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Microorganisms
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Helicobacter pylori and Gastric Carcinogenesis
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Helicobacter pylori and Gastric Carcinogenesis

A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Medical Microbiology".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 19847

Special Issue Editor

Dr. Raquel Mejias-Luque

E-Mail Website
Guest Editor
Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany
Interests: mechanisms of host-pathogen interaction during chronic infection, inflammation and carcinogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Helicobacter pylori infection is one of the most prevalent infections affecting half of the world´s population. If not treated, chronic infection may develop to more severe disease, including peptic ulcer disease, atrophy, dysplasia, intestinal metaplasia, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric adenocarcinoma. In order to colonize and persist in the human stomach, H. pylori has developed a number of strategies by which it manipulates, subverts, and eventually escapes the host´s immune response. Different bacterial virulence factors contribute to the infection. Of those, the cytotoxin-associated gene A (CagA) has been shown to have carcinogenic potential in a mouse model and to be associated with increased risk for gastric cancer development in infected subjects. Nevertheless, other virulence factors have been shown to interfere and alter signaling pathways related to tumorigenesis in host cells as well as to induce DNA damage, thereby contributing to gastric carcinogenesis. More recently, alterations in the gastric microbiota induced by H. pylori are also considered to be related to gastric cancer development and progression.

In this Special Issue, we will focus on the different mechanisms by which H. pylori contributes to the onset and progression of gastric tumors.

Dr. Raquel Mejias-Luque
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Helicobacter pylori
  • infection
  • chronic diseases
  • gastric cancer
  • tumors
  • mechanisms

Published Papers (6 papers)

