Abstract
Prolonged epithelial cell proliferation in the gastric mucosa is a precursor to the development of cancer. Helicobacter pylori (H. pylori) virulence factor CagA stimulates epithelial cell proliferation by interacting with receptor tyrosine kinase c-Met. Cluster-of-differentiation gene CD44 acts as a co-receptor for c-Met, but its role in H. pylori induced epithelial proliferation is unknown. We tested the hypothesis that CD44 plays a functional role in H. pylori induced epithelial cell proliferation. Human and mouse derived fundic gastric organoids, hFGOs and mFGOs respectively, were infected with either G27 H. pylori strain or G27 expressing a deletion of CagA (ΔCagA). H. pylori-induced epithelial proliferation in hFGOs and mFGOs correlated with c-Met phosphorylation, and CagA/CD44/c-Met complex formation. H. pylori-induced proliferation was lost in mFGOs derived from CD44-deficient mice. H. pylori-induced epithelial proliferation was inhibited in hFGOs pre-treated with a CD44 neutralizing antibody. In v...
Highlights
The major cause of chronic inflammation in the stomach is Helicobacter pylori (H. pylori) [1], and it is widely accepted that chronic inflammation is a trigger for the development of gastric cancer [2]
We report the development and use of a novel model of primary human and mouse cultured gastric epithelial cells that are organized into three-dimensional spheroid units containing a lumen, known as gastric organoids
To assay changes in gastric epithelial cell proliferation in relation to the direct interaction with H. pylori, human- and mouse-derived gastric organoids were infected with the bacteria
Summary
The major cause of chronic inflammation in the stomach is Helicobacter pylori (H. pylori) [1], and it is widely accepted that chronic inflammation is a trigger for the development of gastric cancer [2]. Individuals most at risk of developing gastric cancer are those in whom the bacteria colonize the corpus (or fundus) of the stomach, when acid secretion is impaired. The subsequent development of severe inflammation in the gastric fundus leads to atrophy of the acid-secreting parietal cells and subsequently further hypochlorhydria, metaplasia and carcinoma [3,4,5]. Given that individuals most at risk of developing gastric cancer are those in whom the bacteria colonize the corpus [3,4,5], the current research is focused on the use of human- and mouse-derived fundic gastric epithelium, cultured as 3-dimensional structures called gastrointestinal organoids, for the study of H. pylori pathogenesis. The cag pathogenicity island encodes a type IV secretion system that is a multimolecular complex that mediates the translocation of bacterial factors into the host cell [6,7]. CagA exerts effects within host cells that mediate carcinogenesis, including aberrant activation of phosphatidylinositol 3-phosphate kinase (PI3K) and β catenin, disruption of apical-junctional complexes, and loss of cellular polarity [13,14,15]
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