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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
VacA Targets Myeloid Cells in the Gastric Lamina Propria To Promote Peripherally Induced Regulatory T-Cell Differentiation and Persistent Infection.
Altobelli A, Bauer M, Velez K, Cover TL, Müller A
(2019) MBio 10:
MeSH Terms: Animals, Bacterial Proteins, Cell Differentiation, Dendritic Cells, Disease Models, Animal, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Immune Evasion, Interleukin-10, Interleukin-23, Lung, Macrophages, Mice, Mucous Membrane, Myeloid Cells, T-Lymphocytes, Regulatory, Transforming Growth Factor beta
Show Abstract · Added April 11, 2019
The gastric bacterium causes a persistent infection that is directly responsible for gastric ulcers and gastric cancer in some patients and protective against allergic and other immunological disorders in others. The two outcomes of the -host interaction can be modeled in mice that are infected as immunocompetent adults and as neonates, respectively. Here, we have investigated the contribution of the immunomodulator VacA to -specific local and systemic immune responses in both models. We found that neonatally infected mice are colonized at higher levels than mice infected as adults and fail to generate effector T-cell responses to the bacteria; rather, T-cell responses in neonatally infected mice are skewed toward Foxp3-positive (Foxp3) regulatory T cells that are neuropilin negative and express RORγt. We found these peripherally induced regulatory T cells (pTregs) to be enriched, in a VacA-dependent manner, not only in the gastric mucosa but also in the lungs of infected mice. Pulmonary pTreg accumulation was observed in mice that have been infected neonatally with wild-type but not in mice that have been infected as adults or mice infected with a VacA null mutant. Finally, we traced VacA to gastric lamina propria myeloid cells and show that it suppressed interleukin-23 (IL-23) expression by dendritic cells and induced IL-10 and TGF-β expression in macrophages. Taken together, the results are consistent with the idea that creates a tolerogenic environment through its immunomodulator VacA, which skews T-cell responses toward Tregs, favors persistence, and affects immunity at distant sites. has coexisted with humans for at least 60.000 years and has evolved persistence strategies that allow it to evade host immunity and colonize its host for life. The VacA protein is expressed by all strains and is required for high-level persistent infection in experimental mouse models. Here, we show that VacA targets myeloid cells in the gastric mucosa to create a tolerogenic environment that facilitates regulatory T-cell differentiation, while suppressing effector T-cell priming and functionality. Tregs that are induced in the periphery during infection can be found not only in the stomach but also in the lungs of infected mice, where they are likely to affect immune responses to allergens.
Copyright © 2019 Altobelli et al.
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18 MeSH Terms
Intracellular Degradation of Helicobacter pylori VacA Toxin as a Determinant of Gastric Epithelial Cell Viability.
Foegeding NJ, Raghunathan K, Campbell AM, Kim SW, Lau KS, Kenworthy AK, Cover TL, Ohi MD
(2019) Infect Immun 87:
MeSH Terms: Autophagy, Bacterial Proteins, Cell Line, Cell Survival, Epithelial Cells, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Hydrogen-Ion Concentration, Muramidase, Protein Stability, Protein Transport, Proteolysis
Show Abstract · Added February 7, 2019
VacA is a secreted pore-forming toxin that induces cell vacuolation and contributes to the pathogenesis of gastric cancer and peptic ulcer disease. We observed that purified VacA has relatively little effect on the viability of AGS gastric epithelial cells, but the presence of exogenous weak bases such as ammonium chloride (NHCl) enhances the susceptibility of these cells to VacA-induced vacuolation and cell death. Therefore, we tested the hypothesis that NHCl augments VacA toxicity by altering the intracellular trafficking of VacA or inhibiting intracellular VacA degradation. We observed VacA colocalization with LAMP1- and LC3-positive vesicles in both the presence and absence of NHCl, indicating that NHCl does not alter VacA trafficking to lysosomes or autophagosomes. Conversely, we found that supplemental NHCl significantly increases the intracellular stability of VacA. By conducting experiments using chemical inhibitors, stable ATG5 knockdown cell lines, and ATG16L1 knockout cells (generated using CRISPR/Cas9), we show that VacA degradation is independent of autophagy and proteasome activity but dependent on lysosomal acidification. We conclude that weak bases like ammonia, potentially generated during infection by urease and other enzymes, enhance VacA toxicity by inhibiting toxin degradation.
