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Bali P, Lozano-Pope I, Hernandez J, Estrada MV, Benner C, Obonyo M. Protocol to establish an accelerated murine model for Helicobacter-induced gastric cancer. STAR Protoc 2024; 5:103302. [PMID: 39264805 PMCID: PMC11416640 DOI: 10.1016/j.xpro.2024.103302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 07/22/2024] [Accepted: 08/16/2024] [Indexed: 09/14/2024] Open
Abstract
Helicobacter-induced gastric cancer progresses very slowly, even in animal models, making it difficult to study. Here, we present a protocol to establish an accelerated murine model for Helicobacter-induced gastric cancer. We describe steps for infecting mice with Helicobacter felis, harvesting gastric tissue, assessing disease severity by histopathologic scoring, and performing gene expression studies with RT-qPCR and RNA sequencing. The accelerated model shows rapid progression of the disease, with gastric precancerous lesions developing within 6 months post-infection with Helicobacter. For complete details on the use and execution of this protocol, please refer to Bali et al.1.
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Affiliation(s)
- Prerna Bali
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Ivonne Lozano-Pope
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Jonathan Hernandez
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Monica V Estrada
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Christopher Benner
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Marygorret Obonyo
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA; Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
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Wen X, Li D, Wang H, Zhang D, Song J, Zhou Z, Huang W, Xia X, Hu X, Liu W, Gonzales J, Via LE, Zhang L, Wang D. IQGAP1 domesticates macrophages to favor mycobacteria survival via modulating NF-κB signal and augmenting VEGF secretion. Int Immunopharmacol 2024; 138:112549. [PMID: 38944950 DOI: 10.1016/j.intimp.2024.112549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 06/18/2024] [Accepted: 06/20/2024] [Indexed: 07/02/2024]
Abstract
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), still ranks among the leading causes of annual human death by infectious disease. Mtb has developed several strategies to survive for years at a time within the host despite the presence of a robust immune response, including manipulating the progression of the inflammatory response and forming granulomatous lesions. Here we demonstrate that IQGAP1, a highly conserved scaffolding protein, compartmentalizes and coordinates multiple signaling pathways in macrophages infected with Mycobacterium marinum (Mm or M.marinum), the closest relative of Mtb. Upregulated IQGAP1 ultimately suppresses TNF-α production by repressing the MKK3 signal and reducing NF-κBp65 translocation, deactivating the p38MAPK pathway. Accordingly, IQGAP1 silencing and overexpression significantly alter p38MAPK activity by modulating the production of phosphorylated MKK3 during mycobacterial infection. Pharmacological inhibition of IQGAP1-associated microtubule assembly not only alleviates tissue damage caused by M.marinum infection but also significantly decreases the production of VEGF-a critical player for granuloma-associated angiogenesis during pathogenic mycobacterial infection. Similarly, IQGAP1 silencing in Mm-infected macrophages diminishes VEGF production, while IQGAP1 overexpression upregulates VEGF. Our data indicate that mycobacteria induce IQGAP1 to hijack NF-κBp65 activation, preventing the expression of proinflammatory cytokines as well as promoting VEGF production during infection and granuloma formation. Thus, therapies targeting host IQGAP1 may be a promising strategy for treating tuberculosis, particularly in drug-resistant diseases.
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Affiliation(s)
- Xin Wen
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China; Yichang Key Laboratory of Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China
| | - Dan Li
- Department of Tuberculosis, The Third People's Hospital of Yichang, Yichang 443003, PR China
| | - Hankun Wang
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China; Yichang Key Laboratory of Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China
| | - Ding Zhang
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China; Yichang Key Laboratory of Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China
| | - Jingrui Song
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China; Yichang Key Laboratory of Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China
| | - Ziwei Zhou
- State Key Laboratory of Genetic Engineering, Institute of Genetics, MOE Engineering Research Center of Gene Technology, School of Life Science, Fudan University, Shanghai 200433, PR China
| | - Weifeng Huang
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China; Yichang Key Laboratory of Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China
| | - Xuan Xia
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China; Yichang Key Laboratory of Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China
| | - Xiaohong Hu
- Department of Tuberculosis, The Third People's Hospital of Yichang, Yichang 443003, PR China
| | - Wei Liu
- The First College of Clinical Medical Science, China Three Gorges University, Yichang, PR China; Institute of Digestive Disease, China Three Gorges University, Yichang, PR China; Department of Gastroenterology, Yichang Central People's Hospital, Yichang, PR China
| | - Jacqueline Gonzales
- Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda 20982, MD, USA
| | - Laura E Via
- Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda 20982, MD, USA
| | - Lu Zhang
- State Key Laboratory of Genetic Engineering, Institute of Genetics, MOE Engineering Research Center of Gene Technology, School of Life Science, Fudan University, Shanghai 200433, PR China.
| | - Decheng Wang
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China; Yichang Key Laboratory of Institute of Infection and Inflammation, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, PR China.
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Druffner SR, Venkateshwaraprabu S, Khadka S, Duncan BC, Morris MT, Sen-Kilic E, Damron FH, Liechti GW, Busada JT. Comparison of gastric inflammation and metaplasia induced by Helicobacter pylori or Helicobacter felis colonization in mice. Microbiol Spectr 2024; 12:e0001524. [PMID: 38682907 PMCID: PMC11237807 DOI: 10.1128/spectrum.00015-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 03/18/2024] [Indexed: 05/01/2024] Open
Abstract
Gastric cancer is the fifth most diagnosed cancer in the world. Infection by the bacteria Helicobacter pylori (HP) is associated with approximately 75% of gastric cancer cases. HP infection induces chronic gastric inflammation, damaging the stomach and fostering carcinogenesis. Most mechanistic studies on gastric cancer initiation are performed in mice and utilize either mouse-adapted strains of HP or the natural mouse pathogen Helicobacter felis (HF). Here, we identified the differences in gastric inflammation, atrophy, and metaplasia associated with HP and HF infection in mice. PMSS1 HP strain or the CS1 HF strain were co-cultured with mouse peritoneal macrophages to assess their immunostimulatory effects. HP and HF induced similar cytokine production from cultured mouse peritoneal macrophages revealing that both bacteria exhibit similar immunostimulatory effects in vitro. Next, C57BL/6J mice were infected with HP or HF and were assessed 2 months post-infection. HP-infected mice caused modest inflammation within both the gastric corpus and antrum, and did not induce significant atrophy within the gastric corpus. In contrast, HF induced significant inflammation throughout the gastric corpus and antrum. Moreover, HF infection was associated with significant atrophy of the chief and parietal cell compartments and induced the expression of pyloric metaplasia (PM) markers. HP is poorly immunogenic compared to HF. HF induces dramatic CD4+ T cell activation, which is associated with increased gastric cancer risk in humans. Thus, HP studies in mice are better suited for studies on colonization, while HF is more strongly suited for studies on the effects of gastric inflammation on tumorigenesis. . IMPORTANCE Mouse infection models with Helicobacter species are widely used to study Helicobacter pathogenesis and gastric cancer initiation. However, Helicobacter pylori is not a natural mouse pathogen, and mouse-adapted H. pylori strains are poorly immunogenic. In contrast, Helicobacter felis is a natural mouse pathogen that induces robust gastric inflammation and is often used in mice to investigate gastric cancer initiation. Although both bacterial strains are widely used, their disease pathogenesis in mice differs dramatically. However, few studies have directly compared the pathogenesis of these bacterial species in mice, and the contrasting features of these two models are not clearly defined. This study directly compares the gastric inflammation, atrophy, and metaplasia development triggered by the widely used PMSS1 H. pylori and CS1 H. felis strains in mice. It serves as a useful resource for researchers to select the experimental model best suited for their studies.
