Efficacy Study of Helicobacter Pylori Eradication in Patients Undergoing Subtotal Gastrectomy for Gastric Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Gastric Cancer,Stomach Neoplasms
PROVIDER: 2079940 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:This study evaluates whether Helicobacter pylori eradication improves precancerous lesions including glandular atrophy and intestinal metaplasia as well as metachronous cancers or dysplasias after endoscopic mucosal resection for gastric cancer.
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Project description:Helicobacter pylori infection triggers a cascade of inflammatory stages that may lead to the appearance of non-atrophic gastritis, multifocal atrophic gastritis, intestinal metaplasia, dysplasia, and cancer. Deleted in malignant brain tumors 1 (DMBT1) belongs to the group of secreted scavenger receptor cysteine-rich proteins and is considered to be involved in host defense by binding to pathogens. Recent studies have shown that DMBT1 expression is up-regulated in areas of intestinal metaplasia and in gastric tumors. Here, we examined the role of DMBT1 in the development of inflammatory response and gastric precancerous lesions in Caucasian, African American and Hispanic populations as well as in a mouse model. We found that mucosal DMBT1 expression is significantly increased in individuals with more advanced gastric precancerous lesions. We also show that H. pylori infection of Dmbt1-/- mice results in enhanced gastric inflammation and the development of mucous metaplasia that is accompanied by increased cell proliferative rates and reduced IL-33 expression levels in the inflamed mucosa. Taken together, our data suggest that DMBT1 may be mediating mucosal protection that may reduce the risk of developing gastric precancerous lesions in response to H. pylori infection
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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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Project description:Helicobacter pylori (H. pylori) infection is a key initiating factor in the Correa cascade of gastric carcinogenesis, but the comprehensive understanding of the pathogenic mechanisms underlying H. pylori-induced GC remains elusive. Here, we generated a single-cell atlas of gastric tumorigenesis comprising 18 specimens of gastritis, intestinal metaplasia and gastric cancer (GC) with or without H. pylori infection. We identified 48 distinct cell subpopulations including novel rare subtypes, and revealed the influence of H. pylori infection on cellular heterogeneity across neoplastic lesions.
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Project description:Helicobater pylori plays an important role in the development of gastric cancer. Eradication therapy can reducing the morbidity of gastric cancer, but can’t totally prevent it especially when atrophy and more serious precancerous lesions already happened. Prior studies found the gastric bacterial difference among gastritis, intestinal metaplasia and gastric cancer. However, they didn’t reach an agreement. Correa’s model is widely accepted in the development of gastric cancer. The pathological change makes a more suitable environment for bacteria to overgrowth. This study are designed to analyze the gastric microbial difference of non-atrophic gastritis, atrophic gastritis, intestinal metaplasia, intraepithelial neoplasia and gastric cancer.
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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
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Project description:Carcinogenic bacteria, Helicobacter pylori, induce DNA double-strand breaks in infected host cells, while ATM-dependent DNA damage responses in host cells suppress genome instabilities caused by DNA breakages, which resulting in the suppression of H. pylori-induced gastric cancers. Although Helicobacter pylori infection is etiologically related to the inflammation-related malignancy, gastric cancers, it role in the molecular pathogenesis of disease remains unclear. In vitro studies have suggested the infection may cause breaks in double-stranded DNA. We used microarray analysis of H. pylori-infected human gastric biopsies to investigate the effect of H. pylori on gene expression genes involved in DNA repair and DNA damage response. Micro-array analysis and immunohistochemistory showed that ATM (ataxia-telangiectasia mutated) was upregulated in H. pylori gastritis but down regulated in the premalignant lesion, intestinal metaplasia. Studies in gastric cancer cell lines showed that H. pylori-infection induced activation of ATM and formation of γ-H2AX. γ-H2AX formation was present following infection with bout cag pathogenicity island (PAI)- positive and negative strains but more robust with cag PAI positive strains consistent with the fact that both cag PAI positive negative strains are associated with gastric cancer but the risk is higher with cag PAI positive strains. Eradication of H. pylori infection is associated with a reduction in cancer risk even in the most high risk populations. These data provide a plausible molecular mechanism for a direct bacterial-host interaction increasing cancer risk. To identify tumor suppressors affected by H. pylori-infection, microarray screening was used to compare the gene expression profiles of gastric mucosa obtained from individuals with H. pylori-gastritis and with intestinal metaplasia with tissue from uninfected controls.
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Project description: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.
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Project description: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.
2015-12-17 | GSE69144 | GEO