Elsevier

Current Opinion in Pharmacology

Volume 31, December 2016, Pages 31-37
Current Opinion in Pharmacology

Gastrin and upper GI cancers

https://doi.org/10.1016/j.coph.2016.08.013Get rights and content

Highlights

  • •

    Gastrin promotes proximal gastric cancer development but inhibits distal cancer development.

  • •

    PPI use increases serum gastrin levels and may affect gastric carcinogenesis.

  • •

    A subset of gastric antral and cardia stem cells express CCK2R.

  • •

    Hypergastrinemia promotes Barrett's esophageal metaplasia arising from cardia stem cells.

Gastrin was initially identified as the hormone primarily responsible for gastric acid secretion, but was subsequently shown to be a growth factor for the proximal stomach, acting through the gastrin receptor CCK2R. Studies in the past several decades have explored the role of gastrin, along with its incompletely processed precursors, in cancer development. The growth in long-term PPI use has frequently led to elevations in serum gastrin levels in patients with upper GI disease, including GERD, peptic ulcers, and chronic gastritis. However, while accumulated evidence has shown that gastrin likely does not promote — and may even suppress — distal antral gastric cancer, questions have now arisen regarding possible effects of gastrin on the development of gastric cardia cancer or esophageal adenocarcinoma at gastroesophageal junction. Here, we provide an overview of the possible roles of these gastrin peptides in upper GI cancer.

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.

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