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Affiliation(s)
- Sara R. Druffner
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Shrinidhi Venkateshwaraprabu
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Stuti Khadka
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Benjamin C. Duncan
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Maeve T. Morris
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Emel Sen-Kilic
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - Fredrick H. Damron
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
| | - George W. Liechti
- Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
| | - Jonathan T. Busada
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia, USA
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4
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Bali P, Lozano-Pope I, Hernandez J, Estrada MV, Corr M, Turner MA, Bouvet M, Benner C, Obonyo M. TRIF-IFN-I pathway in Helicobacter-induced gastric cancer in an accelerated murine disease model and patient biopsies. iScience 2024; 27:109457. [PMID: 38558931 PMCID: PMC10981133 DOI: 10.1016/j.isci.2024.109457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 12/20/2023] [Accepted: 03/07/2024] [Indexed: 04/04/2024] Open
Abstract
Helicobacter pylori (H. pylori) infection is a known cause of many digestive diseases, including gastritis, peptic ulcers, and gastric cancer. However, the underlying mechanisms by which H. pylori infection triggers these disorders are still not clearly understood. Gastric cancer is a slow progressing disease, which makes it difficult to study. We have developed an accelerated disease progression mouse model, which leverages mice deficient in the myeloid differentiation primary response 88 gene (Myd88-/-) infected with Helicobacter felis (H. felis). Using this model and gastric biopsy samples from patients, we report that activation of the Toll/interleukin-1 receptor (TIR)-domain-containing adaptor inducing interferon-β (TRIF)-type I interferon (IFN-I) signaling pathway promotes Helicobacter-induced disease progression toward severe gastric pathology and gastric cancer development. Further, results implicated downstream targets of this pathway in disease pathogenesis. These findings may facilitate stratification of Helicobacter-infected patients and thus enable treatment prioritization of patients.
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Affiliation(s)
- Prerna Bali
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Ivonne Lozano-Pope
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Jonathan Hernandez
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Monica V. Estrada
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Maripat Corr
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Michael A. Turner
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA
- VA San Diego Healthcare System, San Diego, CA, USA
| | - Michael Bouvet
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA
- VA San Diego Healthcare System, San Diego, CA, USA
| | - Christopher Benner
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Marygorret Obonyo
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
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5
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Druffner SR, Venkateshwaraprabu S, Khadka S, Duncan BC, Morris MT, Sen-Kilic E, Damron FH, Liechti GW, Busada JT. Comparison of gastric inflammation and metaplasia induced by Helicobacter pylori or Helicobacter felis colonization in mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.22.573128. [PMID: 38187587 PMCID: PMC10769338 DOI: 10.1101/2023.12.22.573128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Background Gastric cancer is the fifth most diagnosed cancer in the world. Infection by the bacteria Helicobacter pylori (HP) is associated with approximately 75% of gastric cancer cases. HP infection induces chronic gastric inflammation, damaging the stomach and fostering carcinogenesis. Most mechanistic studies on Helicobacter- induced gastric cancer initiation are performed in mice and utilize either mouse-adapted strains of HP or the natural mouse pathogen Helicobacter felis (HF). Each of these infection models is associated with strengths and weaknesses. Here, we identified the differences in immunogenicity and gastric pathological changes associated with HP and HF infection in mice. Material and Methods PMSS1 HP strain or with the CS1 HF strain were co-cultured with mouse peritoneal macrophages to assess their immunostimulatory effects. C57BL/6J mice were infected with HP or HF, and gastric inflammation, atrophy, and metaplasia development were assessed 2 months post-infection. Results HP and HF induced similar cytokine production from cultured mouse peritoneal macrophages. HP-infected mice caused modest inflammation within both the gastric corpus and antrum and did not induce significant atrophy within the gastric corpus. In contrast, HF induced significant inflammation throughout the gastric corpus and antrum. Moreover, HF infection was associated with significant atrophy of the chief and parietal cell compartments and induced expression of pyloric metaplasia markers. Conclusions HP is poorly immunogenic compared to HF. HF induces dramatic CD4+ T cell activation, which is associated with increased gastric cancer risk in humans. Thus, HP studies in mice are better suited for studies on colonization, while HF is more strongly suited for pathogenesis and cancer initiation studies.
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Borka Balas R, Meliț LE, Mărginean CO. Current Worldwide Trends in Pediatric Helicobacter pylori Antimicrobial Resistance. CHILDREN (BASEL, SWITZERLAND) 2023; 10:403. [PMID: 36832532 PMCID: PMC9954810 DOI: 10.3390/children10020403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/14/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023]
Abstract
Helicobacter pylori (H. pylori) has acquired several resistance mechanisms in order to escape the currently used eradication regimens such as mutations that impair the replication, recombination, and transcription of DNA; the antibiotics capability to interact with protein synthesis and ribosomal activity; the adequate redox state of bacterial cells; or the penicillin-binding proteins. The aim of this review was to identify the differences in pediatric H. pylori antimicrobial-resistance trends between continents and countries of the same continent. In Asian pediatric patients, the greatest antimicrobial resistance was found to metronidazole (>50%), probably due to its wide use for parasitic infections. Aside from the increased resistance to metronidazole, the reports from different Asian countries indicated also high resistance rates to clarithromycin, suggesting that ciprofloxacin-based eradication therapy and bismuth-based quadruple therapy might be optimal choices for the eradication of H. pylori in Asian pediatric population. The scarce evidence for America revealed that H. pylori strains display an increased resistance to clarithromycin (up to 79.6%), but not all studies agreed on this statement. Pediatric patients from Africa also presented the greatest resistance rate to metronidazole (91%), but the results in terms of amoxicillin remain contradictory. Nevertheless, the lowest resistance rates in most of the African studies were found for quinolones. Among European children, the most frequent antimicrobial resistance was also noticed for metronidazole and clarithromycin (up to 59% and 45%) but with a predominance for clarithromycin as compared to other continents. The differences in antibiotic use among continents and countries worldwide is clearly responsible for the discrepancies regarding H. pylori antimicrobial-resistance patterns, emphasizing the crucial role of global judicious antibiotic use in order to control the increasing resistance rates worldwide.
