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Resolution of Gastric Cancer-Promoting Inflammation: A Novel Strategy for Anti-cancer Therapy.
Piazuelo MB, Riechelmann RP, Wilson KT, Algood HMS
(2019) Curr Top Microbiol Immunol 421: 319-359
MeSH Terms: Cytokines, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Inflammation, Stomach Neoplasms, Tumor Microenvironment
Show Abstract · Added June 6, 2019
The connection between inflammation and cancer was initially recognized by Rudolf Virchow in the nineteenth century. During the last decades, a large body of evidence has provided support to his hypothesis, and now inflammation is recognized as one of the hallmarks of cancer, both in etiopathogenesis and ongoing tumor growth. Infection with the pathogen Helicobacter pylori is the primary causal factor in 90% of gastric cancer (GC) cases. As we increase our understanding of how chronic inflammation develops in the stomach and contributes to carcinogenesis, there is increasing interest in targeting cancer-promoting inflammation as a strategy to treat GC. Moreover, once cancer develops and anti-cancer immune responses are suppressed, there is evidence of a substantial shift in the microenvironment and new targets for immune therapy emerge. In this chapter, we provide insight into inflammation-related factors, including T lymphocytes, macrophages, pro-inflammatory chemokines, and cytokines, which promote H. pylori-associated GC initiation and growth. While intervening with chronic inflammation is not a new practice in rheumatology or gastroenterology, this approach has not been fully explored for its potential to prevent carcinogenesis or to contribute to the treatment of GC. This review highlights current and possible strategies for therapeutic intervention including (i) targeting pro-inflammatory mediators, (ii) targeting growth factors and pathways involved in angiogenesis in the gastric tumor microenvironment, and (iii) enhancing anti-tumor immunity. In addition, we highlight a significant number of clinical trials and discuss the importance of individual tumor characterization toward offering personalized immune-related therapy.
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8 MeSH Terms
α-Difluoromethylornithine reduces gastric carcinogenesis by causing mutations in .
Sierra JC, Suarez G, Piazuelo MB, Luis PB, Baker DR, Romero-Gallo J, Barry DP, Schneider C, Morgan DR, Peek RM, Gobert AP, Wilson KT
(2019) Proc Natl Acad Sci U S A 116: 5077-5085
MeSH Terms: Animals, Bacterial Proteins, Carcinogenesis, DNA Damage, Eflornithine, Gene Deletion, Gene Rearrangement, Gerbillinae, Helicobacter pylori, Male, Mutation, Oxidative Stress, RNA, Messenger, Stomach Neoplasms, Virulence
Show Abstract · Added February 26, 2019
Infection by is the primary cause of gastric adenocarcinoma. The most potent virulence factor is cytotoxin-associated gene A (CagA), which is translocated by a type 4 secretion system (T4SS) into gastric epithelial cells and activates oncogenic signaling pathways. The gene encodes for a key component of the T4SS and can undergo gene rearrangements. We have shown that the cancer chemopreventive agent α-difluoromethylornithine (DFMO), known to inhibit the enzyme ornithine decarboxylase, reduces -mediated gastric cancer incidence in Mongolian gerbils. In the present study, we questioned whether DFMO might directly affect pathogenicity. We show that output strains isolated from gerbils treated with DFMO exhibit reduced ability to translocate CagA in gastric epithelial cells. Further, we frequently detected genomic modifications in the middle repeat region of the gene of output strains from DFMO-treated animals, which were associated with alterations in the CagY protein. Gerbils did not develop carcinoma when infected with a DFMO output strain containing rearranged or the parental strain in which the wild-type was replaced by with DFMO-induced rearrangements. Lastly, we demonstrate that in vitro treatment of by DFMO induces oxidative DNA damage, expression of the DNA repair enzyme MutS2, and mutations in , demonstrating that DFMO directly affects genomic stability. Deletion of abrogated the ability of DFMO to induce rearrangements directly. In conclusion, DFMO-induced oxidative stress in leads to genomic alterations and attenuates virulence.
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15 MeSH Terms
Helicobacter pylori pathogen regulates p14ARF tumor suppressor and autophagy in gastric epithelial cells.
