Gastric cancer's bad incidence, prognosis, cellular and molecular heterogeneity amongst others make this disease a major health issue worldwide. Understanding this affliction is a priority for proper ...patients' management and for the development of efficient therapeutical strategies. This review gives an overview of major scientific advances, made during the past 5-years, to improve the comprehension of gastric adenocarcinoma. A focus was made on the different actors of gastric carcinogenesis, including,
cancer stem cells, tumour microenvironment and microbiota. New and recent potential biomarkers were assessed as well as emerging therapeutical strategies involving cancer stem cells targeting as well as immunotherapy. Finally, recent experimental models to study this highly complex disease were discussed, highlighting the importance of gastric cancer understanding in the hard-fought struggle against cancer relapse, metastasis and bad prognosis.
The therapeutic potential of metformin in gastric cancer Courtois, Sarah; Lehours, Philippe; Bessède, Emilie
Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association,
07/2019, Letnik:
22, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Metformin is a biguanide molecule used since 1957 to treat type 2 diabetes patients. In addition to its hypoglycemic effects, epidemiological studies have shown that metformin can be associated with ...a decrease in cancer development risk in diabetic populations. Thus, since 2005 this molecule is largely studied for its antitumoural properties in different types of cancer. The potential antitumoural effect of metformin in gastric cancer has been poorly studied. Here, we detailed the different described mechanisms implicated in the antitumoural effect of metformin in gastric cancer, from the signalling pathways to the functional effects on gastric cancer cell lines and gastric cancer stem cells.
Gastric carcinomas (GC) are heterogeneous tumors, composed of a subpopulation of cluster of differentiation‐44 (CD44)+ tumorigenic and chemoresistant cancer stem cells (CSC). YAP1 and TAZ ...oncoproteins (Y/T) interact with TEA domain family member 1 (TEAD) transcription factors to promote cell survival and proliferation in multiple tissues. Their activity and role in GC remain unclear. This work aimed to analyze Y/T‐TEAD activity and molecular signature in gastric CSC, and to assess the effect of verteporfin, a Food and Drug Administration‐approved drug preventing Y/T‐TEAD interaction, on gastric CSC tumorigenic properties. Y/T‐TEAD molecular signature was investigated using bioinformatical (KmPlot database), transcriptomic and immunostaining analyses in patient‐derived GC and cell lines. Verteporfin effects on Y/T‐TEAD transcriptional activity, CSC proliferation and tumorigenic properties were evaluated using in vitro tumorsphere assays and mouse models of patient‐derived GC xenografts. High expressions of YAP1, TAZ, TEAD1, TEAD4 and their target genes were associated with low overall survival in nonmetastatic human GC patients (n = 444). This Y/T‐TEAD molecular signature was enriched in CD44+ patient‐derived GC cells and in cells resistant to conventional chemotherapy. Verteporfin treatment inhibited Y/T‐TEAD transcriptional activity, cell proliferation and CD44 expression, and decreased the pool of tumorsphere‐forming CD44+/aldehyde dehydrogenase (ALDH)high gastric CSC. Finally, verteporfin treatment inhibited GC tumor growth in vivo; the residual tumor cells exhibited reduced expressions of CD44 and ALDH1, and more importantly, they were unable to initiate new tumorspheres in vitro. All these data demonstrate that Y/T‐TEAD activity controls gastric CSC tumorigenic properties. The repositioning of verteporfin targeting YAP1/TAZ‐TEAD activity could be a promising CSC‐based strategy for the treatment of GC.
What's new?
In gastric cancer, populations of cancer stem cells (CSCs), which initiate and sustain tumor growth and drive tumor recurrence, are maintained through activity of the yes‐associated protein 1 (YAP1), TAZ, and TEA domain transcription factor (TEAD) complex. In this study, employing gastric cancer models, transcriptional activity of the YAP1/TAZ‐TEAD complex was successfully inhibited by the benzoporphyrin derivative verteporfin. Specifically, verteporfin decreased the pool of gastric CSCs in vitro and in vivo and inhibited tumor growth in patient‐derived gastric cancer xenografts. The results suggest that targeting YAP1/TAZ‐TEAD activity with verteporfin is a promising therapeutic strategy for gastric cancer.
