Gastrin induces proliferation in Barrett's metaplasia through activation of the CCK2 receptor

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

doi:10.1053/gast.2003.50091

Cited by 141 publications

(115 citation statements)

References 33 publications

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“…Carboxy-terminal amidated gastrin stimulates the growth of oesophageal, gastric, pancreatic and colon cancer cell lines in culture (Iwase et al 1997, Stepan et al 1999, Haigh et al 2003, inhibits apoptosis in pancreatic cancer cells (Todisco et al 2001), and transgenic overexpression of gastrin induces gastric atrophy and promotes the development of gastric cancer , Fox et al 2003. The larger precursor 80 amino acid progastrin peptide also stimulates proliferation of colon cancer cell lines , inhibits pancreatic cancer apoptosis (Rengifo-Cam et al 2007), and transgenic mice over-expressing progastrin exhibit colonic hyperproliferation, increased mitosis after irradiation and adenomata and carcinomas after exposure to the chemical carcinogen azoxymethane (Cobb et al 2004, Ottewell et al 2005.…”

Section: Introductionmentioning

confidence: 99%

Glycine-extended gastrin inhibits apoptosis in Barrett's oesophageal and oesophageal adenocarcinoma cells through JAK2/STAT3 activation

Beales

Ogunwobi²

2009

Journal of Molecular Endocrinology

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Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC) are regarded as complications of gastrooesophageal reflux disease, although all the factors that contribute to the development of these lesions are unknown. Acid suppressive drugs are widely used for symptomatic therapy of reflux disease but may induce hypersecretion of gastrin peptides. Amidated gastrin (G-17) has been shown to be a growth factor for OAC cells. We have examined the effects of glycine-extended gastrin (G-Gly), an alternative product of progastrin processing on apoptosis in the QhERT Barrett's oesophageal cell line and OE33 and BIC-1 OAC cells. G-Gly inhibited serum-starvation and camptothecininduced apoptosis in all three cell lines, G-17 was only effective in OE33 cells. By contrast to the effects of G-17, the antiapoptotic effect of G-Gly was independent of both the CCK 2 receptor and cyclo-oxygenase-2 activity. G-Gly stimulated JAK2 phosphorylation and kinase activity and JAK2-dependent STAT3 phosphorylation and transcriptional activity. G-Gly also increased mRNA and protein levels of the anti-apoptotic proteins survivin and BCL2L1 but did not affect the levels of BAD, BAX or BCL-2. Novel small molecule inhibitors of JAK2 and STAT3 as well as STAT3 siRNA blocked the anti-apoptotic effects of G-Gly and inhibited the induction of survivin and BCL2L1 in OE33 cells. We conclude that G-Gly inhibits apoptosis in BO and OAC via mechanisms distinct from those activated by G-17 and involving JAK2 and STAT3 activation. Release of gastrin peptides in response to acid suppressive therapy may adversely influence the dynamics of the epithelium in BO.

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Section: Introductionmentioning

confidence: 99%

Glycine-extended gastrin inhibits apoptosis in Barrett's oesophageal and oesophageal adenocarcinoma cells through JAK2/STAT3 activation

Beales

Ogunwobi²

2009

Journal of Molecular Endocrinology

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“…Haigh et al found that the CCK-2 receptor was also expressed in the normal esophagus, reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma (44). Therefore, we believe that high levels of circulating gastrin resulting from chronic bile reflux may cause proliferation of the forestomach squamous epithelium through the same mechanism.…”

Section: Glandular Stomachmentioning

confidence: 79%

The effects of chronic bile reflux on the gastric mucosa of rats

Wang

Tang²,

Cao³

2013

Turk J Gastroenterol

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“…For example, chronic PPI therapy leads to elevations in serum gastrin levels, which have been linked to increased proliferation in Barrett biopsy specimens in vitro. 132,133 Overall, the clinical data support the approach of potent acid suppression as a chemopreventive strategy in patients with Barrett esophagus. However, controlled, prospective clinical trials are still needed before this can be recommended for widespread practice.…”

Section: Prevention Of Cancer In Patients With Barrett Esophagusmentioning

confidence: 89%

Concepts in the Prevention of Adenocarcinoma of the Distal Esophagus and Proximal Stomach

Souza

Spechler

2005

CA: A Cancer Journal for Clinicians

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For decades, the incidence rates for squamous cell carcinoma of the esophagus and adenocarcinoma of the distal stomach have been declining while the rates for adenocarcinomas of the esophagus and gastric cardia have increased profoundly. Recent studies have shown that the gastroesophageal junction (GEJ) is regularly exposed to concentrated gastric acid and to a variety of nitrosating species, noxious agents that may contribute to carcinogenesis in this region. For adenocarcinomas that straddle the GEJ, it can be difficult to determine whether the tumor originated in the esophagus or in the gastric cardia. This classification problem hampers studies on the epidemiology and pathogenesis of GEJ tumors. Current concepts in the prevention of cancers of the distal esophagus and proximal stomach have emerged from advances in our understanding of the specific molecular events that occur during the evolution of these tumors. This report reviews those events and focuses on current concepts in the prevention of adenocarcinomas at the GEJ. The similarities and differences in risk factors, molecular pathogenesis, and in preventive strategies for adenocarcinomas of the esophagus and gastric cardia are highlighted. (CA Cancer J Clin 2005;55:334-351.)

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Gastrin induces proliferation in Barrett's metaplasia through activation of the CCK2 receptor

Cited by 141 publications

References 33 publications

Glycine-extended gastrin inhibits apoptosis in Barrett's oesophageal and oesophageal adenocarcinoma cells through JAK2/STAT3 activation

Glycine-extended gastrin inhibits apoptosis in Barrett's oesophageal and oesophageal adenocarcinoma cells through JAK2/STAT3 activation

The effects of chronic bile reflux on the gastric mucosa of rats

Concepts in the Prevention of Adenocarcinoma of the Distal Esophagus and Proximal Stomach

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