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Affiliation(s)
| | - Lorena Elena Meliț
- Department of Pediatrics I, “George Emil Palade” University of Medicine, Pharmacy, Sciences and Technology, Târgu Mureș, Gheorghe Marinescu Street, No. 38, 540136 Târgu Mureș, Romania
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Amalia R, Panenggak NSR, Doohan D, Rezkitha YAA, Waskito LA, Syam AF, Lubis M, Yamaoka Y, Miftahussurur M. A comprehensive evaluation of an animal model for Helicobacter pylori-associated stomach cancer: Fact and controversy. Helicobacter 2023; 28:e12943. [PMID: 36627714 DOI: 10.1111/hel.12943] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 11/22/2022] [Accepted: 11/22/2022] [Indexed: 01/12/2023]
Abstract
Even though Helicobacter pylori infection was the most causative factor of gastric cancer, numerous in vivo studies failed to induce gastric cancer using H. pylori infection only. The utilization of established animal studies in cancer research is crucial as they aim to investigate the coincidental association between suspected oncogenes and pathogenesis as well as generate models for the development and testing of potential treatments. The methods to establish gastric cancer using infected animal models remain limited, diverse in methods, and showed different results. This study investigates the differences in animal models, which highlight different pathological results in gaster by literature research. Electronic databases searched were performed in PubMed, Science Direct, and Cochrane, without a period filter. A total of 135 articles were used in this study after a full-text assessment was conducted. The most frequent animal models used for gastric cancer were Mice, while Mongolian gerbils and Transgenic mice were the most susceptible model for gastric cancer associated with H. pylori infection. Additionally, transgenic mice showed that the susceptibility to gastric cancer progression was due to genetic and epigenetic factors. These studies showed that in Mongolian gerbil models, H. pylori could function as a single agent to trigger stomach cancer. However, most gastric cancer susceptibilities were not solely relying on H. pylori infection, and numerous factors are involved in cancer progression. Further study using Mongolian gerbils and Transgenic mice is crucial to conduct and establish the best models for gastric cancer associated H. pylori.
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Affiliation(s)
- Rizki Amalia
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
| | - Nur Syahadati Retno Panenggak
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
| | - Dalla Doohan
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Department of Anatomy, Histology and Pharmacology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Yudith Annisa Ayu Rezkitha
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Department of Internal Medicine, Faculty of Medicine, Universitas Muhammadiyah Surabaya, Surabaya, Indonesia
| | - Langgeng Agung Waskito
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Department of Physiology and Medical Biochemistry, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Ari Fahrial Syam
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Masrul Lubis
- Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan.,Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Texas, Houston, USA
| | - Muhammad Miftahussurur
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.,Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine-Dr. Soetomo Teaching Hospital, Universitas Airlangga, Surabaya, Indonesia
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Mărginean CD, Mărginean CO, Meliț LE. Helicobacter pylori-Related Extraintestinal Manifestations—Myth or Reality. CHILDREN 2022; 9:children9091352. [PMID: 36138661 PMCID: PMC9497822 DOI: 10.3390/children9091352] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 08/29/2022] [Accepted: 09/01/2022] [Indexed: 11/16/2022]
Abstract
It is well documented that Helicobacter pylori (H. pylori) can cause both gastrointestinal and extraintestinal manifestations. The latter one represents a major burden in terms of diagnosis and treatment. H. pylori-associated systemic subclinical inflammation is mostly responsible for the development of extraintestinal manifestations, and its early eradication might result in preventing all adverse events related to their occurrence. Thus, it was suggested that H. pylori might be associated with iron deficiency anemia, thrombocytopenia (immune thrombocytopenic purpura), Schonlein Henoch purpura, failure to thrive, vitamin B12 deficiency, diabetes mellitus, body mass index, cardiovascular diseases, as well as certain neurological conditions. Nevertheless, studies showed both pros and cons in terms of the role of H. pylori in the development of previously mentioned clinical entity underlining the crucial need for further studies on these topics. Although most of these extraintestinal manifestations occur during adulthood, we must not forget that H. pylori infection is acquired mainly during childhood, and thus its early diagnosis and eradication might represent the cornerstone in the prevention of H. pylori-induced inflammatory status and consequently of all related extraintestinal conditions.
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Affiliation(s)
- Cristian Dan Mărginean
- Department of Pediatrics I, County Emergency Hospital Târgu Mureș, Gheorghe Marinescu Street No. 50, 540136 Târgu Mureș, Romania
| | - Cristina Oana Mărginean
- Department of Pediatrics I, “George Emil Palade” University of Medicine, Pharmacy, Science, and Technology of Târgu Mureș, Gheorghe Marinescu Street No. 38, 540136 Târgu Mureș, Romania
- Correspondence:
| | - Lorena Elena Meliț
- Department of Pediatrics I, “George Emil Palade” University of Medicine, Pharmacy, Science, and Technology of Târgu Mureș, Gheorghe Marinescu Street No. 38, 540136 Târgu Mureș, Romania
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Ansari S, Yamaoka Y. Animal Models and Helicobacter pylori Infection. J Clin Med 2022; 11:jcm11113141. [PMID: 35683528 PMCID: PMC9181647 DOI: 10.3390/jcm11113141] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 05/25/2022] [Accepted: 05/25/2022] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori colonize the gastric mucosa of at least half of the world’s population. Persistent infection is associated with the development of gastritis, peptic ulcer disease, and an increased risk of gastric cancer and gastric-mucosa-associated lymphoid tissue (MALT) lymphoma. In vivo studies using several animal models have provided crucial evidence for understanding the pathophysiology of H. pylori-associated complications. Numerous animal models, such as Mongolian gerbils, transgenic mouse models, guinea pigs, and other animals, including non-human primates, are being widely used due to their persistent association in causing gastric complications. However, finding suitable animal models for in vivo experimentation to understand the pathophysiology of gastric cancer and MALT lymphoma is a complicated task. In this review, we summarized the most appropriate and latest information in the scientific literature to understand the role and importance of H. pylori infection animal models.