Horvat A, Noto JM, Ramatchandirin B, Zaika E, Palrasu M, Wei J, Schneider BG, El-Rifai W, Peek RM, Zaika AI
(2018) Oncogene 37: 5054-5065
MeSH Terms: Antigens, Bacterial, Autophagy, Bacterial Proteins, Cell Line, Tumor, Down-Regulation, Epithelial Cells, Gastric Mucosa, HCT116 Cells, Helicobacter Infections, Helicobacter pylori, Humans, Signal Transduction, Stomach, Stomach Neoplasms, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases, Up-Regulation, Virulence Factors
Show Abstract · Added September 25, 2018
Infection with Helicobacter pylori is one of the strongest risk factors for development of gastric cancer. Although these bacteria infect approximately half of the world's population, only a small fraction of infected individuals develops gastric malignancies. Interactions between host and bacterial virulence factors are complex and interrelated, making it difficult to elucidate specific processes associated with H. pylori-induced tumorigenesis. In this study, we found that H. pylori inhibits p14ARF tumor suppressor by inducing its degradation. This effect was found to be strain-specific. Downregulation of p14ARF induced by H. pylori leads to inhibition of autophagy in a p53-independent manner in infected cells. We identified TRIP12 protein as E3 ubiquitin ligase that is upregulated by H. pylori, inducing ubiquitination and subsequent degradation of p14ARF protein. Using isogenic H. pylori mutants, we found that induction of TRIP12 is mediated by bacterial virulence factor CagA. Increased expression of TRIP12 protein was found in infected gastric epithelial cells in vitro and human gastric mucosa of H. pylori-infected individuals. In conclusion, our data demonstrate a new mechanism of ARF inhibition that may affect host-bacteria interactions and facilitate tumorigenic transformation in the stomach.
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19 MeSH Terms
Determinants of Raft Partitioning of the Helicobacter pylori Pore-Forming Toxin VacA.
Raghunathan K, Foegeding NJ, Campbell AM, Cover TL, Ohi MD, Kenworthy AK
(2018) Infect Immun 86:
MeSH Terms: Bacterial Proteins, Bacterial Toxins, Helicobacter pylori, Host-Pathogen Interactions, Membrane Microdomains, Stomach Neoplasms, Vacuoles
Show Abstract · Added July 29, 2018
, a Gram-negative bacterium, is a well-known risk factor for gastric cancer. vacuolating cytotoxin A (VacA) is a secreted pore-forming toxin that induces a wide range of cellular responses. Like many other bacterial toxins, VacA has been hypothesized to utilize lipid rafts to gain entry into host cells. Here, we used giant plasma membrane vesicles (GPMVs) as a model system to understand the preferential partitioning of VacA into lipid rafts. We show that a wild-type (WT) toxin predominantly associates with the raft phase. Acid activation of VacA enhances binding of the toxin to GPMVs but is not required for raft partitioning. VacA mutant proteins with alterations at the amino terminus (resulting in impaired membrane channel formation) and a nonoligomerizing VacA mutant protein retain the ability to preferentially associate with lipid rafts. Consistent with these results, the isolated VacA p55 domain was capable of binding to lipid rafts. We conclude that the affinity of VacA for rafts is independent of its capacity to oligomerize or form membrane channels.
Copyright © 2018 American Society for Microbiology.
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7 MeSH Terms
Gastric Carcinomas With Lymphoid Stroma: Categorization and Comparison With Solid-Type Colonic Carcinomas.
Gonzalez RS, Cates JMM, Revetta F, McMahon LA, Washington K
(2017) Am J Clin Pathol 148: 477-484
MeSH Terms: Aged, Aged, 80 and over, Colonic Neoplasms, Epstein-Barr Virus Infections, Female, Humans, Lymphocytes, Male, Microsatellite Instability, Middle Aged, Stomach Neoplasms, Stromal Cells
Show Abstract · Added November 1, 2018
Objectives - To determine whether histologic features could help identify gastric carcinomas with lymphoid stroma associated with microsatellite instability (MSI) (ie, "medullary carcinomas"), Epstein-Barr virus (EBV) infection (termed lymphoepithelioma-like carcinomas in other organ systems), or neither.
