Obesity and increased risk of esophageal adenocarcinoma

Abstract

There has been a substantial increase in the incidence of esophageal adenocarcinoma over the past 40 years. Meta-analyses of large prospective cohorts and population-based case–control studies demonstrate consistent associations between obesity and the development of adenocarcinoma of the esophagus and esophago-gastric junction, with an approximate doubling of risk of esophageal adenocarcinoma among patients who are obese, and an almost five-fold increased risk among those with BMI >40 kg/m². The pathologic precursor, specialized intestinal metaplasia in Barrett’s esophagus, is also associated with increased adiposity. Epidemiologic evidence suggests that this cancer risk is not solely due to increased gastro-esophageal reflux, and that adipose tissue itself, in particular visceral adipose, may fuel carcinogenesis through the production of adipokines, cytokines, growth factors, and increased inflammation. The robust epidemiologic evidence linking obesity with esophageal adenocarcinoma makes it an exemplar model for investigating the molecular mechanisms underpinning obesity-associated malignant progression, which are discussed in this review.

Keywords:

• adenocarcinoma
• adipokines
• Barrett’s esophagus
• esophageal cancer
• gastro-esophageal reflux disease
• obesity
• visceral adiposity

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Esophageal adenocarcinoma (EAC) incidence is rising in parallel with increasing obesity, a phenomenon, which may be attributable to increasing GERD and to metabolic and inflammatory changes associated with obesity.

• Adipose distribution appears to play a key role in Barrett’s esophagus and EAC risk-visceral adiposity as determined by computed tomography is associated with increased risk, compared with subcutaneous fat deposition.

• EAC represents an exemplar model of an obesity-associated cancer, and examination of factors modifying the natural history of the pre-malignant Barrett’s esophagus offers a unique opportunity for the study of primary prevention strategies.

• Gastro-esophageal reflux of acid and/or bile is a key pathophysiologic feature in EAC, and is associated with increased central adiposity.

• Excess adipose tissue initiates a proinflammatory state associated with increased adipose and systemic cytokines, stimulating release of inflammatory mediators, such as IL-6 and TNF-α. These mediators promote progression of BE and tumorigensis via downstream activation of STAT3 and NFκB.

• Adipokines such as leptin may also increase EAC risk in obesity, both via direct interaction with tumor leptin receptors, and indirect effects on glucose metabolism and inflammation.

• Hyperinsulinemia in obesity is associated with increased IGF-1, which acts via tumor IGF-1 receptors to generate mitogenic, anti-apoptotic, and proangiogenic effects that may favor tumor growth, conferring a less favorable prognosis.

Notes