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Research

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15 pages, 3140 KiB  
Article
Microbiome Signatures in a Fast- and Slow-Progressing Gastric Cancer Murine Model and Their Contribution to Gastric Carcinogenesis
by Prerna Bali, Joanna Coker, Ivonne Lozano-Pope, Karsten Zengler and Marygorret Obonyo
Microorganisms 2021, 9(1), 189; https://doi.org/10.3390/microorganisms9010189 - 17 Jan 2021
Cited by 13 | Viewed by 2993
Abstract
Gastric cancer is the third most common cause of death from cancer in the world and infection with Helicobacterpylori (H. pylori) is the main cause of gastric cancer. In addition to Helicobacter infection, the overall stomach microbiota has recently emerged [...] Read more.
Gastric cancer is the third most common cause of death from cancer in the world and infection with Helicobacterpylori (H. pylori) is the main cause of gastric cancer. In addition to Helicobacter infection, the overall stomach microbiota has recently emerged as a potential factor in gastric cancer progression. Previously we had established that mice deficient in myeloid differentiation primary response gene 88 (MyD88, Myd88−/−) rapidly progressed to neoplasia when infected with H. felis. Thus, in order to assess the role of the microbiota in this fast-progressing gastric cancer model we investigated changes of the gastric microbiome in mice with different genotypic backgrounds: wild type (WT), MyD88-deficient (Myd88−/−), mice deficient in the Toll/interleukin-1 receptor (TIR) domain-containing adaptor-inducing interferon-β (TRIF, TrifLps2), and MyD88- and TRIF-deficient (Myd88−/−/TrifLps2, double knockout (DKO)) mice. We compared changes in alpha diversity, beta diversity, relative abundance, and log-fold differential of relative abundance ratios in uninfected and Helicobacter infected mice and studied their correlations with disease progression to gastric cancer in situ. We observed an overall reduction in microbial diversity post-infection with H. felis across all genotypes. Campylobacterales were observed in all infected mice, with marked reduction in abundance at 3 and 6 months in Myd88−/− mice. A sharp increase in Lactobacillales in infected Myd88−/− and DKO mice at 3 and 6 months was observed as compared to TrifLps2 and WT mice, hinting at a possible role of these bacteria in gastric cancer progression. This was further reinforced upon comparison of Lactobacillales log-fold differentials with histological data, indicating that Lactobacillales are closely associated with Helicobacter infection and gastric cancer progression. Our study suggests that differences in genotypes could influence the stomach microbiome and make it more susceptible to the development of gastric cancer upon Helicobacter infection. Additionally, increase in Lactobacillales could contribute to faster development of gastric cancer and might serve as a potential biomarker for the fast progressing form of gastric cancer. Full article
(This article belongs to the Special Issue Helicobacter pylori and Gastric Carcinogenesis)
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18 pages, 2787 KiB  
Article
Polymorphisms in Pepsinogen C and miRNA Genes Associate with High Serum Pepsinogen II in Gastric Cancer Patients
by Valli De Re, Mariangela De Zorzi, Laura Caggiari, Ombretta Repetto, Giulia Brisotto, Raffaela Magris, Stefania Zanussi, Agostino Steffan and Renato Cannizzaro
Microorganisms 2021, 9(1), 126; https://doi.org/10.3390/microorganisms9010126 - 7 Jan 2021
Cited by 4 | Viewed by 2270
Abstract
Background: Pepsinogen (PG) II (PGII) is a serological marker used to estimate the risk of gastric cancer but how PGII expression is regulated is largely unknown. It has been suggested that PGII expression, from the PGC (Progastricsin) gene, is regulated by microRNAs (miRNA), [...] Read more.
Background: Pepsinogen (PG) II (PGII) is a serological marker used to estimate the risk of gastric cancer but how PGII expression is regulated is largely unknown. It has been suggested that PGII expression, from the PGC (Progastricsin) gene, is regulated by microRNAs (miRNA), but how PGII levels vary with Helicobacter pylori (H. pylori) infection and miRNAs genotype remains unclear. Methods: Serum levels of PGI and PGII were determined in 80 patients with gastric cancer and persons at risk for gastric cancer (74 first-degree relatives of patients, 62 patients with autoimmune chronic atrophic gastritis, and 2 patients with dysplasia), with and without H. pylori infection. As control from the general population, 52 blood donors were added to the analyses. Associations between PGII levels and genetic variants in PGC and miRNA genes in these groups were explored based on H. pylori seropositivity and the risk for gastric cancer. The two-dimensional difference in gel electrophoresis (2D-DIGE) and the NanoString analysis of messenger RNA (mRNAs) from gastric cancer tissue were used to determine the pathways associated with increased PGII levels. Results: PGII levels were significantly higher in patients with gastric cancer, and in those with H. pylori infection, than in other patients or controls. A PGI/PGII ratio ≤ 3 was found better than PGI < 25 ng/mL to identify patients with gastric cancer (15.0% vs. 8.8%). For two genetic variants, namely rs8111742 in miR-Let-7e and rs121224 in miR-365b, there were significant differences in PGII levels between genotype groups among patients with gastric cancer (p = 0.02 and p = 0.01, respectively), but not among other study subjects. Moreover, a strict relation between rs9471643 C-allele with H. pylori infection and gastric cancer was underlined. Fold change in gene expression of mRNA isolated from gastric cancer tissue correlated well with polymorphism, H. pylori infection, increased PGII level, and pathway for bacteria cell entry into the host. Conclusions: Serum PGII levels depend in part on an interaction between H. pylori and host miRNA genotypes, which may interfere with the cut-off of PGI/PGII ratio used to identify persons at risk of gastric cancer. Results reported new findings regarding the relation among H. pylori, PGII-related host polymorphism, and genes involved in this interaction in the gastric cancer setting. Full article
(This article belongs to the Special Issue Helicobacter pylori and Gastric Carcinogenesis)
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22 pages, 2870 KiB  
Article
Helicobacter Infection and Gastric Adenoma
by Simone Bertz, Miriam Angeloni, Jan Drgac, Christina Falkeis, Corinna Lang-Schwarz, William Sterlacci, Lothar Veits, Arndt Hartmann and Michael Vieth
Microorganisms 2021, 9(1), 108; https://doi.org/10.3390/microorganisms9010108 - 5 Jan 2021
Cited by 6 | Viewed by 2276
Abstract
