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  • Review Article
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Gastrin — active participant or bystander in gastric carcinogenesis?

Nature Reviews Cancer volume 6, pages 936–946 (2006)Cite this article

Key Points

  • Coordinated activity between somatostatin and gastrin-releasing peptide (GRP) regulates secretion of gastrin from G cells in a negative and positive manner, respectively, to facilitate the release of gastric acid from parietal cells.

  • In transgenic mouse models, hypergastrinaemia contributes to the development of atrophy in the proximal gastric mucosa through the induction of parietal cell apoptosis, leading to the development of gastric adenocarcinoma. This phenomenon has not been confirmed in human gastric cancer.

  • Infection with Helicobacter pylori is associated with increased gastrin levels in serum and components of the bacterium might activate the gastrin promoter directly and indirectly. Conversely, infection with H. pylori reduces somatostatin activity. Furthermore, GRP, somatostatin and gastrin seem to modulate the inflammatory response to the bacterium.

  • Gastrin and GRP have well-documented pro-carcinogenic roles, particularly in animal models, that affect proliferation, angiogenesis and apoptosis, whereas the potential pro-apoptotic signal of somatostatin is lost during carcinogenesis owing to weak expression of somatostatin receptor isoforms.

  • Clinical agonists and antagonists of the three hormones have shown modest activity in patients with gastrointestinal cancer, and rational combinations of these agents might prove to be more clinically beneficial.

Abstract

Gastrin is a pro-proliferative, anti-apoptotic hormone with a central role in acid secretion in the gastric mucosa and a long-standing association with malignant progression in transgenic mouse models. However, its exact role in human gastric malignancy requires further validation. Gastrin expression is tightly regulated by two closely associated hormones, somatostatin and gastrin-releasing peptide, and aspects of their interaction may be deregulated during progression to gastric adenocarcinoma. Furthermore, agonists and antagonists of the receptors for all three hormones have shown modest clinical efficacy against gastric adenocarcinoma, which might provide useful information on the future combined use of these agents.

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Figure 1: The macroscopic and microscopic cellular interactions of the human gastric antro-pyloric and corpic/fundic mucosa.
Figure 2: Gastrin-mediated carcinogenic pathways.

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Acknowledgements

The authors would like to acknowledge J. McClelland from the Academic Unit of Cancer Studies for her input into the diagrams within this article and E. Royal for the personal communication regarding her ongoing studies.

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  1. Academic Unit of Cancer Studies, University of Nottingham, Nottingham, NG7 2UH, UK

    Susan A. Watson, Anna M. Grabowska, Mohamad El-Zaatari & Arjun Takhar

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Susan A. Watson is on the Scientific Advisory Board of Receptor Biologix, who have just purchased the rights to the drug G17DT.

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DATABASES

Entrez Protein

gastrin

GRP

somatostatin

FURTHER INFORMATION

Wolfson Digestive Diseases Centre

Glossary

Proton pump inhibitors

Agents that block acid secretion in the stomach and are used for the treatment of stomach ulcers.

Enterochromaffin-like cell

A neuroendocrine cell, found in the gastric mucosa, that secretes histamine following hormonal stimulation.

Antro-pyloric mucosa

The lower region of the stomach spanning the antrum and pylorus.

Oxyntic mucosa

The region within the gastric mucosa that contains acid-secreting glands.

Parietal cells

Cells of the gastric mucosa that produce gastric acid in response to histamine, gastrin or stimulation by the vagal nerve.

Fundus

The dome-shaped upper part of the stomach.

Secretagogue

A molecule that stimulates the secretion of gastric or pancreatic peptides.

Lauren classification

A histological method for classifying gastric tumours into intestinal or diffuse type. The intestinal type is characterized by the formation of cohesive gland-like tubular structures, whereas the diffuse type involves infiltration and thickening of the stomach wall by individual cells.

Signet ring

A poorly differentiated diffuse type of gastric cancer in which the nuclei of glandular cells are pushed aside by mucin vacuoles within the cell, giving them the appearance of a signet ring.

Isthmus

The region of the gastric gland between the pit and neck that contains immature progenitor cells.

Corpus

The main body of the stomach.

Zymogenic cell

Also known as chief cells, these secrete pepsinogen and are characterized by spherical zymogen granules. They differentiate as they migrate downwards from the isthmus to the base of the gastric gland.

Explosive exocytosis

The rapid release of the contents of cellular vesicles at the cell surface.

Corpus atrophy

Loss of glandular structure within the corpus mucosa which is possibly accompanied by fibrosis, thinning of the lamina propria and replacement of gastric epithelium by intestinal metaplastic epithelium.

Helicobacter felis

A strain of Helicobacter that was originally isolated from a cat and is also able to colonize mice and dogs.

Pseudo-pyloric gland metaplasia

Gastric metaplasia in which gastric glands disappear and are replaced by tubules that closely resemble normal pyloric glands.

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Watson, S., Grabowska, A., El-Zaatari, M. et al. Gastrin — active participant or bystander in gastric carcinogenesis?. Nat Rev Cancer 6, 936–946 (2006). https://doi.org/10.1038/nrc2014

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