Gastrin induces proliferation in Barrettʼs metaplasia through activation of the CCK2 receptor

Haigh, Chris; Attwood, S. E. A.; Thompson, David G.; Jankowski, Janusz A.; Kirton, Chris M.; Pritchard, Mark; Varró, Andrea; Dimaline, R.

doi:10.1097/00042737-200305000-00030

Cited by 4 publications

(5 citation statements)

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“…19 For example, markedly increased expression of CCK-2 receptor by three times in the epithelium of Barrett esophagus individuals and also escalated proliferation of mucosal biopsies from patients with Barrett esophagus. 20 But in the current study, intestinal I/R injury did not increase basic CCK-2 receptor expression in rats. The possible reasons are the timing of tissue collection, different strains of rats or variation between stomach and gut.…”

Section: Discussioncontrasting

confidence: 67%

Gastrin attenuates ischemia-reperfusion-induced intestinal injury in rats

Liu

Luo

Cheng

et al. 2016

Exp Biol Med (Maywood)

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Intestinal ischemia-reperfusion (I/R) injury is a devastating complication when the blood supply is reflowed in ischemic organs. Gastrin has critical function in regulating acid secretion, proliferation, and differentiation in the gastric mucosa. We aimed to determine whether gastrin has an effect on intestinal I/R damage. Intestinal I/R injury was induced by 60-min occlusion of the superior mesenteric artery followed by 60-min reperfusion, and the rats were induced to be hypergastrinemic by pretreated with omeprazole or directly injected with gastrin. Some hypergastrinemic rats were injected with cholecystokinin-2 (CCK-2) receptor antagonist prior to I/R operation. After the animal surgery, the intestine was collected for histological analysis. Isolated intestinal epithelial cells or crypts were harvested for RNA and protein analysis. CCK-2 receptor expression, intestinal mucosal damage, cell apoptosis, and apoptotic protein caspase-3 activity were measured. We found that high gastrin in serum significantly reduced intestinal hemorrhage, alleviated extensive epithelial disruption, decreased disintegration of lamina propria, downregulated myeloperoxidase activity, tumor necrosis factor-a, and caspase-3 activity, and lead to low mortality in response to I/R injury. On the contrary, CCK-2 receptor antagonist L365260 could markedly impair intestinal protection by gastrin on intestinal I/R. Severe edema of mucosal villi with severe intestinal crypt injury and numerous intestinal villi disintegrated were observed again in the hypergastrinemic rats with L365260. The survival in the hypergastrinemic rats after intestinal I/R injury was shortened by L365260. Finally, gastrin could remarkably upregulated intestinal CCK-2 receptor expression. Our data suggest that gastrin by omeprazole remarkably attenuated I/R induced intestinal injury by enhancing CCK-2 receptor expression and gastrin could be a potential mitigator for intestinal I/R damage in the clinical setting.

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Section: Discussioncontrasting

confidence: 67%

Gastrin attenuates ischemia-reperfusion-induced intestinal injury in rats

Liu

Luo

Cheng

et al. 2016

Exp Biol Med (Maywood)

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“…However, concerns that PPI-induced hypergastrinaemia may increase the risk of adenocarcinoma development have also been expressed [6] . In vitro studies have shown that gastrin has proliferative effects on Barrett’s epithelium [7] . A potential causal effect of gastrin on neoplastic progression in human Barrett’s esophagus (BE) has been supported by a study showing that serum gastrin levels were significantly correlated with cellular proliferation in nondysplastic BE patients on PPI therapy [8] .…”