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Affiliation(s)
- Shamshul Ansari
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu 879-5593, Oita, Japan;
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu 879-5593, Oita, Japan;
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX 77030, USA
- Institute of Tropical Disease, Universitas Airlangga, Surabaya 60115, Indonesia
- Correspondence: ; Tel.: +81-97-586-5740
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Presence of Helicobacter Species in Gastric Mucosa of Human Patients and Outcome of Helicobacter Eradication Treatment. J Pers Med 2022; 12:jpm12020181. [PMID: 35207669 PMCID: PMC8879780 DOI: 10.3390/jpm12020181] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/06/2022] [Accepted: 01/24/2022] [Indexed: 12/11/2022] Open
Abstract
The genus Helicobacter is composed of bacteria that colonize both the human and animal gastrointestinal tract. Helicobacter pylori infects half of the world’s population, causing various disorders, such as gastritis, duodenitis and gastric cancer. Additionally, non-Helicobacter pylori Helicobacter species (NHPH) are commonly found in the stomach of pigs, dogs and cats. Most of these species have zoonotic potential and prevalence rates of 0.2–6.0%, and have been described in human patients suffering from gastric disorders undergoing a gastric biopsy. The aim of this study was to determine the occurrence of Helicobacter spp. in the stomach of patients with gastric cancer (n = 17) and obese (n = 63) patients. Furthermore, the outcome of the Helicobacter eradication treatment and the current infection status was evaluated. Overall, based on the genus-specific PCR followed by sequencing, DNA from Helicobacter spp. was detected in 46.3% of the patients, including single infections with H. pylori in 43.8% of the patients and mixed infections with H. pylori and canine- or feline-associated H. felis in 2.5%. About 32.5% of the patients had been subjected to previous Helicobacter eradication therapy and the triple standard therapy was the most frequent scheme (42.3%). In 48.0% of the patients who received eradication treatment, bacteria were still detected, including one mixed infection. In 23.1% of the patients who reported that a subsequent test had been performed to confirm the elimination of the bacteria, Helicobacter were still detected. In conclusion, although in a smaller percentage, NHPH may also be present in the human stomach. Thus, specific NHPH screening should be included in the diagnostic routine. The continued presence of H. pylori in the stomach of patients recently subjected to eradication schemes raises questions about the efficacy of the current Helicobacter treatments.
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Link A, Bornschein J, Thon C. Helicobacter pylori induced gastric carcinogenesis - The best molecular model we have? Best Pract Res Clin Gastroenterol 2021; 50-51:101743. [PMID: 33975683 DOI: 10.1016/j.bpg.2021.101743] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/19/2021] [Accepted: 03/25/2021] [Indexed: 01/31/2023]
Abstract
Gastric carcinogenesis can be described as a consequence of multilevel molecular alterations that is triggered by a cascade of events. Historically, diet and environmental factors have been identified to substantially contribute to carcinogenesis before the discovery of Helicobacter pylori (H. pylori). But H. pylori infection has revolutionized the understanding of gastric carcinogenesis. Although the model of H. pylori-driven carcinogenesis remains valid, there is a continuous effort to precisely delineate the molecular pathways involved and to understand the interplay with additional risk factors including recent relevant knowledge on the stomach microbiota. In this review, we provide an updated view on the models of gastric carcinogenesis. This includes historically appreciated H. pylori-induced models and expands these taking recent molecular data into consideration. Based on the data provided, we conclude that indeed H. pylori-carcinogenesis remains one of the best-established models at least for a subset of gastric cancers. Implementation of the recently identified molecular subtypes in novel genetic animal models is required to expand our knowledge on H. pylori-independent carcinogenesis.
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Affiliation(s)
- Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Section of Molecular Gastroenterology and Microbiota-associated Diseases, Otto-von-Guericke University, Magdeburg, Germany.
| | - Jan Bornschein
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford University Hospitals, Headington, Oxford, UK
| | - Cosima Thon
- Department of Gastroenterology, Hepatology and Infectious Diseases, Section of Molecular Gastroenterology and Microbiota-associated Diseases, Otto-von-Guericke University, Magdeburg, Germany
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12
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Okada F, Izutsu R, Goto K, Osaki M. Inflammation-Related Carcinogenesis: Lessons from Animal Models to Clinical Aspects. Cancers (Basel) 2021; 13:cancers13040921. [PMID: 33671768 PMCID: PMC7926701 DOI: 10.3390/cancers13040921] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/11/2021] [Accepted: 02/12/2021] [Indexed: 12/13/2022] Open
Abstract
Simple Summary In multicellular organisms, inflammation is the body’s most primitive and essential protective response against any external agent. Inflammation, however, not only causes various modern diseases such as cardiovascular disorders, neurological disorders, autoimmune diseases, metabolic syndrome, infectious diseases, and cancer but also shortens the healthy life expectancy. This review focuses on the onset of carcinogenesis due to chronic inflammation caused by pathogen infections and inhalation/ingestion of foreign substances. This study summarizes animal models associated with inflammation-related carcinogenesis by organ. By determining factors common to inflammatory carcinogenesis models, we examined strategies for the prevention and treatment of inflammatory carcinogenesis in humans. Abstract Inflammation-related carcinogenesis has long been known as one of the carcinogenesis patterns in humans. Common carcinogenic factors are inflammation caused by infection with pathogens or the uptake of foreign substances from the environment into the body. Inflammation-related carcinogenesis as a cause for cancer-related death worldwide accounts for approximately 20%, and the incidence varies widely by continent, country, and even region of the country and can be affected by economic status or development. Many novel approaches are currently available concerning the development of animal models to elucidate inflammation-related carcinogenesis. By learning from the oldest to the latest animal models for each organ, we sought to uncover the essential common causes of inflammation-related carcinogenesis. This review confirmed that a common etiology of organ-specific animal models that mimic human inflammation-related carcinogenesis is prolonged exudation of inflammatory cells. Genotoxicity or epigenetic modifications by inflammatory cells resulted in gene mutations or altered gene expression, respectively. Inflammatory cytokines/growth factors released from inflammatory cells promote cell proliferation and repair tissue injury, and inflammation serves as a “carcinogenic niche”, because these fundamental biological events are common to all types of carcinogenesis, not just inflammation-related carcinogenesis. Since clinical strategies are needed to prevent carcinogenesis, we propose the therapeutic apheresis of inflammatory cells as a means of eliminating fundamental cause of inflammation-related carcinogenesis.
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Affiliation(s)
- Futoshi Okada
- Division of Experimental Pathology, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan; (R.I.); (K.G.); (M.O.)
