Association of insulin and insulin-like growth factors with Barrett's oesophagus

Greer, Katarina B.; Thompson, Cheryl L.; Brenner, Lacie; Bednarchik, Beth; Dawson, Dawn M.; Willis, Joseph E.; Grady, William M.; Falk, Gary W.; Cooper, Gregory S.; Li, Li; Chak, Amitabh

doi:10.1136/gutjnl-2011-300641

Cited by 69 publications

(61 citation statements)

References 39 publications

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“…27,28 There has been a steep rise in the frequency of central obesity, which might contribute to Barrett's carcinogenesis by promoting GERD and by increasing the production of hormones that promote cell proliferation, such as leptin and insulin-like growth factors. 29,30 H. pylori infection, which may protect the esophagus from GERD by causing a gastritis that reduces gastric acid production, has declined in frequency during the same period when esophageal adenocarcinoma has risen in developed countries. 31 Another hypothesis links the rising incidence of esophageal adenocarcinoma with increased dietary intake of nitrate, which has resulted from the widespread use of nitratebased fertilizers.…”

Section: Epidemiol Ogymentioning

confidence: 98%

Barrett's Esophagus

Spechler¹,

Souza²

2014

N Engl J Med

427

325

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I t has been estimated that 5.6% of adults in the United States have Barrett's esophagus, 1 the condition in which a metaplastic columnar mucosa that confers a predisposition to cancer replaces an esophageal squamous mucosa damaged by gastroesophageal reflux disease (GERD). 2 GERD and Barrett's esophagus are major risk factors for esophageal adenocarcinoma, a deadly tumor whose frequency in the United States has increased by a factor of more than 7 during the past four decades. 3,4 The metaplastic columnar mucosa of Barrett's esophagus causes no symptoms, and the condition has clinical importance only because it confers a predisposition to cancer. PathogenesisMetaplasia, the process wherein one adult cell type replaces another, is a consequence of chronic tissue injury. 5 In patients with chronic esophageal injury from GERD, Barrett's metaplasia develops when mucus-secreting columnar cells replace reflux-damaged esophageal squamous cells. The cells that give rise to this metaplasia are not known. It has been proposed that GERD might induce alterations in the expression of key developmental transcription factors, causing mature esophageal squamous cells to change into columnar cells (transdifferentiation) or causing immature esophageal progenitor cells to undergo columnar rather than squamous differentiation (transcommitment). 5,6 In a rat model of reflux esophagitis, metaplasia develops from bone marrow stem cells that enter the blood and settle in the reflux-damaged esophagus. 7 Studies in mouse models have suggested that metaplasia might result from upward migration of stem cells from the proximal stomach (the gastric cardia) 8 or from proximal expansion of embryonic-type cells at the gastroesophageal junction. 9 It is not clear which of these processes contribute to the pathogenesis of Barrett's esophagus in humans. Di agnosisThe diagnosis of Barrett's esophagus requires findings on endoscopy that columnar mucosa extends above the gastroesophageal junction, lining the distal esophagus, plus esophageal-biopsy results that confirm the presence of columnar metaplasia. 2 Endoscopically, the gastroesophageal junction is identified as the most proximal extent of gastric folds, and the columnar mucosa is salmon-colored and coarse, in contrast to the pale, glossy esophageal squamous mucosa (Fig. 1). The extent of esophageal columnar metaplasia determines whether long-segment or short-segment Barrett's esophagus (≥3 cm or <3 cm of columnar metaplasia, respectively) is diagnosed. 10 However, authorities disagree on the histologic type of columnar mucosa that establishes a diagnosis of Barrett's esophagus.U.S. gastroenterology societies require esophageal biopsies showing intestinal metaplasia with goblet cells (also called specialized intestinal metaplasia or specialized columnar epithelium) for a definitive diagnosis of Barrett's esophagus The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF NEWCASTLE on August 27, 2014. For personal use only. No other uses without permission.

