Visceral Obesity, Metabolic Syndrome, and Esophageal Adenocarcinoma

Abstract

Esophageal adenocarcinoma (EAC) represents an exemplar of obesity-associated carcinogenesis, with a progressive increase in EAC risk with increased body mass index. In this context, there is increased focus on visceral adipose tissue and associated metabolic dysfunction, including hypertension, diabetes mellitus and hyperlipidemia, or combinations of these in the metabolic syndrome. Visceral obesity (VO) may promote EAC via both directly impacting on gastro-esophageal reflux disease and Barrett's esophagus, as well as via reflux-independent effects, involving adipokines, growth factors, insulin resistance, and the microbiome. In this review these pathways are explored, including the impact of VO on the tumor microenvironment, and on cancer outcomes. The current evidence-based literature regarding the role of dietary, lifestyle, pharmacologic and surgical interventions to modulate the risk of EAC is explored.

Role of Obesity, Physical Exercise, Adipose Tissue-Skeletal Muscle Crosstalk and Molecular Advances in Barrett’s Esophagus and Esophageal Adenocarcinoma

“…A key relevant pathway linking obesity with EAC could be the occurrence of GERD, as long as the severe GERD is associated with an up to 40-fold increased risk of EAC [ 103 ]. GERD is a global disorder and unquestionably a disease that is directly linked to obesity [ 24 ].…”

“…The TME is composed of cellular components such as endothelial cells, immune cells such as microglia, granulocytes, lymphocytes, macrophages, and tumor stromal cells, including stromal fibroblasts and non-cellular components of the extracellular matrix [ 60 ]. Low-grade fat inflammation in obesity is comparable to that of the TME, clearly suggesting the ability of altered adipose tissue to stimulate tumor growth [ 103 , 155 ]. Data from animal models indicate that pro-inflammatory cytokines are essential for the development of BE [ 156 ].…”

Insulin/IGF-1 Signaling Is Downregulated in Barrett’s Esophagus Patients Undergoing a Moderate Calorie and Protein Restriction Program: A Randomized 2-Year Trial

“…Central obesity, intrinsically associated with insulin resistance and hyperinsulinemia, has been previously identified as an important risk factor for the development of esophageal adenocarcinoma [ 5 , 6 , 7 ]. The main mechanisms involved include anatomic factors such as increased abdominal and intraperitoneal fat accumulation, as well as diseases associated with predisposing patients to increased gastroesophageal reflux, such as hiatal hernia formation.…”

“…Obesity, central adiposity, type 2 diabetes, and insulin resistance are widespread. Their role as risk factors for oncological diseases is well documented [ 2 , 3 , 4 ], including in the context of esophageal adenocarcinoma (EAC) and its precancerous lesion, Barrett’s esophagus (BE) [ 5 , 6 , 7 ]. Barrett’s esophagus, a metaplastic change resulting from long-standing reflux disease, is identified in 5-15% of chronic reflux-affected patients [ 8 ].…”

Spatial organisation and homeostasis of epithelial lineages at the gastroesophageal junction is regulated by the divergent Wnt mucosal microenvironment

“…Further increasing obesity and altered microbiota trends are implicated as additional risk factors of BE and carcinogenesis [6][7][8] . Due to the deadly nature and fast-increasing incidence of GEJ adenocarcinomas accounting for a 6-fold increase during the past four decades, with a five-year survival of 15%, have gained the attention of clinicians and researchers [9][10][11][12] .…”