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Oesophageal adenocarcinoma and gastric cancer: should we mind the gap?

Nature Reviews Cancer volume 16, pages 305–318 (2016)Cite this article

Subjects

Key Points

  • There has been a dramatic increase in the incidence of oesophageal adenocarcinoma (OAC) and intestinal-type gastric cancer (GC) arising near the gastric–oesophageal junction (GOJ).

  • OAC and intestinal-type GC share many common molecular features.

  • OAC and intestinal-type GC are derived from the inflammation–metaplasia cascade that occurs in the oesophageal epithelium in OAC and in the gastric epithelium in intestinal-type GC.

  • Barrett oesophagus and OAC may originate from gastric stem cells derived from the cardia.

Abstract

Over recent decades we have witnessed a shift in the anatomical distribution of gastric cancer (GC), which increasingly originates from the proximal stomach near the junction with the oesophagus. In parallel, there has been a dramatic rise in the incidence of oesophageal adenocarcinoma (OAC) in the lower oesophagus, which is associated with antecedent Barrett oesophagus (BO). In this context, there has been uncertainty regarding the characterization of adenocarcinomas spanning the area from the lower oesophagus to the distal stomach. Most relevant to this discussion is the distinction, if any, between OAC and intestinal-type GC of the proximal stomach. It is therefore timely to review our current understanding of OAC and intestinal-type GC, integrating advances from cell-of-origin studies and comprehensive genomic alteration analyses, ultimately enabling better insight into the relationship between these two cancers.

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Figure 1: Dynamic epidemiology of gastric cancer and oesophageal adenocarcinoma.
Figure 2: Sequential steps in oesophageal and gastric carcinogenesis.
Figure 3: Stem cells in the oesophagus and stomach, and origins of Barrett oesophagus and gastric cancer.
Figure 4: Molecular subtypes of gastric cancer and oesophageal adenocarcinoma.

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Authors and Affiliations

  1. Division of Digestive and Liver Diseases and Herbert Irving Cancer Research Center, Columbia University College of Physicians and Surgeons, 1130 St Nicholas Avenue, New York, 10032, New York, USA

    Yoku Hayakawa & Timothy C. Wang

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, 02215, Massachusetts, USA

    Nilay Sethi & Adam J. Bass

  3. Division of Clinical Pathology and Cell Biology, Department of Pathology, Columbia University College of Physicians and Surgeons, New York, 10032, New York, USA

    Antonia R. Sepulveda

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  1. Yoku Hayakawa
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PowerPoint slides

Glossary

Correa pathway

A cascade that describes the sequential steps during disease progression from superficial chronic gastritis, gastric atrophy and intestinal metaplasia to gastric dysplasia and cancer, proposed by Correa and colleagues.

Goblet cells

Columnar cells in the intestinal glands that secrete mucins such as MUC2 into the gut lumen.

Hypochlorhydria

A decrease or lack of hydrochloric acid in the gastric juice. Hypochlorhydria is accompanied by a gastric atrophy and intestinal metaplasia sequence, in which the number of acid-secreting parietal cells is decreased.

Proton pump inhibitors

(PPIs). Drugs commonly used for patients with gastric ulcer that inhibit gastric acid secretion by binding to the H+/K+-ATPase.

Hypergastrinaemia

Elevated levels of serum gastrin. As gastrin promotes gastric acid secretion from parietal cells, hypergastrinaemia occurs in a negative feedback manner when acid secretion is suppressed by certain drugs such as proton pump inhibitors (PPIs).

Hiatal hernia

A condition in which part of the stomach, including the cardia, slides up towards the oesophageal hiatus in the chest cavity.

Stratified squamous epithelium

Consists of several layers of keratin-expressing squamous cells on a basal membrane, and it is seen in the skin, mouth, oesophagus and vagina.

LGR5

A receptor that can bind to R-spondin and activate the WNT–β-catenin pathway.

Parietal cells

Gastric epithelial cells that reside in the corpus and secrete gastric acid.

Chief cells

Gastric epithelial cells that reside in the base of corpus glands and secrete digestive enzymes such as pepsin.

Enterochromaffin-like (ECL) cells

Gastric epithelial neuroendocrine cells that promote acid secretion from parietal cells by producing histamine.

LRIG1

Expressed in intestinal and epidermal stem cells and regulates quiescence of these cells.

SOX2

Expressed in multiple stem cells including embryonic stem cells and adult tissue stem cells, and is essential for maintaining self-renewal and pluripotency.

LGR5–DTR mouse

A mouse in which diphtheria toxin receptor (DTR) is expressed in leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5)+ cells. Given that cells in mice do not normally express DTR, only LGR5+ cells are killed and ablated when diphtheria toxin (DT) is given. In the stomach, mature chief cells express LGR5, thus DT administration causes specific cell death in the chief cell population.

Signet ring cancer cells

Cancer cells that contain a large quantity of mucins in the cytoplasm and have a thin nucleus in the cell periphery.

G-cells

Gastric epithelial cells in the antrum that secrete gastrin.

D-cells

Gastric epithelial cells in the antrum that secrete somatostatin.

+4 position

The cell position in a gastrointestinal gland is usually counted and numbered from the base of the gland (that is, the cell at the bottom of the gland is called position +1). Until leucine-rich repeat- containing G protein-coupled receptor 5 (LGR5)+ stem cells were discovered, it was thought that major gastrointestinal stem cells resided at the +4 position, based on label-retaining assays.

CCKBR

A receptor for the gastrin peptide. It has been thought to be involved in gastric acid secretion in CCKBR+ neuroendocrine cells and parietal cells.

Residual embryonic cells

(RECs). Potential precursors of Barrett oesophagus; these cells are most evident in the gastric cardia in the embryonic stage, but some can persist in adult mice.

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Hayakawa, Y., Sethi, N., Sepulveda, A. et al. Oesophageal adenocarcinoma and gastric cancer: should we mind the gap?. Nat Rev Cancer 16, 305–318 (2016). https://doi.org/10.1038/nrc.2016.24

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