostate. In women, obesity-associated cancers include endometrial, gallbladder, breast (postmenopausal women), pancreas and colon. Data presented as relative risk per 5 kg/m2 higher BMI. Adapted from [3].

Figure 2. Inflammation and Adipocytes

Interactions among circulating and local factors contribute to obesity-associated inflammation. Adipocytes are cells specialized for storage of nutrients in the form of triglyceride and cholesterol. Leptin and adiponectin are examples of adipokines produced in response to adipocyte size and overall energy balance. After reaching an undefined trigger (adipocyte size, hypoxia, insulin resistance), immune cells, including macrophages, are recruited to adipocytes. This activates an inflammatory signaling response that leads to secretion of TNFα, IL6, PA1, MCP1, IFNγ and VEGF. Resulting chronic inflammation leads to insulin resistance, cardiovascular disease, and different cancers.

Figure 3. Obesity-induced Factors Contribute to Colorectal Carcinogenesis Mechanisms by which obesity could contribute to development of CRC

Western-style diets lead to increased adiposity and changes in the microbiota, to adapt to the increased energy supply. Adipokines such as leptin and adiponectin could allow for establishment of a tumor microenvironment. In obese individuals, hyperlipidemia and insulin resistance lead to low-grade systemic inflammation, which promotes tumor cell proliferation and angiogenesis and reduces apoptosis. These mechanisms are likely to vary among individuals and little is known about their interactions.

Figure 4. Obesity and Esophageal Cancer Mechanisms by which obesity could contribute to carcinogenesis in the esophagus

In early stages of obesity, leptin and adiponectin contribute to the frequency and development of BE. The transition from benign metaplasia to dysplasia is thought to be partially mediated by changes in the microbiota, in addition to an acid environment. Development of aneuploidy and subsequent cancer have been associated with chronic low-grade inflammation and altered levels of IGF1. It is not clear whether obesity contributes to metastasis of esophageal cancer.