Gastric Cancer: A Stem Cell Disease?

Gastric stem cells have been recently identified and are not yet fully characterized. Each gastric gland or unit is composed of different specialized cells and a small number of discrete stem cells. These gastric stem cells play key roles. They have self-renewal and multipotent properties and are the origin of specialized gastric epithelial cells. These properties are the basis for the stem cells’ role in tissue homeostasis, tissue repair, and cancer. In tumors, growing evidence indicates that a cell subpopulation with stem cell features, the so-called cancer stem cells (CSCs), represents the “fuel” for the tumor: they are at the origin of tumor initiation, growth, and dissemination, and they also display resistance to conventional chemotherapy treatments. The recent identification of CSCs in gastric carcinoma opens the door to the development of new therapeutic strategies targeting more specifically the CSCs at the origin of the disease, which is the third leading cause of cancer-related deaths worldwide

Genome-wide identification of host-segregating SNPs for source attribution of clinical Campylobacter coli isolates

International audienceCampylobacter is among the most common causes of gastroenteritis worldwide. Campylobacter jejuni and Campylobacter coli are the most common species causing human-disease. DNA-sequence-based methods for strain characterization have focussed largely on C. jejuni, responsible for 80-90% of infections, meaning that C. coli epidemiology has lagged behind. Here we have analyzed the genome of 450 C. coli isolates to determine genetic markers that can discriminate isolates sampled from 3 major reservoir hosts (chickens, cattle and pigs). These markers were then applied to identify the source of infection of 147 C. coli from French clinical cases. Using STRUCTURE software, 259 potential host-segregating markers were revealed by probabilistic characterization of SNP frequency variation in strain collections from three different hosts. These SNPs were found in 41 genes or intergenic regions, mostly coding for proteins involved in motility and membrane functions. Source attribution of clinical isolates based on the differential presence of these markers confirmed chicken as the most common source of C. coli infection in France.IMPORTANCE Genome-wide and source attribution studies based on Campylobacter species have shown their importance for the understanding of foodborne infections. Although the use of MLST based on 7 genes from C. jejuni is a powerful method to structure populations, when applied to C. coli results have not clearly demonstrated their robustness. Therefore, we aim here to provide more accurate data based on the identification of single-nucleotide polymorphisms. Results from this study reveal an important number of host-segregating SNPs, found in proteins implied in motility, membrane functions or DNA repair systems. These findings offer new interesting opportunities for further study on C. coli adaptation to its environment. Additionally, the results demonstrate that poultry is potentially the main reservoir of C. coli in France

Autophagy induced by Helicobacter pylori infection is necessary for gastric cancer stem cell emergence

Background: The main cause of gastric cancer is the infection by the bacterium Helicobacter pylori which induces a chronic inflammation and an epithelial-to-mesenchymal transition (EMT) leading to the emergence of cells with cancer stem cell (CSC) properties. However, the underlying mechanisms have not been fully characterized. Moreover, H. pylori modulates the host cell autophagic process, but a few studies have investigated the role of this process in tumoral transformation. The aim of this study was to determine whether H. pylori-induced autophagy has a role in CSC emergence. Methods: Autophagic flux in response to H. pylori infection was characterized in AGS cell line expressing the tandem-tagged mCherry-GFP-LC3 protein and using a ratiometric flow cytometry analysis. Then, AGS and MKN45 cell lines were treated with bafilomycin or chloroquine, two pharmaceutical well-known inhibitors of autophagy, and different EMT and CSC characteristics were analyzed. Results: First, a co-expression of the gastric CSC marker CD44 and the autophagic marker LC3 in mice and human stomach tissues infected with H. pylori was observed. Then, we demonstrated in vitro that H. pylori was able to activate the autophagy process with a reduced autophagic flux. Finally, infected cells were treated with autophagy inhibitors, which reduced (i) appearance of mesenchymal phenotypes and migration ability related to EMT and (ii) CD44 expression as well as tumorsphere formation capacities reflecting CSC properties. Conclusion: In conclusion, all these data show that H. pylori-induced autophagy is implicated in gastric CSC emergence and could represent an interesting therapeutic target.This work was supported by the French foundation Ligue contre le Cancer (Pyrénées Atlantiques)

TAZ Controls Helicobacter pylori-Induced Epithelial–Mesenchymal Transition and Cancer Stem Cell-Like Invasive and Tumorigenic Properties

