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H. pylori Virulence Factors in the Induction of Gastric Cancer

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A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: closed (31 January 2017) | Viewed by 94126

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Prof. Dr. Jean E. Crabtree

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Molecular Gastroenterology Section, Leeds Institute of Biomedical and Clinical Sciences, Wellcome Trust Brenner Building, St. James's University Hospital, Leeds LS9 7TF, UK
Interests: Helicobacter pylori; host-pathogen interactions in gastrointestinal tract; infection and gastrointestinal cancer; mucosal immunology
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Prof. Dr. Silja Wessler

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Department of Molecular Biology, Division of Microbiology, Paris-Lodron University of Salzburg, Billroth Str. 11, A-5020 Salzburg, Austria
Interests: Helicobacter pylori; host-pathogen interactions; pathogenic factors; signal transduction

Special Issue Information

Dear Colleagues,

Helicobacter pylori is a class-I carcinogen and one of the most successful pathogens known today. Globally circa 50% of the world´s population is infected with H. pylori. Infection results in long-term chronic gastritis and is associated with increased risk of peptic ulceration, gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. H. pylori infection levels are highest in developing countries where early H. pylori infection in children is associated with important extra-gastric manifestations such as anaemia, growth impairment and increased diarrhoeal disease. With H. pylori infection levels decreasing in developed countries the future areas of high incidence of H. pylori-associated gastric cancer are likely to be in developing countries.

Recent advances in microbial pathogenesis have shed light on the role of H. pylori in neoplasia. Determinants are the manifold strategies of pathogen-host interaction at the epithelial interface that involve different H. pylori factors which interfere with epithelial cells and cells from the immune system. This review series provides the current knowledge on all essential aspects in the rapidly evolving area of H. pylori research. The reviews focus on the vacuolating cytotoxin A (VacA), which interacts with gastric epithelial cells, but also T cells. The cytotoxin associated gene A (CagA) is another important virulence factor of H. pylori functioning as an effector protein, which is translocated through the pilus of a type IV secretion system into the cytoplasm of host cells. Once injected, CagA can deregulate cancer-associated signal transduction pathways. Additional H. pylori factors involve γ-glutamyl transpeptidase (GGT) or high temperature requirement A (HtrA) representing new players in the complex network of H. pylori mechanisms. The development of appropriate animal models of H. pylori infection has allowed in vivo analysis of the role of specific H. pylori virulence factors in neoplasia. These reviews target both clinicians and microbiologists. They provide an important up-to-date summary of our current knowledge of H. pylori factors and the multiple strategies of how it affects public health all over the world.

Prof. Dr. Jean E. Crabtree
Prof. Dr. Silja Wessler
Guest Editors

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

3 pages, 216 KiB

Open AccessEditorial

Special Issue “H. pylori Virulence Factors in the Induction of Gastric Cancer”

by Jean E. Crabtree and Silja Wessler

Toxins 2018, 10(5), 176; https://doi.org/10.3390/toxins10050176 - 26 Apr 2018

Cited by 3 | Viewed by 3939

Abstract

Twenty-five years ago, Helicobacter pylori was identified as the causative agent of gastric disorders,
ranging from acute inflammation [...] Full article

(This article belongs to the Special Issue H. pylori Virulence Factors in the Induction of Gastric Cancer)

Research

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3072 KiB

Open AccessArticle

The Middle Fragment of Helicobacter pylori CagA Induces Actin Rearrangement and Triggers Its Own Uptake into Gastric Epithelial Cells