Copyright © 2019 American Society for Microbiology.
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14 MeSH Terms
MEK Inhibitor Reverses Metaplasia and Allows Re-Emergence of Normal Lineages in Helicobacter pylori-Infected Gerbils.
Yang Q, Yasuda T, Choi E, Toyoda T, Roland JT, Uchida E, Yoshida H, Seto Y, Goldenring JR, Nomura S
(2019) Gastroenterology 156: 577-581.e4
MeSH Terms: Acrylonitrile, Aniline Compounds, Animals, Benzimidazoles, Biopsy, Needle, Disease Models, Animal, Gastric Mucosa, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Immunohistochemistry, Male, Metaplasia, Random Allocation, Reference Values, Treatment Outcome
Added November 14, 2018
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16 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
Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach.
Choi E, Lantz TL, Vlacich G, Keeley TM, Samuelson LC, Coffey RJ, Goldenring JR, Powell AE
(2018) Gut 67: 1595-1605
MeSH Terms: Animals, Biomarkers, Cell Lineage, Disease Models, Animal, Gastric Mucosa, Membrane Glycoproteins, Mice, Mice, Knockout, Nerve Tissue Proteins, Predictive Value of Tests, Sensitivity and Specificity, Stem Cells, Stomach Ulcer, Wound Healing
Show Abstract · Added September 27, 2017
OBJECTIVE - Lrig1 is a marker of proliferative and quiescent stem cells in the skin and intestine. We examined whether Lrig1-expressing cells are long-lived gastric progenitors in gastric glands in the mouse stomach. We also investigated how the Lrig1-expressing progenitor cells contribute to the regeneration of normal gastric mucosa by lineage commitment to parietal cells after acute gastric injury in mice.
DESIGN - We performed lineage labelling using (Lrig1/YFP) or (Lrig1/LacZ) mice to examine whether the Lrig1-YFP-marked cells are gastric progenitor cells. We studied whether Lrig1-YFP-marked cells give rise to normal gastric lineage cells in damaged mucosa using Lrig1/YFP mice after treatment with DMP-777 to induce acute injury. We also studied Lrig1- (Lrig1 knockout) mice to examine whether the Lrig1 protein is required for regeneration of gastric corpus mucosa after acute injury.
RESULTS - Lrig1-YFP-marked cells give rise to gastric lineage epithelial cells both in the gastric corpus and antrum, in contrast to published results that Lgr5 only marks progenitor cells within the gastric antrum. Lrig1-YFP-marked cells contribute to replacement of damaged gastric oxyntic glands during the recovery phase after acute oxyntic atrophy in the gastric corpus. Lrig1 null mice recovered normally from acute gastric mucosal injury indicating that Lrig1 protein is not required for lineage differentiation. Lrig1+ isthmal progenitor cells did not contribute to transdifferentiating chief cell lineages after acute oxyntic atrophy.
CONCLUSIONS - Lrig1 marks gastric corpus epithelial progenitor cells capable of repopulating the damaged oxyntic mucosa by differentiating into normal gastric lineage cells in mouse stomach.
© 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.
1 Communities
3 Members
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14 MeSH Terms
Increased expression of deleted in malignant brain tumors (DMBT1) gene in precancerous gastric lesions: Findings from human and animal studies.
