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Control of gut differentiation and intestinal-type gastric carcinogenesis

Nature Reviews Cancer volume 3, pages 592–600 (2003)Cite this article

Key Points

  • Gastric cancer is histologically classified into two main types — intestinal and diffuse.

  • The carcinogenic pathway of intestinal-type gastric carcinomas is believed to begin with Helicobacter pylori infection, followed by chronic gastritis, atrophic gastritis and intestinal metaplasia.

  • Much has been learned recently about the transcriptional control of gut differentiation. Inappropriate activation of the intestine-specific transcription factor CDX2 is one of the most likely contributing factors in the induction of intestinal metaplasia of the stomach.

  • Intestinal metaplasia has been observed not only in the stomach, but also in other digestive organs such as the oesophagus, biliary tracts and gallbladder — possibly as a consequence of inflammatory lesions and regeneration.

  • Several genetic changes have been identified in intestinal-type gastric cancer. These include APC mutations and defects in the MLH1/microsatellite instability pathway, although these defects are only rarely observed. Mutation and/or loss of TP53 have been detected in more than half of the intestinal-type gastric cancers. However, the mechanisms that underlie most cases of this type of cancer remain to be determined.

Abstract

Gastric cancer is one of the world's most common cancers. Its carcinogenic pathway is mainly associated with Helicobacter pylori infection, subsequent inflammation and tissue regeneration. During the regeneration process, cells deviate from the normal pathway of gastric differentiation to an 'intestinal phenotype', which is thought to be precancerous and associated with the intestinal type of gastric cancer. Inappropriate activation of intestine-specific transcription factors could contribute to the occurrence of the intestinal-type cancer of the stomach.

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Figure 1: Models of the gastric carcinogenic pathway.
Figure 2: Regional expression of transcription factors in the developing gut.
Figure 3: Target genes of CDX2.
Figure 4: Causes of intestinal metaplasia and related cancers in digestive organs.

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Acknowledgements

The author thanks S. Yasugi, K. Nakachi, Y. Akiyama and Y.-Q. Bai for their valuable discussions. Supported in part by Grants-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Department of Molecular Oncology, Graduate School of Medicine and Dentistry, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, 113-8519, Tokyo, Japan

    Yasuhito Yuasa

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  1. Yasuhito Yuasa
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DATABASES

LocusLink

APC

CagA

CDX1

CDX2

IL-1β

neurogenin-3

PDX1

RUNX3

Sox2

TFF1

TFF2

TFF3

TGF-β

WAF1

WNT

FURTHER INFORMATION

The Canadian H. pylori web site

Cancer Research UK information on gastric cancer

NCI gastric cancer home page

Oncology channel's information on gastric cancer

Glossary

ENDODERM

The endoderm becomes the innermost layer of the embryo and produces the gut tube and its associated organs, including the liver and lungs.

SPLANCHNIC MESODERM

The mesoderm becomes sandwiched between the ectoderm and endoderm of the embryo. It generates the blood, heart, kidney, gonads, bones and connective tissues. The splanchnic mesoderm is the area of mesoderm closest to the endoderm.

SOMITOGENESIS

Formation of somites — paired blocks of mesoderm bracketing the neural tube that arise by segmentation of the paraxial mesoderm at all levels from the anterior hindbrain to the caudal (tail) region.

HOX GENES

Transcription factors that are characterized by a 60-amino-acid domain (the homeodomain) that binds to certain regions of DNA and controls regional specification along the anterior–posterior axis. Mouse and human genomes contain four copies (a–d) of the HOX complex located on four different chromosomes. The equivalent genes in each complex are called a paralogous group.

GASTRIC ANTRUM

The distal third of the stomach.

GENETIC MOSAIC ANALYSIS

To analyse spatial complexity of differentiation, chimeric mice are produced by injection of genetically manipulated embryonic stem cells (for example, Gata4−/−) into ROSA26 blastocysts bearing a ubiquitously expressed β-galactosidase transgene.

HYPOCHLORHYDRIA

Deficiency of hydrochloric acid in the gastric juice, often as a consequence of atrophic gastritis.

PANETH CELLS

Cells in the bottom of the intestinal crypt, containing eosinophil granules and secreting a variety of factors, including host defence factors against microbial pathogens.

GOBLET CELLS

A form of epithelial cell containing mucin and that is bulged like a goblet.

FUNDIC GLAND

A gland that is located in the fundus and body of the stomach. It contains highly specialized cells, which produce pepsinogen (chief cells) and acid (parietal cells).

MICROSATELLITE INSTABILITY

Characterized by expansion or contraction of short repeated DNA sequences (that is, microsatellite repeats) caused by insertion or deletion of repeated units. This instability, known also as a 'mutator phenotype' or 'replication error', indicates probable defects in the DNA mismatch-repair genes.

BARRETT'S OESOPHAGUS

The normal squamous oesophageal epithelium is replaced by columnar epithelium during the process of healing after repetitive injury to the oesophageal mucosa.

HEPATOLITHIASIS

Formation of calculi in the intrahepatic biliary tract. It frequently occurs in association with bacterial infection of the biliary tract or bile stasis. Most of these stones are made of calcium bilirubinate.

CHOLELITHIASIS

Formation of calculi in the biliary tract. Most of gallbladder calculi are made of cholesterol.

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Yuasa, Y. Control of gut differentiation and intestinal-type gastric carcinogenesis. Nat Rev Cancer 3, 592–600 (2003). https://doi.org/10.1038/nrc1141

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