by Abolghasem Tohidpour, Rebecca J. Gorrell, Anna Roujeinikova and Terry Kwok

Toxins 2017, 9(8), 237; https://doi.org/10.3390/toxins9080237 - 28 Jul 2017

Cited by 13 | Viewed by 6797

Abstract

Cytotoxin-associated gene product A (CagA) is a major virulence factor secreted by Helicobacter pylori. CagA activity in the gastric epithelium is associated with higher risk of gastric cancer development. Bacterial type IV secretion system (T4SS)-mediated translocation of CagA into the cytosol of human epithelial cells occurs via a poorly understood mechanism that requires CagA interaction with the host membrane lipid phosphatidylserine (PS) and host cell receptor integrin α₅β₁. Here we have characterized the isolated recombinant middle fragment of CagA (CagA-M) that contains the positively-charged PS-binding region (aa 613–636) and a putative β₁ integrin binding site, but lacks the EPIYA region, secretion signal peptide and the CagA multimerization motif. We show that CagA-M, when immobilized on latex beads, is capable of binding to, and triggering its own uptake into, gastric epithelial cells in the absence of infection with cagA-positive H. pylori. Using site-directed mutagenesis, fluorescent and electron microscopy, and highly-specific inhibitors, we demonstrate that the cell-binding and endocytosis-like internalization of CagA-M are dependent on (1) binding to PS; (2) β₁ integrin activity; and (3) actin dynamics. Interaction of CagA-M with the host cells is accompanied by the development of long filopodia-like protrusions (macrospikes). This novel morphology is different from the hummingbird phenotype induced by the translocation of full-length CagA. The determinants within CagA-M and within the host that are important for endocytosis-like internalization into host cells are very similar to those observed for T4SS-mediated internalization of full-length CagA, suggesting that the latter may involve an endocytic pathway. Full article

(This article belongs to the Special Issue H. pylori Virulence Factors in the Induction of Gastric Cancer)

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Review

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20 pages, 25436 KiB

Open AccessFeature PaperReview

Epidemiology of Helicobacter pylori and CagA-Positive Infections and Global Variations in Gastric Cancer

by Jin Young Park, David Forman, Langgeng Agung Waskito, Yoshio Yamaoka and Jean E. Crabtree

Toxins 2018, 10(4), 163; https://doi.org/10.3390/toxins10040163 - 19 Apr 2018

Cited by 153 | Viewed by 14625

Abstract

Gastric cancer is a major health burden and is the fifth most common malignancy and the third most common cause of death from cancer worldwide. Development of gastric cancer involves several aspects, including host genetics, environmental factors, and Helicobacter pylori infection. There is increasing evidence from epidemiological studies of the association of H. pylori infection and specific virulence factors with gastric cancer. Studies in animal models indicate H. pylori is a primary factor in the development of gastric cancer. One major virulence factor in H. pylori is the cytotoxin-associated gene A (cagA), which encodes the CagA protein in the cag pathogenicity island (cag PAI). Meta-analysis of studies investigating CagA seropositivity irrespective of H. pylori status identified that CagA seropositivity increases the risk of gastric cancer (OR = 2.87, 95% CI: 1.95–4.22) relative to the risk of H. pylori infection alone (OR = 2.31, 95% CI: 1.58–3.39). Eradicating H. pylori is a strategy for reducing gastric cancer incidence. A meta-analysis of six randomised controlled trials (RCTs) suggests that searching for and eradicating H. pylori infection reduces the subsequent incidence of gastric cancer with a pooled relative risk of 0.66 (95% CI: 0.46–0.95). The introduction in regions of high gastric cancer incidence of population-based H. pylori screening and treatment programmes, with a scientifically valid assessment of programme processes, feasibility, effectiveness and possible adverse consequences, would impact the incidence of H. pylori-induced gastric cancer. Given the recent molecular understanding of the oncogenic role of CagA, targeting H. pylori screening and treatment programmes in populations with a high prevalence of H. pylori CagA-positive strains, particularly the more oncogenic East Asian H. pylori CagA strains, may be worth further investigation to optimise the benefits of such strategies. Full article

(This article belongs to the Special Issue H. pylori Virulence Factors in the Induction of Gastric Cancer)

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937 KiB

Open AccessReview

Helicobacter pylori Vacuolating Toxin and Gastric Cancer

by Mark S. McClain, Amber C. Beckett and Timothy L. Cover

Toxins 2017, 9(10), 316; https://doi.org/10.3390/toxins9100316 - 12 Oct 2017

Cited by 110 | Viewed by 10144

Abstract

Helicobacter pylori VacA is a channel-forming toxin unrelated to other known bacterial toxins. Most H. pylori strains contain a vacA gene, but there is marked variation among strains in VacA toxin activity. This variation is attributable to strain-specific variations in VacA amino acid sequences, as well as variations in the levels of VacA transcription and secretion. In this review, we discuss epidemiologic studies showing an association between specific vacA allelic types and gastric cancer, as well as studies that have used animal models to investigate VacA activities relevant to gastric cancer. We also discuss the mechanisms by which VacA-induced cellular alterations may contribute to the pathogenesis of gastric cancer. Full article