Garay J, Piazuelo MB, Lopez-Carrillo L, Leal YA, Majumdar S, Li L, Cruz-Rodriguez N, Serrano-Gomez SJ, Busso CS, Schneider BG, Delgado AG, Bravo LE, Crist AM, Meadows SM, Camargo MC, Wilson KT, Correa P, Zabaleta J
(2017) Oncotarget 8: 47076-47089
MeSH Terms: Animals, Disease Models, Animal, Ethnic Groups, Gastric Mucosa, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Helicobacter Infections, Humans, Mice, Mice, Knockout, Neoplasm Staging, Precancerous Conditions, Receptors, Cell Surface, Stomach Neoplasms
Show Abstract · Added June 29, 2017
Helicobacter pylori infection triggers a cascade of inflammatory stages that may lead to the appearance of non-atrophic gastritis, multifocal atrophic, intestinal metaplasia, dysplasia, and cancer. Deleted in malignant brain tumors 1 (DMBT1) belongs to the group of secreted scavenger receptor cysteine-rich proteins and is considered to be involved in host defense by binding to pathogens. Initial studies showed its deletion and loss of expression in a variety of tumors but the role of this gene in tumor development is not completely understood. Here, we examined the role of DMBT1 in gastric precancerous lesions in Caucasian, African American and Hispanic individuals as well as in the development of gastric pathology in a mouse model of H. pylori infection. We found that in 3 different populations, mucosal DMBT1 expression was significantly increased (2.5 fold) in individuals with dysplasia compared to multifocal atrophic gastritis without intestinal metaplasia; the increase was also observed in individuals with advanced gastritis and positive H. pylori infection. In our animal model, H. pylori infection of Dmbt1-/- mice resulted in significantly higher levels of gastritis, more extensive mucous metaplasia and reduced Il33 expression levels in the gastric mucosa compared to H. pylori-infected wild type mice. Our data in the animal model suggest that in response to H. pylori infection DMBT1 may mediate mucosal protection reducing the risk of developing gastric precancerous lesions. However, the increased expression in human gastric precancerous lesions points to a more complex role of DMBT1 in gastric carcinogenesis.
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15 MeSH Terms
Optimizing surgical resection of the bleeding Meckel diverticulum in children.
Robinson JR, Correa H, Brinkman AS, Lovvorn HN
(2017) J Pediatr Surg 52: 1610-1615
MeSH Terms: Adolescent, Child, Child, Preschool, Diagnostic Tests, Routine, Digestive System Surgical Procedures, Female, Gastric Mucosa, Gastrointestinal Hemorrhage, Humans, Male, Meckel Diverticulum, Retrospective Studies, Tertiary Care Centers, Treatment Outcome
Show Abstract · Added November 8, 2017
PURPOSE - Meckel diverticula containing gastric heterotopia predispose to local hyperacidity, mucosal ulceration, and gastrointestinal bleeding in children. Eradication of acid-producing oxyntic cells is performed by either of two surgical methods: segmental enterectomy including the diverticulum or diverticulectomy only.
METHODS - Retrospective review of all children having surgical resection of a Meckel diverticulum at a tertiary-referral children's hospital from 2002 to 2016 was performed. Demographic data, surgical method, pathological specimens, and outcomes were evaluated.
RESULTS - 102 children underwent surgical resection of a Meckel diverticulum during the study period. 27 (26.5%) children presented with bleeding, of which 16 (59%) had diverticulectomy only, and 11 (41%) had segmental ileal resection. All Meckel diverticula in children presenting with bleeding contained gastric heterotopia, and resection margins were free of gastric mucosa. Histologically, 19 specimens showed microscopic features of ulceration, on average 2.95mm (SD 4.49) from the nearest gastric mucosa (range: 0-16mm). Mean length of hospitalization after ileal resection was 4.0days (SD 1.2) compared to 1.6days (SD 0.9) for diverticulectomy only (p<0.001), with no re-bleeding occurrences.
CONCLUSION - In the operative management of children having a bleeding Meckel diverticulum, diverticulectomy-only completely eradicates gastric heterotopia without increased risk of continued bleeding or complications and significantly shortens hospitalization.
LEVEL OF EVIDENCE - Treatment Study: Level III.
Copyright © 2017 Elsevier Inc. All rights reserved.
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14 MeSH Terms
Integrated expression analysis identifies transcription networks in mouse and human gastric neoplasia.