- Chromosome Engineering Research Center, Tottori University, Yonago 683-8503, Japan
- Correspondence: ; Tel.: +81-859-38-6241
| | - Runa Izutsu
- Division of Experimental Pathology, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan; (R.I.); (K.G.); (M.O.)
| | - Keisuke Goto
- Division of Experimental Pathology, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan; (R.I.); (K.G.); (M.O.)
- Division of Gastrointestinal and Pediatric Surgery, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan
| | - Mitsuhiko Osaki
- Division of Experimental Pathology, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan; (R.I.); (K.G.); (M.O.)
- Chromosome Engineering Research Center, Tottori University, Yonago 683-8503, Japan
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13
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Peng X, Wang T, Gao H, Yue X, Bian W, Mei J, Zhang Y. The interplay between IQGAP1 and small GTPases in cancer metastasis. Biomed Pharmacother 2021; 135:111243. [PMID: 33434854 DOI: 10.1016/j.biopha.2021.111243] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/27/2020] [Accepted: 12/31/2020] [Indexed: 01/07/2023] Open
Abstract
The metastatic spread of tumor cells to distant anatomical locations is a critical cause for disease progression and leads to more than 90 % of cancer-related deaths. IQ motif-containing GTPase-activating protein 1 (IQGAP1), a prominent regulator in the cancer metastasis process, is a scaffold protein that interacts with components of the cytoskeleton. As a critical node within the small GTPase network, IQGAP1 acts as a binding partner of several small GTPases, which in turn function as molecular switches to control most cellular processes, including cell migration and invasion. Given the significant interaction between IQGAP1 and small GTPases in cancer metastasis, we briefly elucidate the role of IQGAP1 in regulating cancer metastasis and the varied interactions existing between IQGAP1 and small GTPases. In addition, the potential regulators for IQGAP1 activity and its interaction with small GTPases are also incorporated in this review. Overall, we comprehensively summarize the role of IQGAP1 in cancer tumorigenicity and metastasis, which may be a potential anti-tumor target to restrain cancer progression.
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Affiliation(s)
- Xiafeng Peng
- Department of Gynecology and Obstetrics, Wuxi Maternal and Child Health Hospital, the Affiliated Hospital to Nanjing Medical University, Wuxi, 214023, China; First Clinical Medicine College, Nanjing Medical University, Nanjing, 211166, China.
| | - Tiejun Wang
- Department of Gynecology and Obstetrics, Wuxi Maternal and Child Health Hospital, the Affiliated Hospital to Nanjing Medical University, Wuxi, 214023, China.
| | - Han Gao
- School of Medicine, Jiangnan University, Wuxi, 214122, China.
| | - Xin Yue
- First Clinical Medicine College, Nanjing Medical University, Nanjing, 211166, China.
| | - Weiqi Bian
- First Clinical Medicine College, Nanjing Medical University, Nanjing, 211166, China.
| | - Jie Mei
- Department of Gynecology and Obstetrics, Wuxi Maternal and Child Health Hospital, the Affiliated Hospital to Nanjing Medical University, Wuxi, 214023, China; Wuxi Clinical Medical College, Nanjing Medical University, Wuxi, 214023, China.
| | - Yan Zhang
- Department of Gynecology and Obstetrics, Wuxi Maternal and Child Health Hospital, the Affiliated Hospital to Nanjing Medical University, Wuxi, 214023, China.
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14
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Bali P, Coker J, Lozano-Pope I, Zengler K, Obonyo M. Microbiome Signatures in a Fast- and Slow-Progressing Gastric Cancer Murine Model and Their Contribution to Gastric Carcinogenesis. Microorganisms 2021; 9:microorganisms9010189. [PMID: 33477306 PMCID: PMC7829848 DOI: 10.3390/microorganisms9010189] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/10/2021] [Accepted: 01/13/2021] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer is the third most common cause of death from cancer in the world and infection with Helicobacter
pylori (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, Trif
Lps2), and MyD88- and TRIF-deficient (Myd88-/-
/Trif
Lps2, 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 Trif
Lps2 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.
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Affiliation(s)
- Prerna Bali
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; (P.B.); (I.L.-P.)
| | - Joanna Coker
- Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; (J.C.); (K.Z.)
| | - Ivonne Lozano-Pope
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; (P.B.); (I.L.-P.)
| | - Karsten Zengler
- Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; (J.C.); (K.Z.)
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093, USA
- Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA
| | - Marygorret Obonyo
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; (P.B.); (I.L.-P.)
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093, USA
- Correspondence:
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15
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Robinson K, Atherton JC. The Spectrum of Helicobacter-Mediated Diseases. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2020; 16:123-144. [PMID: 33197219 DOI: 10.1146/annurev-pathol-032520-024949] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Helicobacter pylori is the leading cause of peptic ulcer disease. The infection has been implicated in more than 75% of duodenal ulcer cases and 17% of gastric ulcer cases. H. pylori has been classified as a human carcinogen, since it is the main cause of distal gastric adenocarcinoma and B cell mucosa-associated lymphoid tissue lymphoma. Evidence also links H. pylori with extragastric conditions including iron deficiency anemia, idiopathic thrombocytopenic purpura, and vitamin B12 deficiency. Studies indicate that H. pylori may be protective against other conditions of the gastrointestinal tract (e.g., reflux esophagitis and related pathologies) and elsewhere in the body (e.g., asthma). The infection is asymptomatic in the vast majority of cases; more serious outcomes occur in only 10-15% of infected individuals. Despite extensive research over the past 3 decades, there is no effective vaccine, and the circumstances leading to disease development remain unclear. In addition, there is now a growing prevalence of antimicrobial resistance in H. pylori. This review discusses these important issues.