(This article belongs to the Special Issue H. pylori Virulence Factors in the Induction of Gastric Cancer)

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1248 KiB

Open AccessReview

Sequence Polymorphism and Intrinsic Structural Disorder as Related to Pathobiological Performance of the Helicobacter pylori CagA Oncoprotein

by Hiroko Nishikawa and Masanori Hatakeyama

Toxins 2017, 9(4), 136; https://doi.org/10.3390/toxins9040136 - 13 Apr 2017

Cited by 21 | Viewed by 7111

Abstract

CagA, an oncogenic virulence factor produced by Helicobacter pylori, is causally associated with the development of gastrointestinal diseases such as chronic gastritis, peptic ulcers, and gastric cancer. Upon delivery into gastric epithelial cells via bacterial type IV secretion, CagA interacts with a number of host proteins through the intrinsically disordered C-terminal tail, which contains two repeatable protein-binding motifs, the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif and the CagA multimerization (CM) motif. The EPIYA motif, upon phosphorylation by host kinases, binds and deregulates Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2), a bona fide oncoprotein, inducing pro-oncogenic mitogenic signaling and abnormal cell morphology. Through the CM motif, CagA inhibits the kinase activity of polarity regulator partitioning-defective 1b (PAR1b), causing junctional and polarity defects while inducing actin cytoskeletal rearrangements. The magnitude of the pathobiological action of individual CagA has been linked to the tandem repeat polymorphisms of these two binding motifs, yet the molecular mechanisms by which they affect disease outcome remain unclear. Recent studies using quantitative techniques have provided new insights into how the sequence polymorphisms in the structurally disordered C-terminal region determine the degree of pro-oncogenic action of CagA in the gastric epithelium. Full article

(This article belongs to the Special Issue H. pylori Virulence Factors in the Induction of Gastric Cancer)

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Proteolysis in Helicobacter pylori-Induced Gastric Cancer

by Gernot Posselt, Jean E. Crabtree and Silja Wessler

Toxins 2017, 9(4), 134; https://doi.org/10.3390/toxins9040134 - 11 Apr 2017

Cited by 26 | Viewed by 9067

Abstract

Persistent infections with the human pathogen and class-I carcinogen Helicobacter pylori (H. pylori) are closely associated with the development of acute and chronic gastritis, ulceration, gastric adenocarcinoma and lymphoma of the mucosa-associated lymphoid tissue (MALT) system. Disruption and depolarization of the epithelium is a hallmark of H. pylori-associated disorders and requires extensive modulation of epithelial cell surface structures. Hence, the complex network of controlled proteolysis which facilitates tissue homeostasis in healthy individuals is deregulated and crucially contributes to the induction and progression of gastric cancer through processing of extracellular matrix (ECM) proteins, cell surface receptors, membrane-bound cytokines, and lateral adhesion molecules. Here, we summarize the recent reports on mechanisms how H. pylori utilizes a variety of extracellular proteases, involving the proteases Hp0169 and high temperature requirement A (HtrA) of bacterial origin, and host matrix-metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs) and tissue inhibitors of metalloproteinases (TIMPs). H. pylori-regulated proteases represent predictive biomarkers and attractive targets for therapeutic interventions in gastric cancer. Full article

(This article belongs to the Special Issue H. pylori Virulence Factors in the Induction of Gastric Cancer)

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252 KiB

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Helicobacter pylori Strains and Gastric MALT Lymphoma

by Pauline Floch, Francis Mégraud and Philippe Lehours

Toxins 2017, 9(4), 132; https://doi.org/10.3390/toxins9040132 - 8 Apr 2017

Cited by 62 | Viewed by 6559

Abstract

This article summarizes the main findings concerning Helicobacter pylori 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. Full article

(This article belongs to the Special Issue H. pylori Virulence Factors in the Induction of Gastric Cancer)