Helicobacter pylori infection, the main risk factor for gastric cancer (GC), leads to an epithelial–mesenchymal transition (EMT) of gastric epithelium contributing to gastric cancer stem cell (CSC) emergence. The Hippo pathway e ectors yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ) control cancer initiation and progression in many cancers including GC. Here, we investigated the role of TAZ in the early steps of H. pylori-mediated gastric carcinogenesis. TAZ implication in EMT, invasion, and CSC-related tumorigenic properties were evaluated in three gastric epithelial cell lines infected by H. pylori. We showed that H. pylori infection increased TAZ nuclear expression and transcriptional enhancer TEA domain (TEAD) transcription factors transcriptional activity. Nuclear TAZ and zinc finger E-box-binding homeobox 1 (ZEB1) were co-overexpressed in cells harboring a mesenchymal phenotype in vitro, and in areas of regenerative hyperplasia in gastric mucosa of H. pylori-infected patients and experimentally infected mice, as well as at the invasive front of gastric carcinoma. TAZsilencing reduced ZEB1 expression andEMTphenotype, and strongly inhibited invasion and tumorsphere formation induced by H. pylori. In conclusion, TAZ activation in response to H. pylori infection contributes to H. pylori-induced EMT, invasion, and CSC-like tumorigenic properties. TAZ overexpression in H. pylori-induced pre-neoplastic lesions and in GC could therefore constitute a biomarker of early transformation in gastric carcinogenesis.Ligue Nationale Française Contre le Cancer (French National League against Cancer)/[]//FranciaUniversidad de Costa Rica/[]/UCR/Costa RicaMinisterio de Ciencia, Innovación, Tecnología y Telecomunicaciones/[]/MICITT/Costa RicaFrench National Cancer Institute/[PLBio 2014-152]/INCa/FranciaLigue Contre le Cancer/[]//FranciaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA

The Hippo Kinase LATS2 Controls Helicobacter pylori-Induced Epithelial-Mesenchymal Transition and Intestinal Metaplasia in Gastric Mucosa

Gastric carcinoma is related mostly to CagA+-Helicobacter pylori infection, which disrupts the gastric mucosa turnover and elicits an epithelial-mesenchymal transition (EMT) and preneoplastic transdifferentiation. The tumor suppressor Hippo pathway controls stem cell homeostasis; its core, constituted by the large tumor suppressor 2 (LATS2) kinase and its substrate Yes-associated protein 1 (YAP1), was investigated in this context.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA

A prospective, observational study of fidaxomicin use for Clostridioides difficile infection in France.

To describe the characteristics, management and outcomes of hospitalised patients with Clostridioides difficile infection (CDI) treated with and without fidaxomicin. This prospective, multicentre, observational study (DAFNE) enrolled hospitalised patients with CDI, including 294 patients treated with fidaxomicin (outcomes recorded over a 3-month period) and 150 patients treated with other CDI therapies during three 1-month periods. The primary endpoint was baseline and CDI characteristics of fidaxomicin-treated patients. At baseline, the fidaxomicin-treated population included immunocompromised patients (39.1%) and patients with severe (59.2%) and recurrent (36.4%) CDI. Fidaxomicin was associated with a high rate of clinical cure (92.2%) and low CDI recurrence (16.3% within 3 months). Clinical cure rates were ≥90% in patients aged ≥65 years, those receiving concomitant antibiotics and those with prior or severe CDI. There were 121/296 (40.9%) patients with adverse events (AEs), 5.4% with fidaxomicin-related AEs and 1.0% with serious fidaxomicin-related AEs. No fidaxomicin-related deaths were reported. Fidaxomicin is an effective and well-tolerated CDI treatment in a real-world setting in France, which included patients at high risk of adverse outcomes.Trial registration: Description of the use of fidaxomicin in hospitalised patients with documented Clostridium difficile infection and the management of these patients (DAFNE), NCT02214771, www.ClinicalTrials.gov