Chen Z, Soutto M, Rahman B, Fazili MW, Peng D, Blanca Piazuelo M, Chen H, Kay Washington M, Shyr Y, El-Rifai W
(2017) Genes Chromosomes Cancer 56: 535-547
MeSH Terms: Animals, Computational Biology, Disease Models, Animal, Gastric Mucosa, Gene Expression Profiling, Gene Regulatory Networks, Humans, Mice, Oligonucleotide Array Sequence Analysis, Stomach, Stomach Neoplasms
Show Abstract · Added April 18, 2017
Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. The Tff1 knockout (KO) mouse model develops gastric lesions that include low-grade dysplasia (LGD), high-grade dysplasia (HGD), and adenocarcinomas. In this study, we used Affymetrix microarrays gene expression platforms for analysis of molecular signatures in the mouse stomach [Tff1-KO (LGD) and Tff1 wild-type (normal)] and human gastric cancer tissues and their adjacent normal tissue samples. Combined integrated bioinformatics analysis of mouse and human datasets indicated that 172 genes were consistently deregulated in both human gastric cancer samples and Tff1-KO LGD lesions (P < .05). Using Ingenuity pathway analysis, these genes mapped to important transcription networks that include MYC, STAT3, β-catenin, RELA, NFATC2, HIF1A, and ETS1 in both human and mouse. Further analysis demonstrated activation of FOXM1 and inhibition of TP53 transcription networks in human gastric cancers but not in Tff1-KO LGD lesions. Using real-time RT-PCR, we validated the deregulated expression of several genes (VCAM1, BGN, CLDN2, COL1A1, COL1A2, COL3A1, EpCAM, IFITM1, MMP9, MMP12, MMP14, PDGFRB, PLAU, and TIMP1) that map to altered transcription networks in both mouse and human gastric neoplasia. Our study demonstrates significant similarities in deregulated transcription networks in human gastric cancer and gastric tumorigenesis in the Tff1-KO mouse model. The data also suggest that activation of MYC, STAT3, RELA, and β-catenin transcription networks could be an early molecular step in gastric carcinogenesis.
© 2017 Wiley Periodicals, Inc.
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11 MeSH Terms
Genetic Manipulation of Virulence Function by Host Carcinogenic Phenotypes.
Suarez G, Romero-Gallo J, Sierra JC, Piazuelo MB, Krishna US, Gomez MA, Wilson KT, Peek RM
(2017) Cancer Res 77: 2401-2412
MeSH Terms: Animals, Antigens, Bacterial, Bacterial Proteins, Carcinogenesis, Disease Models, Animal, Gastric Mucosa, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Humans, Risk Factors, Stomach Neoplasms
Show Abstract · Added February 18, 2017
is the strongest risk factor for gastric adenocarcinoma, yet only a minority of infected persons ever develop this malignancy. One cancer-linked locus is the type 4 secretion system (T4SS), which translocates an oncoprotein into host cells. A structural component of the T4SS is CagY, which becomes rapidly altered during adaptation in mice and rhesus monkeys, rendering the T4SS nonfunctional; however, these models rarely develop gastric cancer. We previously demonstrated that the strain 7.13 rapidly induces gastric cancer in Mongolian gerbils. We now use this model, in conjunction with samples from patients with premalignant lesions, to define the effects of a carcinogenic host environment on the virulence phenotype of to understand how only a subset of infected individuals develop cancer. sequence differences and T4SS function were directly related to the severity of inflammation in human gastric mucosa in either a synchronous or metachronous manner. Serial infections of Mongolian gerbils with strain 7.13 identified an oscillating pattern of T4SS function. The development of dysplasia or cancer selected for attenuated virulence phenotypes, but robust T4SS function could be restored upon infection of new hosts. Changes in the genetic composition of mirrored T4SS function, although the mechanisms of alterations differed in human isolates (mutations) versus gerbil isolates (addition/deletion of motifs). These results indicate that host carcinogenic phenotypes modify T4SS function via altering allowing the bacteria to persist and induce carcinogenic consequences in the gastric niche. .
©2017 American Association for Cancer Research.
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12 MeSH Terms