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Affiliation(s)
- Karen Robinson
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, United Kingdom.,Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham NG7 2RD United Kingdom;
| | - John C Atherton
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, United Kingdom.,Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham NG7 2RD United Kingdom;
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16
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Henriques PC, Costa LM, Seabra CL, Antunes B, Silva-Carvalho R, Junqueira-Neto S, Maia AF, Oliveira P, Magalhães A, Reis CA, Gartner F, Touati E, Gomes J, Costa P, Martins MCL, Gonçalves IC. Orally administrated chitosan microspheres bind Helicobacter pylori and decrease gastric infection in mice. Acta Biomater 2020; 114:206-220. [PMID: 32622054 DOI: 10.1016/j.actbio.2020.06.035] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 06/22/2020] [Accepted: 06/25/2020] [Indexed: 12/13/2022]
Abstract
Persistent Helicobacter pylori (H. pylori) infection is related to 90% of gastric cancers. With bacterial resistance rising and treatment inefficiency affecting 15% of the patients, alternative treatments urge. Chitosan microspheres (ChMics) have been proposed as an H. pylori-binding system. This work evaluates ChMics biocompatibility, mucopenetration and capacity to treat H. pylori infection in mice after oral administration. ChMics of different size (XL, ∼120 µm and XS, ∼40 µm) and degree of acetylation (6% and 16%) were developed and revealed to be able to adhere both human and mouse-adapted H. pylori strains without cytotoxicity towards human gastric cells. Ex vivo studies showed that smaller (XS) microspheres penetrate further within the gastric foveolae, suggesting their ability to reach deeply adherent bacteria. In vivo assays showed 88% reduction of infection when H. pylori-infected mice (C57BL/6) were treated with more mucoadhesive XL6 and XS6 ChMics. Overall, ChMics clearly demonstrate ability to reduce H. pylori gastric infection in mice, with chitosan degree of acetylation being a dominant factor over microspheres' size on H. pylori removal efficiency. These results evidence the strong potential of this strategy as an antibiotic-free approach to fight H. pylori infection, where microspheres are orally administered, bind H. pylori in the stomach, and remove them through the gastrointestinal tract. STATEMENT OF SIGNIFICANCE: Approximately 90% of gastric cancers are caused by the carcinogenic agent Helicobacter pylori, which infects >50% of the world population. Bacterial resistance, reduced antibiotic bioavailability, and the intricate distribution of bacteria in mucus and within gastric foveolae hamper the success of most strategies to fight H. pylori. We demonstrate that an antibiotic-free therapy based on bare chitosan microspheres that bind and remove H. pylori from stomach can achieve 88% reduction of infection from H. pylori-infected mice. Changing size and mucoadhesive properties, microspheres can reach different areas of gastric mucosa: smaller and less mucoadhesive can penetrate deeper into the foveolae. This promising, simple and inexpensive strategy paves the way for a faster bench-to-bedside transition, therefore holding great potential for clinical application.
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Affiliation(s)
- Patrícia C Henriques
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
| | - Lia M Costa
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
| | - Catarina L Seabra
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias s/n, 4200-465 Porto, Portugal
| | - Bernardo Antunes
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
| | - Ricardo Silva-Carvalho
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
| | - Susana Junqueira-Neto
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias s/n, 4200-465 Porto, Portugal
| | - André F Maia
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal
| | - Pedro Oliveira
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Ana Magalhães
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias s/n, 4200-465 Porto, Portugal
| | - Celso A Reis
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias s/n, 4200-465 Porto, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal; Faculdade de Medicina, Universidade do Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Fátima Gartner
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias s/n, 4200-465 Porto, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Eliette Touati
- Unit of Helicobacter Pathogenesis, Department of Microbiology, CNRS UMR2001, Institut Pasteur, 25-28 Rue du Dr. Roux, 75015, Paris, France
| | - Joana Gomes
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias s/n, 4200-465 Porto, Portugal
| | - Paulo Costa
- UCIBIO/REQUIMTE, MedTech-Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4150-755 Porto, Portugal
| | - M Cristina L Martins
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
| | - Inês C Gonçalves
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal; INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135 Porto, Portugal.
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17
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Alpízar-Alpízar W, Skindersoe ME, Rasmussen L, Kriegbaum MC, Christensen IJ, Lund IK, Illemann M, Laerum OD, Krogfelt KA, Andersen LP, Ploug M. Helicobacter pylori Colonization Drives Urokinase Receptor (uPAR) Expression in Murine Gastric Epithelium During Early Pathogenesis. Microorganisms 2020; 8:microorganisms8071019. [PMID: 32660136 PMCID: PMC7409347 DOI: 10.3390/microorganisms8071019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 07/04/2020] [Accepted: 07/07/2020] [Indexed: 12/16/2022] Open
Abstract
(1) Background: Persistent Helicobacter pylori infection is the most important risk factor for gastric cancer. The urokinase receptor (uPAR) is upregulated in lesions harboring cancer invasion and inflammation. Circumstantial evidence tends to correlate H. pylori colonization with increased uPAR expression in the human gastric epithelium, but a direct causative link has not yet been established in vivo; (2) Methods: In a mouse model of H. pylori-induced gastritis, we investigated the temporal emergence of uPAR protein expression in the gastric mucosa in response to H. pylori (SS1 strain) infection; (3) Results: We observed intense uPAR immunoreactivity in foveolar epithelial cells of the gastric corpus due to de novo synthesis, compared to non-infected animals. This uPAR induction represents a very early response, but it increases progressively over time as do infiltrating immune cells. Eradication of H. pylori infection by antimicrobial therapy causes a regression of uPAR expression to its physiological baseline levels. Suppression of the inflammatory response by prostaglandin E2 treatment attenuates uPAR expression. Notwithstanding this relationship, H. pylori does induce uPAR expression in vitro in co-cultures with gastric cancer cell lines; (4) Conclusions: We showed that persistent H. pylori colonization is a necessary event for the emergence of a relatively high uPAR protein expression in murine gastric epithelial cells.
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Affiliation(s)
- Warner Alpízar-Alpízar
- The Finsen Laboratory, Rigshospitalet, 2100 Copenhagen, Denmark; (M.C.K.); (I.J.C); (I.K.L.); (M.I.); (O.D.L.)
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2100 Copenhagen, Denmark
- Centre for Research on Microscopic Structures (CIEMic) and Department of Biochemistry, University of Costa Rica, 2060 San José, Costa Rica
- Correspondence: (W.A.-A.); (M.P.)
| | - Mette E. Skindersoe
- Department of Bacteria, Parasites and Fungi, Statens Serum Institute, 2300 Copenhagen, Denmark; (M.E.S.); (K.A.K.)
- Bacthera, Kogle Allé 6, 2970 Hoersholm, Denmark
| | - Lone Rasmussen
- Department of Clinical Microbiology, Rigshospitalet, 2100 Copenhagen, Denmark; (L.P.A.); (L.R.)
| | - Mette C. Kriegbaum
- The Finsen Laboratory, Rigshospitalet, 2100 Copenhagen, Denmark; (M.C.K.); (I.J.C); (I.K.L.); (M.I.); (O.D.L.)
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2100 Copenhagen, Denmark
| | - Ib J. Christensen
- The Finsen Laboratory, Rigshospitalet, 2100 Copenhagen, Denmark; (M.C.K.); (I.J.C); (I.K.L.); (M.I.); (O.D.L.)
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2100 Copenhagen, Denmark
- Hvidovre Hospital, University of Copenhagen, 2650 Copenhagen, Denmark
| | - Ida K. Lund
- The Finsen Laboratory, Rigshospitalet, 2100 Copenhagen, Denmark; (M.C.K.); (I.J.C); (I.K.L.); (M.I.); (O.D.L.)