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Section: Epidemiol Ogymentioning

confidence: 98%

Barrett's Esophagus

Spechler¹,

Souza²

2014

N Engl J Med

427

325

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“…Circulating levels of IGF binding protein-3 are inversely associated with the presence of Barrett’s esophagus. 31 A polymorphism in the gene encoding IGF1 is associated with Barrett’s esophagus, 36 and a polymorphism in the gene encoding the IGF1 receptor modifies the effect of obesity on the risk for Barrett’s esophagus and EAC. 37 A polymorphism in the gene encoding IGF2 is also associated with EAC, perhaps more so among smokers.…”

Section: Epidemiologymentioning

confidence: 99%

Epidemiology, Diagnosis, and Management of Esophageal Adenocarcinoma

2015

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Esophageal adenocarcinoma (EAC) is rapidly increasing in incidence in Western cultures. Barrett’s esophagus (BE) is the presumed precursor lesion for this cancer. Several other risk factors for this cancer have been described, including chronic heartburn, tobacco use, Caucasian race, and obesity. Despite these known associations, most patients with EAC present with symptoms of dysphagia from late-stage tumors—only a small minority of patients are identified in screening and surveillance programs. Diagnostic analysis of EAC usually commences with upper endoscopy, followed by cross-sectional imaging. Endoscopic ultrasound is useful to assess local extent of disease as well as the involvement regional lymph nodes. T1a EAC may be treated endoscopically; some patients with T1b disease might also benefit from endoscopic therapy. Locally advanced disease is generally managed with esophagectomy, often accompanied by neoadjuvant chemoradiotherapy or chemotherapy. The prognosis is based on tumor stage: patients with T1a tumors have an excellent prognoses, whereas few patients with advanced disease have longterm survival.

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“…A complex array of adipose-tissue infiltrating immune cells are responsible for the majority of the cytokines produced, although it is not completely understood how this inflammation leads to insulin resistance (for a full review of this complex area, see Lee and Lee [2014]). Increased circulating insulin promotes carcinogenesis partly by stimulating the production of IGF-1 and it also downregulates production of IGF binding proteins 1 (IGFBP-1) and 3 (IGFBP-3) [Greer et al 2012]. This leads to an increase in bioavailable IGF-1, which can bind to the IGF receptor complex, activating pathways that promote tissue proliferation.…”

Section: The Metabolic Syndrome and Insulin Resistancementioning

confidence: 99%

The role of obesity in oesophageal cancer development

Long

Beales

2014

Therap Adv Gastroenterol

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Abstract:The incidence of oesophageal adenocarcinoma has increased dramatically in the developed world in the last half century. Over approximately the same period there has been an increase in the prevalence of obesity. Multiple epidemiological studies and metaanalyses have confirmed that obesity, especially abdominal, visceral obesity, is a risk factor for gastro-oesophageal reflux, Barrett's oesophagus and oesophageal adenocarcinoma. Although visceral obesity enhances gastro-oesophageal reflux, the available data also show that visceral obesity increases the risk of Barrett's oesophagus and adenocarcinoma via reflux-independent mechanisms. Several possible mechanisms could link obesity with the risk of oesophageal adenocarcinoma in addition to mechanical effects increasing reflux. These include reduced gastric Helicobacter pylori infection, altered intestinal microbiome, factors related to lifestyle, the metabolic syndrome and associated low-grade inflammation induced by obesity and the secretion of mediators by adipocytes which may directly influence the oesophageal epithelium. Of these adipocyte-derived mediators, increased leptin levels have been independently associated with progression to oesophageal adenocarcinoma and in laboratory studies leptin enhances malignant behaviours in cell lines. Adiponectin is also secreted by adipocytes and levels decline with obesity: decreased serum adiponectin levels are associated with malignant progression in Barrett's oesophagus and experimentally adiponectin exerts anticancer effects in Barrett's cell lines and inhibits growth factor signalling. At present there are no proven chemopreventative interventions that may reduce the incidence of obesity-associated oesophageal cancer: observational studies suggest that the combined use of a statin and aspirin or another cyclo-oxygenase inhibitor is associated with a significantly reduced cancer incidence in patients with Barrett's oesophagus.

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Association of insulin and insulin-like growth factors with Barrett's oesophagus

Cited by 69 publications

References 39 publications

Barrett's Esophagus

Barrett's Esophagus

Epidemiology, Diagnosis, and Management of Esophageal Adenocarcinoma

The role of obesity in oesophageal cancer development

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