Review: Diagnosis of Helicobacter pylori infection

International audienceNew imaging techniques are still the topic of many evaluations for both the diagnosis of Helicobacter pylori gastritis and the detection of early gastric cancer. Concerning invasive tests, there were studies on the reuse of the rapid urease test material for other tests, and a novel fluorescent method to be used for histology but with limited sensitivity. Progress occurred essentially in the molecular methods area, especially next‐generation sequencing which is applied to detect both H pylori and the mutations associated with antibiotic resistance. For non‐invasive tests, a few studies have been published on the validity of breath collection bags, the shortening of the testing time, the performance of different analysers or the added value of citric acid in the protocol. The accuracy of serological immunochromatographic tests is also improving. Multiplex serology detecting antibodies to certain proteins allows confirmation of a current infection. Dried blood spots can be used to collect and store blood without a loss of accuracy. Finally, the serum antibody titer can be useful in predicting the risk of gastric cancer. Several stool antigen tests were evaluated with good results, and a novel test using immunomagnetic beads coated with monoclonal antibodies is potentially interesting. PCR detection in stools can also be effective but needs an efficient DNA extraction method. The use of easyMAG® (bioMérieux) combined with Amplidiag® H pylori + ClariR (Mobidiag) appears to be powerful

Metformin Modifies the Gut Microbiota of Mice Infected with Helicobacter pylori

Metformin is widely prescribed to treat type 2 diabetes. Diabetes patients treated with metformin have a decreased risk of cancers, including gastric cancer. Among the factors influencing digestive carcinogenesis, gut microbiota interactions have been intensively studied. Metformin exhibits direct antimicrobial activity toward Helicobacterpylori, which plays a crucial role in gastric carcinogenesis. Mice were infected with H. pylori and treated for 12 days with either metformin or phosphate-buffered saline (PBS) as a control. At the end of the treatment period, the mice were euthanized and cecal and intestinal contents and stool were collected. The gut microbiota of the three different digestive sites (stool, cecal, and intestinal contents) were characterized through 16S RNA gene sequencing. In mice infected with H. pylori, metformin significantly decreased alpha diversity indices and led to significant variation in the relative abundance of some bacterial taxa including Clostridium and Lactobacillus, which were directly inhibited by metformin in vitro. PICRUSt analysis suggested that metformin modifies functional pathway expression, including a decrease in nitrate reducing bacteria in the intestine. Metformin significantly changed the composition and predicted function of the gut microbiota of mice infected with H. pylori; these modifications could be implicated in digestive cancer prevention

Survey of the antimicrobial resistance of Helicobacter pylori in France in 2018 and evolution during the previous 5 years

International audienceBackground and objectives: Surveillance of Helicobacter pylori resistance to antibiotics was carried out in France in 2014, 2016, and 2018. We report here the results of the 2018 survey as well as the evolution over the 5-year period.Materials and methods: In this observational study, gastric biopsies were obtained by 62 gastroenterologists randomly selected in 5 regions of France and sent to a central laboratory where culture, antimicrobial susceptibility testing, and a real-time PCR were performed in order to detect H pylori and its mutations associated with clarithromycin resistance.Results and conclusion: During the year 2018, 951 patients were included: 55.3% women, mean age: 52.4 years ± 15.7, 71.6% born in France. Among them, 359 patients were H pylori positive by both culture and real-time PCR, and 7 more by PCR only. There were 244 naive patients, 110 previously treated patients, and unknown for 5. Primary resistance to clarithromycin was 20.9% [16.3-26.4], to levofloxacin 17.6% [13.4-22.9], and to metronidazole 58.6% [52.3%-64.6%]. Secondary resistance for these antibiotics was 56.4%, 22.7%, and 87.3%, respectively. There was no resistance to amoxicillin and tetracycline and very low resistance to rifampicin (1.2%) in both naive and treated patients. Primary resistance to clarithromycin decreased from 22.2% to 20.3% between 2014 and 2016, and appears to be stable since then. This can be linked to a stable consumption of macrolides over the 3-year time period. Primary levofloxacin resistance was relatively stable while metronidazole resistance increased. Interestingly, in both naive and treated patients, amoxicillin and rifampicin resistance were rare

Metformin can inhibit Helicobacter pylori growth

International audienceAim: Helicobacter pylori infection is a worldwide infection, its eradication rates with conventional therapies have fallen to unacceptable levels. In this context we were interested in metformin, to determine its effect on H. pylori growth.Materials & methods: Antimicrobial susceptibility tests and survival curves were performed in vitro and a H. pylori-infected mice model was used to determine metformin effect in vivo.Results: Helicobacter pylori survival and growth were decreased in presence of metformin. Furthermore, metformin-treated mice had significantly less bacteria in their stomach than the untreated mice.Conclusion: Our work is the first to demonstrate a direct antimicrobial effect of metformin on H. pylori, indicating that this molecule has not yet revealed its full potential