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2100 Copenhagen, Denmark
| | - Martin Illemann
- The Finsen Laboratory, Rigshospitalet, 2100 Copenhagen, Denmark; (M.C.K.); (I.J.C); (I.K.L.); (M.I.); (O.D.L.)
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2100 Copenhagen, Denmark
| | - Ole D. Laerum
- The Finsen Laboratory, Rigshospitalet, 2100 Copenhagen, Denmark; (M.C.K.); (I.J.C); (I.K.L.); (M.I.); (O.D.L.)
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2100 Copenhagen, Denmark
| | - Karen A. Krogfelt
- Department of Bacteria, Parasites and Fungi, Statens Serum Institute, 2300 Copenhagen, Denmark; (M.E.S.); (K.A.K.)
- Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark
- Department of Virus and microbiological Diagnostics, Statens Serum Institute, 2300 Copenhagen, Denmark
| | - Leif P. Andersen
- Department of Clinical Microbiology, Rigshospitalet, 2100 Copenhagen, Denmark; (L.P.A.); (L.R.)
| | - Michael Ploug
- The Finsen Laboratory, Rigshospitalet, 2100 Copenhagen, Denmark; (M.C.K.); (I.J.C); (I.K.L.); (M.I.); (O.D.L.)
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2100 Copenhagen, Denmark
- Correspondence: (W.A.-A.); (M.P.)
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18
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Balic JJ, Saad MI, Dawson R, West AJ, McLeod L, West AC, D'Costa K, Deswaerte V, Dev A, Sievert W, Gough DJ, Bhathal PS, Ferrero RL, Jenkins BJ. Constitutive STAT3 Serine Phosphorylation Promotes Helicobacter-Mediated Gastric Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:1256-1270. [PMID: 32201262 DOI: 10.1016/j.ajpath.2020.01.021] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 12/17/2019] [Accepted: 01/27/2020] [Indexed: 12/16/2022]
Abstract
Gastric cancer is associated with chronic inflammation (gastritis) triggered by persistent Helicobacter pylori (H. pylori) infection. Elevated tyrosine phosphorylation of the latent transcription factor STAT3 is a feature of gastric cancer, including H. pylori-infected tissues, and aligns with nuclear transcriptional activity. However, the transcriptional role of STAT3 serine phosphorylation, which promotes STAT3-driven mitochondrial activities, is unclear. Here, by coupling serine-phosphorylated (pS)-STAT3-deficient Stat3SA/SA mice with chronic H. felis infection, which mimics human H. pylori infection in mice, we reveal a key role for pS-STAT3 in promoting Helicobacter-induced gastric pathology. Immunohistochemical staining for infiltrating immune cells and expression analyses of inflammatory genes revealed that gastritis was markedly suppressed in infected Stat3SA/SA mice compared with wild-type mice. Stomach weight and gastric mucosal thickness were also reduced in infected Stat3SA/SA mice, which was associated with reduced proliferative potential of infected Stat3SA/SA gastric mucosa. The suppressed H. felis-induced gastric phenotype of Stat3SA/SA mice was phenocopied upon genetic ablation of signaling by the cytokine IL-11, which promotes gastric tumorigenesis via STAT3. pS-STAT3 dependency by Helicobacter coincided with transcriptional activity on STAT3-regulated genes, rather than mitochondrial and metabolic genes. In the gastric mucosa of mice and patients with gastritis, pS-STAT3 was constitutively expressed irrespective of Helicobacter infection. Collectively, these findings suggest an obligate requirement for IL-11 signaling via constitutive pS-STAT3 in Helicobacter-induced gastric carcinogenesis.
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Affiliation(s)
- Jesse J Balic
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Mohamed I Saad
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Ruby Dawson
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Alice J West
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Louise McLeod
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Alison C West
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Kimberley D'Costa
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Virginie Deswaerte
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Anouk Dev
- Department of Gastroenterology and Hepatology, Monash Health, Melbourne, Victoria, Australia
| | - William Sievert
- Department of Gastroenterology and Hepatology, Monash Health, Melbourne, Victoria, Australia
| | - Daniel J Gough
- Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia
| | - Prithi S Bhathal
- Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
| | - Richard L Ferrero
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia; Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
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19
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Shalapour S, Karin M. Cruel to Be Kind: Epithelial, Microbial, and Immune Cell Interactions in Gastrointestinal Cancers. Annu Rev Immunol 2020; 38:649-671. [PMID: 32040356 DOI: 10.1146/annurev-immunol-082019-081656] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
A plethora of experimental and epidemiological evidence supports a critical role for inflammation and adaptive immunity in the onset of cancer and in shaping its response to therapy. These data are particularly robust for gastrointestinal (GI) cancers, such as those affecting the GI tract, liver, and pancreas, on which this review is focused. We propose a unifying hypothesis according to which intestinal barrier disruption is the origin of tumor-promoting inflammation that acts in conjunction with tissue-specific cancer-initiating mutations. The gut microbiota and its products impact tissue-resident and recruited myeloid cells that promote tumorigenesis through secretion of growth- and survival-promoting cytokines that act on epithelial cells, as well as fibrogenic and immunosuppressive cytokines that interfere with the proper function of adaptive antitumor immunity. Understanding these relationships should improve our ability to prevent cancer development and stimulate the immune system to eliminate existing malignancies.