Methods - We identified 17 solid-type gastric carcinomas with lymphoid stroma, assessed EBV and MSI status, and compared features across groups. We also compared them with 51 solid-type colorectal adenocarcinomas.
Results - In the stomach, EBV-associated carcinomas (n = 8) contained intratumoral germinal centers (P = .024) and eosinophils (P = .030) and lacked necrosis (P = .019) compared with MSI-associated carcinomas (n = 5) and non-EBV, non-MSI carcinomas (n = 4). In the colon, MSI-driven carcinomas (n = 40) more frequently contained intratumoral lymphocytes (P = .017) and neutrophils (P = .0050) and less often metastasized to distant sites (P = .0040) than poorly differentiated carcinomas lacking MSI (n = 11).
Conclusions - Morphology may help classify gastric carcinomas with lymphoid stroma, although ancillary testing appears more reliable. Lymphoepithelioma-like carcinoma and medullary carcinoma should not be used interchangeably.
© American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
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MeSH Terms
Helicobacter pylori Vacuolating Toxin and Gastric Cancer.
McClain MS, Beckett AC, Cover TL
(2017) Toxins (Basel) 9:
MeSH Terms: Alleles, Animals, Bacterial Proteins, Disease Models, Animal, Helicobacter pylori, Humans, Risk Factors, Stomach, Stomach Neoplasms, Virulence
Show Abstract · Added March 21, 2018
VacA is a channel-forming toxin unrelated to other known bacterial toxins. Most strains contain a 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 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.
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10 MeSH Terms
The gastric microbiome, its interaction with Helicobacter pylori, and its potential role in the progression to stomach cancer.
Noto JM, Peek RM
(2017) PLoS Pathog 13: e1006573
MeSH Terms: Adenocarcinoma, Disease Progression, Gastrointestinal Microbiome, Helicobacter Infections, Helicobacter pylori, Humans, Stomach Neoplasms
Added March 14, 2018
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2 Members
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7 MeSH Terms
Pan-genomic analyses identify key pathogenic loci modified by carcinogenic host microenvironments.
Noto JM, Chopra A, Loh JT, Romero-Gallo J, Piazuelo MB, Watson M, Leary S, Beckett AC, Wilson KT, Cover TL, Mallal S, Israel DA, Peek RM
(2018) Gut 67: 1793-1804
MeSH Terms: Bacterial Proteins, Carcinogenesis, Helicobacter Infections, Helicobacter pylori, Humans, In Vitro Techniques, Polymorphism, Single Nucleotide, Stomach Neoplasms
Show Abstract · Added September 20, 2017
OBJECTIVE - is the strongest risk factor for gastric cancer; however, the majority of infected individuals do not develop disease. Pathological outcomes are mediated by complex interactions among bacterial, host and environmental constituents, and two dietary factors linked with gastric cancer risk are iron deficiency and high salt. We hypothesised that prolonged adaptation of to in vivo carcinogenic microenvironments results in genetic modification important for disease.
DESIGN - Whole genome sequencing of genetically related strains that differ in virulence and targeted sequencing following prolonged exposure of bacteria to in vitro carcinogenic conditions were performed.
RESULTS - A total of 180 unique single nucleotide polymorphisms (SNPs) were identified among the collective genomes when compared with a reference genome. Importantly, common SNPs were identified in isolates harvested from iron-depleted and high salt carcinogenic microenvironments, including an SNP within (FurR88H). To investigate the direct role of low iron and/or high salt, was continuously cultured under low iron or high salt conditions to assess genetic variation. Exposure to low iron or high salt selected for the FurR88H variant after only 5 days. To extend these results, was sequenced in 339 clinical strains. Among the isolates examined, 17% (40/232) of strains isolated from patients with premalignant lesions harboured the FurR88H variant, compared with only 6% (6/107) of strains from patients with non-atrophic gastritis alone (p=0.0034).