This article summarizes the main findings concerning
associated with gastric MALT lymphoma (GML). Considered together, GML strains based on their virulence factor profile appear to be less virulent ...than those associated with peptic ulcers or gastric adenocarcinoma. A particular Lewis antigen profile has been identified in GML strains and could represent an alternative adaptive mechanism to escape the host immune response thereby allowing continuous antigenic stimulation of infiltrating lymphocytes.
Background
Knowledge of antimicrobial susceptibility, especially to macrolides, has become crucial for the management of Helicobacter pylori infection. Our aim was to evaluate two new PCR kits able ...to detect H. pylori in gastric biopsies as well as the mutations associated with macrolide resistance.
Materials and Methods
Two hundred successive biopsies (received from gastroenterologists all over France) were used. The two new kits tested were Amplidiag H. pylori+ClariR from Mobidiag Espoo, Finland, and RIDA®GENE H. pylori from R‐Biopharm, Darmstadt, Germany. Culture and a validated in‐house real‐time PCR were also performed, and in the case of a positive culture, Etest for clarithromycin was carried out. Discrepancies were solved by looking at the pathologic data.
Results
Culture was positive in 68 cases (34%), and with our in‐house real‐time PCR in these 68 cases plus 5 others (N = 73, 36%). All were also detected by the two new kits. In addition, RIDA®GENE H. pylori detected one more positive also detected by Amplidiag H. pylori+ClariR, and Amplidiag detected two other positives. Of these three additional cases, pathology confirmed the positivity for two. Only one case diagnosed by Amplidiag could be considered as a false positive. With regard to clarithromycin resistance, 22 cases were detected. The corresponding mutations (A2142/43G) were all identified with the three PCRs.
Conclusions
These two new kits which have an excellent sensitivity and specificity are convenient to use, adaptable to different thermocyclers, provide quick results, and deserve to be used in H. pylori diagnosis for a better choice of treatment regimen.
Medline, PubMed and the Cochrane databases were searched on epidemiology and diagnosis of Helicobacter pylori for the period of April 2011–March 2012. Several studies have shown that the prevalence ...of H. pylori infection is decreasing in adults and children in many countries. Various diagnostic tests are available, and most of them have high sensitivity and specificity. The Maastricht IV/Florence consensus report states that the urea breath test using 13C urea remains the best test to diagnose H. pylori infection. Among the stool antigen tests, the ELISA monoclonal antibody test is recommended. All these tests were used, either as a single diagnostic test or in combination, to investigate H. pylori infection among different populations throughout the world. Of particular interest, current improvements in high‐resolution endoscopic technologies enable increased diagnostic accuracy for the detection of H. pylori infection, but none of these techniques, at present, are specific enough for obtaining a real‐time diagnosis of H. pylori infection.
Background
The diagnosis of Helicobacter pylori infection can be made by PCR on gastric biopsies. The objective of this study was to evaluate retrospectively the performance of the Allplex™ H pylori ...and ClariR PCR Assay (Seegene).
Material and Methods
A collection of 180 DNA samples extracted from gastric biopsies was used in this study: 90 DNAs from H pylori‐negative patients and 90 from H pylori‐positive patients. The Allplex™ H pylori and ClariR Assay was performed on a CFX96™ real‐time PCR System and analyzed using the Seegene Viewer software. The real‐time PCR used as the reference was our in‐house H pylori PCR, and discrepant results were tested by the Amplidiag® H pylori + ClariR PCR (Mobidiag).
Results
The performance of the Allplex™ H pylori and ClariR Assay showed 100% sensitivity, 97.6% specificity, 98% PPV, and 100% NPV. Regarding the detection of H pylori in the 90 expected negative samples, eight late amplifications were obtained (Ct > 39). Six of these eight samples were also positive using the Amplidiag® H pylori + ClariR kit and were therefore considered as true positives. For the two remaining cases, non‐pathological evidence of H pylori infection was found. H pylori was detected in all 90 positive samples. Compared with our in‐house H pylori PCR, all H pylori WT cases or mutated cases were correctly detected.
Conclusions
The Allplex™ H pylori and ClariR Assay showed an excellent performance and can be integrated into the armamentarium of diagnostic tests for H pylori infection. This kit has the advantage of differentiating the main mutations associated with macrolide resistance.
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.
PDF