Section: Introductionmentioning

confidence: 99%

Role of Proton Pump Inhibitor on Esophageal Carcinogenesis and Pancreatic Acinar Cell Metaplasia Development: An Experimental In Vivo Study

et al. 2014

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Chronic gastro-duodenal reflux in the esophagus is a major risk for intestinal metaplasia and Barrett’s adenocarcinoma. A role for chronic use of proton pump inhibitor (PPI) in the increased incidence of esophageal adenocarcinoma in Western countries has been previously suggested. The aim of this work was to study the effect of chronic administration of omeprazole (a proton pump inhibitor) per os in a model of reflux induced esophageal carcinogenesis. One week after esophago-gastro-jejunostomy, 115 Sprague-Dawley rats were randomized to receive 10 mg/Kg per day of omeprazole or placebo, 5 days per week. The esophago-gastric specimens were collected 28±2 weeks after randomization and analyzed in a blinded fashion. Mortality and esophageal metaplasia rates did not differ between the two groups (p = 0.99 for mortality, p = 0.36 for intestinal metaplasia and p = 0.66 for multi-layered epithelium). Gastric pancreatic acinar cell metaplasia (PACM) was more frequently observed in PPI-treated rats (p = 0.003). Severe ulcer lesions significantly prevailed in the placebo group (p = 0.03). Locally invasive esophageal epithelial neoplasia were observed in 23/39 PPI-treated versus 14/42 placebo-animals (p = 0.03). In conclusion, chronic omeprazole treatment improved the healing of esophageal ulcerative lesions. Locally invasive neoplastic lesions and PACM prevailed among PPI-treated animals. However, neither an effect on the overall mortality nor on the incidence of pre-neoplastic lesions was observed in this work.

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“…Gastrin exerts its effects mainly through activation of the cholecystokinin-2 receptor (CCK2R) [Ferrand and Wang, 2006]. CCK2R is overexpressed in BE and EAC [Harris et al 2004; Haigh et al 2003], and gastrin likely stimulates proliferation of Barrett’s epithelium through activation of this receptor. Haigh and colleagues showed that Barrett’s tissue not only expresses twice the number of CCK2 receptors as normal squamous esophageal epithelium, but also that incubation of Barrett’s tissue with amidated gastrin induces increased cellular proliferation, which can be abolished by treatment with a CCK2R antagonist [Haigh et al 2003].…”

Section: Discussionmentioning

confidence: 99%

“…CCK2R is overexpressed in BE and EAC [Harris et al 2004; Haigh et al 2003], and gastrin likely stimulates proliferation of Barrett’s epithelium through activation of this receptor. Haigh and colleagues showed that Barrett’s tissue not only expresses twice the number of CCK2 receptors as normal squamous esophageal epithelium, but also that incubation of Barrett’s tissue with amidated gastrin induces increased cellular proliferation, which can be abolished by treatment with a CCK2R antagonist [Haigh et al 2003]. Moreover, in vitro and in vivo , exogenously applied gastrins (G17, gly-G17, and progastrin) promote growth in various gastrointestinal cancer cell lines [Grabowska and Watson, 2007], and transgenic mice that overexpress amidated gastrin are more likely to develop gastric adenocarcinoma [Fox et al 2003; Wang et al 2000].…”

Section: Discussionmentioning

confidence: 99%

Correlation between serum gastrin and cellular proliferation in Barrett’s esophagus

Green

Mlynarczyk

Vaccaro

et al. 2010

Therap Adv Gastroenterol

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In nondysplastic BE patients on PPI therapy, serum gastrin levels were significantly correlated with cellular proliferation. These pilot data lend support to a potential causal effect of gastrin on neoplastic progression in BE. Longitudinal studies of patients with BE are needed to determine whether hypergastrinemia is a risk factor for the development of dysplasia and adenocarcinoma or could be used as a biomarker for disease progression.

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Gastrin induces proliferation in Barrettʼs metaplasia through activation of the CCK2 receptor

Cited by 4 publications

References 0 publications

Gastrin attenuates ischemia-reperfusion-induced intestinal injury in rats

Gastrin attenuates ischemia-reperfusion-induced intestinal injury in rats

Role of Proton Pump Inhibitor on Esophageal Carcinogenesis and Pancreatic Acinar Cell Metaplasia Development: An Experimental In Vivo Study

Correlation between serum gastrin and cellular proliferation in Barrett’s esophagus

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