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The homing receptor CD44 is involved in the progression of precancerous gastric lesions in patients infected with Helicobacter pylori and in development of mucous metaplasia in mice (human)

ABSTRACT: Gastric cancer continues to be one of the most common cancers, with the third highest cancer-related mortality in the world. After infection with Helicobacter pylori, a cascade of inflammatory events that can lead to gastric cancer is triggered. This inflammatory response to the infection is characterized by the infiltration of mononuclear and polymorphonuclear cells into the infected mucosa. The transition of these cells from the circulation to the tissues is mediated through the interaction of receptors on the immune cells and their ligands in the endothelial compartment. CD44 is the receptor for hyaluronan, but it also interacts with osteopontin and collagen, among other molecules. Previous reports have shown that CD44 expression is increased in advanced gastric lesions. However, the association of this molecule with the progression of these lesions over time has not been investigated. In addition, there is a lack of understanding of the CD44-dependent cellular processes that lead to gastritis, and possibly to gastric cancer. Here we studied a subset of subjects from a cohort of individuals with various degrees of gastric inflammation to determine gene expression changes associated with disease progression over a period of six years. We report that CD44 expression is significantly increased in individuals whose gastric lesions progressed over time (from multifocal atrophic gastritis to intestinal metaplasia or from intestinal metaplasia to dysplasia) along the gastric precancerous cascade. We also show that CD44-/- mice develop less severe and less extensive Helicobacter pylori-induced metaplasia, and show fewer infiltrating Gr1+ cells compared to wild type mice. Thus, we present data suggesting that CD44 is associated with disease progression. Mechanisms associated with these effects include induction of interferon gamma responses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE69144 | GEO | 2015/12/17

SECONDARY ACCESSION(S): PRJNA284640

REPOSITORIES: GEO

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Project description:Chronic infection with the bacterial pathogen Helicobacter pylori is a risk factor for the development of gastric cancer, yet remains asymptomatic in a majority of individuals. We report here that the C57Bl6 mouse model of experimental infection with the closely related H. felis recapitulates this wide range in host susceptibility. A majority of infected mice develop premalignant lesions such as gastric atrophy, compensatory epithelial hyperplasia and intestinal metaplasia, whereas a minority is completely protected from preneoplasia. Protection is associated with the failure to mount an IFN-gamma response to the infection and an associated high Helicobacter burden. We demonstrate that IFN-gamma is essential for clearance of Helicobacter, but also mediates the formation of preneoplastic lesions. We further provide evidence that IFN-gamma triggers a specific transcriptional program in murine gastric epithelial cells in vitro and in vivo, and induces their preferential transformation to the hyperplastic phenotype. In summary, our data suggest a dual role for IFN-gamma in Helicobacter pathogenesis that could provide an explanation for the differential susceptibility to H. pylori-induced gastric pathology in the human population. Keywords: response to in vitro stimulus / comparison of histopathological states We chose mice for gene expression profiling that following Helicobacter infection had (a) symptoms of gastritis, but no epithelial changes, (b) atrophic gastritis accompanied by corpus gland hyperplasia or (c) atrophic gastritis accompanied by intestinal metaplasia. An uninfected control group was also included in the analysis, as were two groups of mice that lacked mature T- and B-cells due to a deletion mutation in the rag1 gene (Rag-1-/-) and that were either experimentally infected or served as Rag-1-/- uninfected controls. To see the effects of IFNg on murine gastric epithelial cells we analysed an immortalized murine primary gastric epithelial cell line treated with three different concentrations of IFNg in comparison to an untreated control.

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The homing receptor CD44 is involved in the progression of precancerous gastric lesions in patients infected with Helicobacter pylori and in development of mucous metaplasia in mice (human)

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