Gastrin and upper GI cancers
Graphical abstract
Section snippets
Historical background
Interest in the possible growth effects of the peptide hormone gastrin emerged shortly after its isolation and characterization by Gregory and Tracy in 1964. Gastrin, produced by G cells in the gastric antrum, was identified as the circulating hormone responsible for acid secretion from parietal cells through release of histamine from enterochromaffin-like (ECL) cells. In addition to severe gastric acid hypersecretion, gastrinoma patients who exhibit Zollinger–Ellison (ZE) syndrome were noted
PPIs, Helicobacter pylori, and gastric cancer
Given the role of gastrin as a growth factor, the concern was raised as to whether PPIs could increase the risk of gastric adenocarcinoma. Gastric cancer was known to develop under conditions of hypochlorhydria, particularly in the setting of H. pylori-associated pangastritis that involves both the antrum and corpus. Further, it was recognized that colonization of the human stomach by H. pylori was highly dependent on gastric pH, given that H. pylori is an acid neutralophile, preferring a
Gastrin and gastric cancer in mouse models
The notion that hypergastrinemia might promote gastric cancer emerged in 2000 with a detailed analysis of the stomach of insulin-gastrin (INS-GAS) transgenic mice. These mice consisted of the insulin promoter upstream of the human gastrin coding sequences, and resulted in the overexpression of amidated gastrin (primarily G-17) in the pancreatic β-cells, leading to 2-fold elevations in circulating levels of amidated gastrin [22]. INS-GAS mouse stomach showed increased gastric acid secretion and
Downstream gastrin targets: the gastrin receptor CCK2R
Investigation of downstream targets of amidated gastrin began soon after the isolation and cloning of the CCK2R, a seven transmembrane G-protein coupled receptor, from canine parietal cells in 1992 by the Kopin laboratory. In the stomach, CCK2R was found to be expressed almost exclusively in the gastric fundus, where it could be detected mostly on parietal and ECL cells, consistent with its role in acid secretion [33]. Recently discovered gastric stem cells which express Mist1 in the isthmus of
Possible roles of incompletely processed gastrins
The biology of gastrin also extends beyond activities associated with amidated gastrin and the CCK2R. Transcription of the gastrin gene first gives rise to a gastrin precursor, known as preprogastrin. Preprogastrin is converted into progastrin through cleavage of the 21 amino acids N-terminus signal peptide. Progastrin is then cleaved by endoproteases, leading to the formation of the glycine-extended gastrin 34 (G34-gly). G34-gly then undergoes proteolytic cleavage to obtain the final amidated
CCK2R labels antral stem cells
The explanation for these effects of gastrin isoforms on the gastric antrum became clear with the finding that the CCK2R was expressed on the +4 antral stem cell [41••]. Using CCK2R-CreERT mice, CCK2R+ cells were found to be actively cycling but long-lived stem cells that could lineage trace the entire antral epithelium (Figure 1). These CCK2R+ antral stem cells were mostly not overlapping with Lgr5+ stem cells, and actually showed higher rates of proliferation. Treatment with progastrin
Gastrin and cancers at GEJ
In the past, most gastric cancer arose from distal antral stomach with a intestinal type histology [54••]. This type of gastric cancer, most strong linked to H. pylori infection, was often linked to low gastrin levels, given that gastrin-producing G cells were eliminated by H. pylori-induced intestinal metaplasia. However, in the last several decades, the tumor sites of gastric cancer have migrated proximally, that is, the gastric cancer in the corpus, cardia, and gastroesophageal junction
Conclusions
Gastrin appears to play an important role in modulating upper gastrointestinal cancers. Low level of serum gastrin may be a risk factor for antral gastric cancers, while hypergastrinemia may predispose to proximal and GEJ cancers including BE and EAC.
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
TCW is supported by the National Institute of Health grant R37 DK052778, RO1 CA093405, U54 CA163004, and the Clyde Wu Family Foundation.
References (63)
- et al.
Effect of gastrin receptor blockade on endocrine cells in rats during achlorhydria
Gastroenterology
(1992) - et al.
Effect of chronic hypergastrinemia on human enterochromaffin-like cells: insights from patients with sporadic gastrinomas
Gastroenterology
(2002) - et al.
Serum gastrin levels in different stages of distal gastric carcinogenesis: is there a role for serum gastrin in tumor growth?
Turk J Gastroenterol
(2014) - et al.
Synergistic inhibitory effects of gastrin and histamine receptor antagonists on Helicobacter-induced gastric cancer
Gastroenterology
(2005) - et al.
Long-term proton pump inhibitor administration worsens atrophic corpus gastritis and promotes adenocarcinoma development in Mongolian gerbils infected with Helicobacter pylori
Gut
(2011) - et al.
Gastrin and cancer: a review
Cancer Lett
(2006) - et al.
Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma
Oncogene
(2005) - et al.
Inhibition of gastric carcinogenesis by the hormone gastrin is mediated by suppression of TFF1 epigenetic silencing
Gastroenterology
(2011) - et al.
Cellular expression of CCK-A and CCK-B/gastrin receptors in human gastric mucosa
Regul Pept
(2001) - et al.
Analysis of gastrin receptor gene expression in proliferating cells in the neck zone of gastric fundic glands using laser capture microdissection
FEBS Lett
(2001)
Gastrin stimulates the growth of gastric pit cell precursors by inducing its own receptors
Am J Physiol Gastrointest Liver Physiol
The use of murine-derived fundic organoids in studies of gastric physiology
J Physiol
Histidine decarboxylase gene expression in rat fundus is regulated by gastrin
FEBS Lett
Gastrin induces CXC chemokine expression in gastric epithelial cells through activation of NF-kappaB
Am J Physiol Gastrointest Liver Physiol
Indian Hedgehog mediates gastrin-induced proliferation in stomach of adult mice
Gastroenterology
Overexpression of glycine-extended gastrin inhibits parietal cell loss and atrophy in the mouse stomach
Cancer Res
Gastrin is an essential cofactor for helicobacter-associated gastric corpus carcinogenesis in C57BL/6 mice
Am J Pathol
Elevated serum gastrin is associated with a history of advanced neoplasia in Barrett's esophagus
Am J Gastroenterol
Barrett oesophagus: lessons on its origins from the lesion itself
Nat Rev Gastroenterol Hepatol
Gastrin and the trophic control of gastric mucosa
Scand J Gastroenterol Suppl
Opposite effects of gastrin on cell proliferation in the antrum and other parts of the upper-gastrointestinal tract in the rat
Am J Dig Dis
Effects of very long (up to 10 years) proton pump blockade on human gastric mucosa
Digestion
Gastrin receptor antagonist YM022 prevents hypersecretion after long-term acid suppression
Am J Physiol
Gastric ECL-cell hyperplasia and carcinoids in rodents following chronic administration of H2-antagonists SK&F 93479 and oxmetidine and omeprazole
Toxicol Pathol
Pathophysiological effects of long-term acid suppression in man
Dig Dis Sci
Deletion of Men1 and somatostatin induces hypergastrinemia and gastric carcinoids
Gut
Early events in proton pump inhibitor-associated exacerbation of corpus gastritis
Aliment Pharmacol Ther
Increase of Helicobacter pylori-associated corpus gastritis during acid suppressive therapy: implications for long-term safety
Am J Gastroenterol
Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication
N Engl J Med
Changing patterns of Helicobacter pylori gastritis in long-standing acid suppression
Helicobacter
Serum gastrin levels during long-term omeprazole treatment
Aliment Pharmacol Ther
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