Background: We aimed to provide insight into the actual frequencies of gastric adenoma types and their association with gastritis status and associated mucosal changes with a focus on Helicobacter infection and the operative link on gastritis assessment (OLGA)/operative link on gastric intestinal metaplasia [...] Read more.
Background: We aimed to provide insight into the actual frequencies of gastric adenoma types and their association with gastritis status and associated mucosal changes with a focus on Helicobacter infection and the operative link on gastritis assessment (OLGA)/operative link on gastric intestinal metaplasia assessment (OLGIM) staging. Methods: From the archive of the Institute of Pathology in Bayreuth, we collected a consecutive series of 1058 gastric adenomas diagnosed between 1987 and 2017. Clinicopathological parameters retrieved from diagnostic reports included adenoma type and localization, associated mucosal changes in antrum and corpus (i.e., type of gastritis, the extent of intestinal metaplasia and atrophy), gender, date of birth, and date of diagnosis. Results: Intestinal-type adenoma was the most frequent adenoma (89.1%), followed by foveolar-type adenoma (4.3%), pyloric gland adenoma (3.4%), adenomas associated with hereditary tumor syndromes (2.8%), and oxyntic gland adenoma (0.4%). Adenomas were found in the background of Helicobacter pylori (H. pylori) gastritis in 23.9%, Ex-H. pylori gastritis in 36.0%, autoimmune gastritis in 24.8%, chemical reactive gastritis in 7.4%, and others in 0.1%. More than 70% of patients with gastric adenomas had low-risk stages in OLGA and OLGIM. Conclusions: We found a higher frequency of foveolar-type adenoma than anticipated from the literature. It needs to be questioned whether OLGA/OLGIM staging can be applied to all patients. Full article
(This article belongs to the Special Issue Helicobacter pylori and Gastric Carcinogenesis)
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20 pages, 1839 KiB  
Article
Impact of Helicobacter pylori Infection and Its Major Virulence Factor CagA on DNA Damage Repair
by Eleftherios Kontizas, Spyros Tastsoglou, Timokratis Karamitros, Yiannis Karayiannis, Panagoula Kollia, Artemis G. Hatzigeorgiou and Dionyssios N. Sgouras
Microorganisms 2020, 8(12), 2007; https://doi.org/10.3390/microorganisms8122007 - 16 Dec 2020
Cited by 9 | Viewed by 3448
Abstract
Helicobacter pylori infection induces a plethora of DNA damages. Gastric epithelial cells, in order to maintain genomic integrity, require an integrous DNA damage repair (DDR) machinery, which, however, is reported to be modulated by the infection. CagA is a major H. pylori virulence [...] Read more.
Helicobacter pylori infection induces a plethora of DNA damages. Gastric epithelial cells, in order to maintain genomic integrity, require an integrous DNA damage repair (DDR) machinery, which, however, is reported to be modulated by the infection. CagA is a major H. pylori virulence factor, associated with increased risk for gastric carcinogenesis. Its pathogenic activity is partly regulated by phosphorylation on EPIYA motifs. Our aim was to identify effects of H. pylori infection and CagA on DDR, investigating the transcriptome of AGS cells, infected with wild-type, ΔCagA and EPIYA-phosphorylation-defective strains. Upon RNA-Seq-based transcriptomic analysis, we observed that a notable number of DDR genes were found deregulated during the infection, potentially resulting to base excision repair and mismatch repair compromise and an intricate deregulation of nucleotide excision repair, homologous recombination and non-homologous end-joining. Transcriptome observations were further investigated on the protein expression level, utilizing infections of AGS and GES-1 cells. We observed that CagA contributed to the downregulation of Nth Like DNA Glycosylase 1 (NTHL1), MutY DNA Glycosylase (MUTYH), Flap Structure-Specific Endonuclease 1 (FEN1), RAD51 Recombinase, DNA Polymerase Delta Catalytic Subunit (POLD1), and DNA Ligase 1 (LIG1) and, contrary to transcriptome results, Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APE1) upregulation. Our study accentuates the role of CagA as a significant contributor of H. pylori infection-mediated DDR modulation, potentially disrupting the balance between DNA damage and repair, thus favoring genomic instability and carcinogenesis. Full article
(This article belongs to the Special Issue Helicobacter pylori and Gastric Carcinogenesis)
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20 pages, 3301 KiB  
Article
Dysregulated Immune Responses by ASK1 Deficiency Alter Epithelial Progenitor Cell Fate and Accelerate Metaplasia Development during H. pylori Infection
by Yoku Hayakawa, Yoshihiro Hirata, Masahiro Hata, Mayo Tsuboi, Yukiko Oya, Ken Kurokawa, Sohei Abe, Junya Arai, Nobumi Suzuki, Hayato Nakagawa, Hiroaki Fujiwara, Keisuke Tateishi, Shin Maeda and Kazuhiko Koike
Microorganisms 2020, 8(12), 1995; https://doi.org/10.3390/microorganisms8121995 - 14 Dec 2020
Cited by 5 | Viewed by 2510
Abstract
The mechanism of H. pylori-induced atrophy and metaplasia has not been fully understood. Here, we demonstrate the novel role of Apoptosis signal-regulating kinase 1 (ASK1) and downstream MAPKs as a regulator of host immune responses and epithelial maintenance against H. pylori infection. [...] Read more.
The mechanism of H. pylori-induced atrophy and metaplasia has not been fully understood. Here, we demonstrate the novel role of Apoptosis signal-regulating kinase 1 (ASK1) and downstream MAPKs as a regulator of host immune responses and epithelial maintenance against H. pylori infection. ASK1 gene deficiency resulted in enhanced inflammation with numerous inflammatory cells including Gr-1+CD11b+ myeloid-derived suppressor cells (MDSCs) recruited into the infected stomach. Increase of IL-1β release from apoptotic macrophages and enhancement of TH1-polarized immune responses caused STAT1 and NF-κB activation in epithelial cells in ASK1 knockout mice. Dysregulated immune and epithelial activation in ASK1 knockout mice led to dramatic expansion of gastric progenitor cells and massive metaplasia development. Bone marrow transplantation experiments revealed that ASK1 in inflammatory cells is critical for inducing immune disorder and metaplastic changes in epithelium, while ASK1 in epithelial cells regulates cell proliferation in stem/progenitor zone without changes in inflammation and differentiation. These results suggest that H. pylori-induced immune cells may regulate epithelial homeostasis and cell fate as an inflammatory niche via ASK1 signaling. Full article
(This article belongs to the Special Issue Helicobacter pylori and Gastric Carcinogenesis)
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Review