663 KiB

Open AccessFeature PaperReview

NF‐κB Signaling in Gastric Cancer

by Olga Sokolova and Michael Naumann

Toxins 2017, 9(4), 119; https://doi.org/10.3390/toxins9040119 - 28 Mar 2017

Cited by 177 | Viewed by 9905

Abstract

Gastric cancer is a leading cause of cancer death worldwide. Diet, obesity, smoking and chronic infections, especially with Helicobacter pylori, contribute to stomach cancer development. H. pylori possesses a variety of virulence factors including encoded factors from the cytotoxin‐associated gene pathogenicity island (cagPAI) or vacuolating cytotoxin A (VacA). Most of the cagPAI‐encoded products form a type 4 secretion system (T4SS), a pilus‐like macromolecular transporter, which translocates CagA into the cytoplasm of the host cell. Only H. pylori strains carrying the cagPAI induce the transcription factor NF‐κB, but CagA and VacA are dispensable for direct NF‐κB activation. NF‐κB‐driven gene products include cytokines/chemokines, growth factors, anti‐apoptotic factors, angiogenesis regulators and metalloproteinases. Many of the genes transcribed by NF‐κB promote gastric carcinogenesis. Since it has been shown that chemotherapy‐caused cellular stress could elicit activation of the survival factor NF‐κB, which leads to acquisition of chemoresistance, the NF‐κB system is recommended for therapeutic targeting. Research is motivated for further search of predisposing conditions, diagnostic markers and efficient drugs to improve significantly the overall survival of patients. In this review, we provide an overview about mechanisms and consequences of NF‐κB activation in gastric mucosa in order to understand the role of NF‐κB in gastric carcinogenesis. Full article

(This article belongs to the Special Issue H. pylori Virulence Factors in the Induction of Gastric Cancer)

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Type IV Secretion and Signal Transduction of Helicobacter pylori CagA through Interactions with Host Cell Receptors

by Steffen Backert and Nicole Tegtmeyer

Toxins 2017, 9(4), 115; https://doi.org/10.3390/toxins9040115 - 24 Mar 2017

Cited by 74 | Viewed by 10077

Abstract

Helicobacter pylori is a highly successful human bacterium, which is exceptionally equipped to persistently inhabit the human stomach. Colonization by this pathogen is associated with gastric disorders ranging from chronic gastritis and peptic ulcers to cancer. Highly virulent H. pylori strains express the well-established adhesins BabA/B, SabA, AlpA/B, OipA, and HopQ, and a type IV secretion system (T4SS) encoded by the cag pathogenicity island (PAI). The adhesins ascertain intimate bacterial contact to gastric epithelial cells, while the T4SS represents an extracellular pilus-like structure for the translocation of the effector protein CagA. Numerous T4SS components including CagI, CagL, CagY, and CagA have been shown to target the integrin-β₁ receptor followed by translocation of CagA across the host cell membrane. The interaction of CagA with membrane-anchored phosphatidylserine and CagA-containing outer membrane vesicles may also play a role in the delivery process. Translocated CagA undergoes tyrosine phosphorylation in C-terminal EPIYA-repeat motifs by oncogenic Src and Abl kinases. CagA then interacts with an array of host signaling proteins followed by their activation or inactivation in phosphorylation-dependent and phosphorylation-independent fashions. We now count about 25 host cell binding partners of intracellular CagA, which represent the highest quantity of all currently known virulence-associated effector proteins in the microbial world. Here we review the research progress in characterizing interactions of CagA with multiple host cell receptors in the gastric epithelium, including integrin-β₁, EGFR, c-Met, CD44, E-cadherin, and gp130. The contribution of these interactions to H. pylori colonization, signal transduction, and gastric pathogenesis is discussed. Full article

(This article belongs to the Special Issue H. pylori Virulence Factors in the Induction of Gastric Cancer)

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789 KiB

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Helicobacter pylori Outer Membrane Protein-Related Pathogenesis

by Yuichi Matsuo, Yasutoshi Kido and Yoshio Yamaoka

Toxins 2017, 9(3), 101; https://doi.org/10.3390/toxins9030101 - 11 Mar 2017

Cited by 69 | Viewed by 14425

Abstract

Helicobacter pylori colonizes the human stomach and induces inflammation, and in some cases persistent infection can result in gastric cancer. Attachment to the gastric mucosa is the first step in establishing bacterial colonization, and outer membrane proteins (OMPs) play a pivotal role in binding to human cells. Some OMP interaction molecules are known in H. pylori, and their associated host cell responses have been gradually clarified. Many studies have demonstrated that OMPs are essential to CagA translocation into gastric cells via the Type IV secretion system of H. pylori. This review summarizes the mechanisms through which H. pylori utilizes OMPs to colonize the human stomach and how OMPs cooperate with the Type IV secretion system. Full article

(This article belongs to the Special Issue H. pylori Virulence Factors in the Induction of Gastric Cancer)

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