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Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer

Key Points

  • The stomach is a versatile organ that protects against countless forms of endogenous and exogenous injury, mainly through the production of acid

  • The injury response of the stomach can be classified into two main patterns: one that protects against endogenous acid (superficial response) and one that adapts when the source of acid is lost or compromised (glandular response)

  • The glandular response is a process that is best understood in the gastric corpus and involves a replacement of injured epithelium with metaplastic cells, a process known as spasmolytic polypeptide-expressing metaplasia (SPEM)

  • Studies have highlighted the epithelial plasticity of the gastric corpus, in particular the ability of postmitotic zymogenic chief cells to re-enter the cell cycle and fuel the repair of injured epithelium

Abstract

Subjected to countless daily injuries, the stomach still functions as a remarkably efficient digestive organ and microbial filter. In this Review, we follow the lead of the earliest gastroenterologists who were fascinated by the antiseptic and digestive powers of gastric secretions. We propose that it is easiest to understand how the stomach responds to injury by stressing the central role of the most important gastric secretion, acid. The stomach follows two basic patterns of adaptation. The superficial response is a pattern whereby the surface epithelial cells migrate and rapidly proliferate to repair erosions induced by acid or other irritants. The stomach can also adapt through a glandular response when the source of acid is lost or compromised (that is, the process of oxyntic atrophy). We primarily review the mechanisms governing the glandular response, which is characterized by a metaplastic change in cellular differentiation known as spasmolytic polypeptide-expressing metaplasia (SPEM). We propose that the stomach, like other organs, exhibits marked cellular plasticity: the glandular response involves reprogramming mature cells to serve as auxiliary stem cells that replace lost cells. Unfortunately, such plasticity might mean that the gastric epithelium undergoes cycles of differentiation and de-differentiation that increase the risk of accumulating cancer-predisposing mutations.

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Figure 1: The anatomical and glandular organization of the human stomach.
Figure 2: The superficial and glandular responses in the gastric corpus.
Figure 3: Distinguishing the possible cellular origins of spasmolytic polypeptide-expressing metaplasia.
Figure 4: The expansion of spasmolytic polypeptide-expressing metaplasia and the cyclical hit model: a possible mechanism for dysplasia.

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Acknowledgements

J.B.S. holds a Postdoctoral Enrichment Program Award from the Burroughs Wellcome Fund and is also supported by the American Gastroenterology Association Gastric Cancer Foundation Research Scholar Award. J.C.M. is supported by National Institute of Diabetes and Digestive and Kidney Diseases awards DK094989, DK105129 and DK110406, by the Alvin J. Siteman Cancer Center–Barnes Jewish Hospital Foundation Cancer Frontier Fund, NIH National Cancer Institute P30 CA091842 and The Barnard Trust.

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Correspondence to Jason C. Mills.

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PowerPoint slides

Glossary

Superficial response

How the stomach (both corpus and antrum) repairs erosive injury (most commonly, owing to acid) on the epithelial surface.

Surface epithelium

Mucus-secreting cells that line the surface of the stomach; also referred to as surface, foveolar or pit cells.

Glandular response

How the stomach adapts to injury involving loss of acid-secreting parietal cells and digestive enzyme-secreting chief cells from gastric glands in the corpus.

Gastric pits

The surface epithelium invaginates into gastric units that are funnel-shaped and dive downward towards the gastric muscular wall. The mouth-like opening of each gastric unit represents the gastric pit; the zone where the pit narrows into the gland harbours actively dividing stem cells and is called the isthmus.

Gastric glands

We use here the human pathology definition of the gastric gland as being separate from the gastric pit. The glandular portion of a gastric unit is located at the base (that is, nearest the stomach muscular wall) and extends up to the isthmus. In the corpus, the gastric gland comprises parietal, chief, mucous neck and endocrine cells. In the antrum, the gastric gland contains mucous and endocrine cells.

Achlorhydria

The absence of hydrochloric acid in gastric secretions.

Ménétrier disease

A rare gastric condition characterized by hypertrophied gastric folds, hyperplasia of the surface epithelium and hypochlorhydria or achlorhydria.

Oxyntic atrophy

A process characterized by the loss of acid-producing, or oxyntic, glands from the corpus.

Zollinger–Ellison syndrome

A clinical syndrome defined by gastric acid hypersecretion owing to a gastrin-producing tumour (that is, gastrinoma).

Hypochlorhydria

Decreased or low hydrochloric acid in gastric secretions.

Transdifferentiation

The conversion of a cell type of one lineage to a cell type of a different lineage.

Atrophic front

The stomach-adapted bacterium Helicobacter pylori is known to cause atrophy and metaplasia of the corpus in a subset of chronically infected patients; this atrophy spreads along a front from the antrum into the corpus along the lesser curvature.

Cyclical hit model of tumorigenesis

A proposal that mutations can accumulate and be stored in differentiated cells. Following injury, differentiated cells can re-enter the cell cycle and proliferate. During their proliferative phase, mutations can be acquired. As cells re-differentiate, the acquired mutations are stored. These stored mutations may accumulate with little effect until the cells either undergo apoptosis or become trapped in a (proliferative) dysplastic state.

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Sáenz, J., Mills, J. Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer. Nat Rev Gastroenterol Hepatol 15, 257–273 (2018). https://doi.org/10.1038/nrgastro.2018.5

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