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19 pages, 1402 KiB  
Review
Helicobacter pylori-Derived Outer Membrane Vesicles (OMVs): Role in Bacterial Pathogenesis?
by Miroslaw Jarzab, Gernot Posselt, Nicole Meisner-Kober and Silja Wessler
Microorganisms 2020, 8(9), 1328; https://doi.org/10.3390/microorganisms8091328 - 31 Aug 2020
Cited by 37 | Viewed by 5539
Abstract
Persistent infections with the human pathogen Helicobacter pylori (H. pylori) have been closely associated with the induction and progression of a wide range of gastric disorders, including acute and chronic gastritis, ulceration in the stomach and duodenum, mucosa-associated lymphoid tissue (MALT) [...] Read more.
Persistent infections with the human pathogen Helicobacter pylori (H. pylori) have been closely associated with the induction and progression of a wide range of gastric disorders, including acute and chronic gastritis, ulceration in the stomach and duodenum, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric adenocarcinoma. The pathogenesis of H. pylori is determined by a complicated network of manifold mechanisms of pathogen–host interactions, which involves a coordinated interplay of H. pylori pathogenicity and virulence factors with host cells. While these molecular and cellular mechanisms have been intensively investigated to date, the knowledge about outer membrane vesicles (OMVs) derived from H. pylori and their implication in bacterial pathogenesis is not well developed. In this review, we summarize the current knowledge on H. pylori-derived OMVs. Full article
(This article belongs to the Special Issue Helicobacter pylori and Gastric Carcinogenesis)
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