CONCLUSION - These results indicate that specific genetic variation arises within strains during in vivo adaptation to conditions conducive for gastric carcinogenesis.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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4 Members
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8 MeSH Terms
Oxidative Phosphorylation System in Gastric Carcinomas and Gastritis.
Feichtinger RG, Neureiter D, Skaria T, Wessler S, Cover TL, Mayr JA, Zimmermann FA, Posselt G, Sperl W, Kofler B
(2017) Oxid Med Cell Longev 2017: 1320241
MeSH Terms: Electron Transport Complex I, Female, Gastritis, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Helicobacter Infections, Helicobacter pylori, Humans, Male, Neoplasm Proteins, Oxidative Phosphorylation, Stomach Neoplasms
Show Abstract · Added March 21, 2018
Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria to aerobic glycolysis occurs in many types of tumors. However, the significance of this switching for the development of gastric carcinoma and what connection it may have to infection of the gut, a primary cause of gastric cancer, are poorly understood. Therefore, we investigated the expression of OXPHOS complexes in two types of human gastric carcinomas ("intestinal" and "diffuse"), bacterial gastritis with and without metaplasia, and chemically induced gastritis by using immunohistochemistry. Furthermore, we analyzed the effect of HP infection on several key mitochondrial proteins. Complex I expression was significantly reduced in intestinal type (but not diffuse) gastric carcinomas compared to adjacent control tissue, and the reduction was independent of HP infection. Significantly, higher complex I and complex II expression was present in large tumors. Furthermore, higher complex II and complex III protein levels were also obvious in grade 3 versus grade 2. No differences of OXPHOS complexes and markers of mitochondrial biogenesis were found between bacterially caused and chemically induced gastritis. Thus, intestinal gastric carcinomas, but not precancerous stages, are frequently characterized by loss of complex I, and this pathophysiology occurs independently of HP infection.
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12 MeSH Terms
Dynamics of infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial.
Mera RM, Bravo LE, Camargo MC, Bravo JC, Delgado AG, Romero-Gallo J, Yepez MC, Realpe JL, Schneider BG, Morgan DR, Peek RM, Correa P, Wilson KT, Piazuelo MB
(2018) Gut 67: 1239-1246
MeSH Terms: Adult, Aged, Anti-Bacterial Agents, Disease Progression, Drug Administration Schedule, Female, Follow-Up Studies, Helicobacter Infections, Helicobacter pylori, Humans, Male, Metaplasia, Middle Aged, Precancerous Conditions, Risk Factors, Stomach Neoplasms
Show Abstract · Added June 29, 2017
OBJECTIVE - To evaluate the long-term effect of cumulative time exposed to infection on the progression of gastric lesions.
DESIGN - 795 adults with precancerous gastric lesions were randomised to receive anti- treatment at baseline. Gastric biopsies were obtained at baseline and at 3, 6, 12 and 16 years. A total of 456 individuals attended the 16-year visit. Cumulative time of exposure was calculated as the number of years infected during follow-up. Multivariable logistic regression models were used to estimate the risk of progression to a more advanced diagnosis (versus no change/regression) as well as gastric cancer risk by intestinal metaplasia (IM) subtype. For a more detailed analysis of progression, we also used a histopathology score assessing both severity and extension of the gastric lesions (range 1-6). The score difference between baseline and 16 years was modelled by generalised linear models.
RESULTS - Individuals who were continuously infected with for 16 years had a higher probability of progression to a more advanced diagnosis than those who cleared the infection and remained negative after baseline (p=0.001). Incomplete-type IM was associated with higher risk of progression to cancer than complete-type (OR, 11.3; 95% CI 1.4 to 91.4). The average histopathology score increased by 0.20 units/year (95% CI 0.12 to 0.28) among individuals continuously infected with . The effect of cumulative time of infection on progression in the histopathology score was significantly higher for individuals with atrophy (without IM) than for individuals with IM (p<0.001).
CONCLUSIONS - Long-term exposure to infection was associated with progression of precancerous lesions. Individuals infected with with these lesions may benefit from eradication, particularly those with atrophic gastritis without IM. Incomplete-type IM may be a useful marker for the identification of individuals at higher risk for cancer.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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16 MeSH Terms