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Affiliation(s)
- Shabnam Shalapour
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA; , .,Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA; , .,Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.,Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA
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20
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Rodrigues MF, Guerra MR, Alvarenga AVRD, Souza DZDO, Costa RAVES, Cupolilo SMN. HELICOBACTER PYLORI INFECTION AND GASTRIC CANCER PRECURSOR LESIONS: PREVALENCE AND ASSOCIATED FACTORS IN A REFERENCE LABORATORY IN SOUTHEASTERN BRAZIL. ARQUIVOS DE GASTROENTEROLOGIA 2019; 56:419-424. [PMID: 31800739 DOI: 10.1590/s0004-2803.201900000-84] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 10/15/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND Helicobacter pylori infection is the most important risk factor for gastric atrophy and intestinal metaplasia, both considered gastric cancer precursor lesions. Therefore, the investigation of the occurrence of H. pylori infection, precursor lesions and associated factors guides the adoption of specific strategies for the control this type of cancer. OBJECTIVE To evaluate the prevalence of H. pylori infection in patients undergoing upper digestive endoscopy, as well as the prevalence of intestinal metaplasia, atrophy and chronic inflammation and their association with H. pylori infection. METHODS A retrospective study was performed based on reports of gastric endoscopic biopsies performed in a private laboratory affiliated to the Brazilian Public Health System (SUS). Patients were evaluated for age, gender and type of health service. The samples were evaluated for the presence of H. pylori, and also of chronic inflammation, intestinal metaplasia and glandular atrophy. RESULTS Of a total of 4,604 patients (mean age 51±16.6), 63.9% were female and 63.1% coming from private health care service. The prevalence of H. pylori infection was 31.7% (n=1,459), and the percentage of infection was significantly higher in patients from public health service (42.0%) in relation to patients from private health service (25.6%). Among H. pylori (+) patients, a higher percentage of intestinal metaplasia (17.7% vs 13.3%) and glandular atrophy (17.6% vs 6.9%) were observed when compared to those H. pylori (-) (P<0.01). From the patients H. pylori (+) with at least one type of precursor lesion (n=418), 161 (38.5%) had metaplasia and chronic inflammation, 160 (38.3%) had atrophy and chronic inflammation and finally 97 (23.2%) presented metaplasia, atrophy and chronic inflammation simultaneously. CONCLUSION The present study reinforces the association of H. pylori infection with gastric cancer precursor lesions in a Brazilian population, emphasizing the importance of infection prevention measures, as well as the treatment of infected patients, especially in regions with lower socioeconomic levels that show a higher prevalence of infection by H. pylori.
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Affiliation(s)
| | - Maximiliano Ribeiro Guerra
- Universidade Federal de Juiz de Fora, Programa de Pós-Graduação em Saúde Coletiva, Juiz de Fora, MG, Brasil
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21
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Banks M, Graham D, Jansen M, Gotoda T, Coda S, di Pietro M, Uedo N, Bhandari P, Pritchard DM, Kuipers EJ, Rodriguez-Justo M, Novelli MR, Ragunath K, Shepherd N, Dinis-Ribeiro M. British Society of Gastroenterology guidelines on the diagnosis and management of patients at risk of gastric adenocarcinoma. Gut 2019; 68:1545-1575. [PMID: 31278206 PMCID: PMC6709778 DOI: 10.1136/gutjnl-2018-318126] [Citation(s) in RCA: 393] [Impact Index Per Article: 65.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Revised: 05/06/2019] [Accepted: 05/17/2019] [Indexed: 12/11/2022]
Abstract
Gastric adenocarcinoma carries a poor prognosis, in part due to the late stage of diagnosis. Risk factors include Helicobacter pylori infection, family history of gastric cancer-in particular, hereditary diffuse gastric cancer and pernicious anaemia. The stages in the progression to cancer include chronic gastritis, gastric atrophy (GA), gastric intestinal metaplasia (GIM) and dysplasia. The key to early detection of cancer and improved survival is to non-invasively identify those at risk before endoscopy. However, although biomarkers may help in the detection of patients with chronic atrophic gastritis, there is insufficient evidence to support their use for population screening. High-quality endoscopy with full mucosal visualisation is an important part of improving early detection. Image-enhanced endoscopy combined with biopsy sampling for histopathology is the best approach to detect and accurately risk-stratify GA and GIM. Biopsies following the Sydney protocol from the antrum, incisura, lesser and greater curvature allow both diagnostic confirmation and risk stratification for progression to cancer. Ideally biopsies should be directed to areas of GA or GIM visualised by high-quality endoscopy. There is insufficient evidence to support screening in a low-risk population (undergoing routine diagnostic oesophagogastroduodenoscopy) such as the UK, but endoscopic surveillance every 3 years should be offered to patients with extensive GA or GIM. Endoscopic mucosal resection or endoscopic submucosal dissection of visible gastric dysplasia and early cancer has been shown to be efficacious with a high success rate and low rate of recurrence, providing that specific quality criteria are met.
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Affiliation(s)
- Matthew Banks
- University College London Hospital, University College London Hospitals NHS Foundation Trust, London, UK
- Research Department of Targeted Intervention, University College London, London, UK
| | - David Graham
- University College London Hospital, University College London Hospitals NHS Foundation Trust, London, UK
- Division of Surgery and Interventional Science, University College London Division of Biosciences, London, UK
| | - Marnix Jansen
- Department of Histopathology, University College London, London, UK
| | - Takuji Gotoda
- Gastroenterology, Nihon University School of Medicine Graduate School of Medicine, Itabashi-ku, Tokyo, Japan
| | | | - Massimiliano di Pietro
- MRC Cancer Unit, University of Cambridge, Cambridge, UK
- Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Noriya Uedo
- Department of Gastrointestinal Oncology, Endoscopic Training and Learning Center, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
| | | | - D Mark Pritchard
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | | | | | - Marco R Novelli
- Department of Histopathology, University College London, London, UK
| | - Krish Ragunath
- Nottingham Digestive Diseases Centre, Nottingham University Hospital, Nottingham, UK
| | - Neil Shepherd
- Gloucestershire Cellular Pathology Laboratory, Cheltenham General Hospital, Cheltenham, Gloucestershire, UK
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22
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Increased LIGHT expression and activation of non-canonical NF-κB are observed in gastric lesions of MyD88-deficient mice upon Helicobacter felis infection. Sci Rep 2019; 9:7030. [PMID: 31065023 PMCID: PMC6504916 DOI: 10.1038/s41598-019-43417-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 04/08/2019] [Indexed: 12/12/2022] Open
Abstract
Helicobacter pylori infection induces a number of pro-inflammatory signaling pathways contributing to gastric inflammation and carcinogenesis. Among those, NF-κB signaling plays a pivotal role during infection and malignant transformation of the gastric epithelium. However, deficiency of the adaptor molecule myeloid differentiation primary response 88 (MyD88), which signals through NF-κB, led to an accelerated development of gastric pathology upon H. felis infection, but the mechanisms leading to this phenotype remained elusive. Non-canonical NF-κB signaling was shown to aggravate H. pylori-induced gastric inflammation via activation of the lymphotoxin β receptor (LTβR). In the present study, we explored whether the exacerbated pathology observed in MyD88-deficient (Myd88−/−) mice was associated with aberrant activation of non-canonical NF-κB. Our results indicate that, in the absence of MyD88, H. felis infection enhances the activation of non-canonical NF-κB that is associated with increase in Cxcl9 and Icam1 gene expression and CD3+ lymphocyte recruitment. In addition, activation of signal transducer and activator of transcription 3 (STAT3) signaling was higher in Myd88−/− compared to wild type (WT) mice, indicating a link between MyD88 deficiency and STAT3 activation in response to H. felis infection. Thereby, MyD88 deficiency results in accelerated and aggravated gastric pathology induced by Helicobacter through activation of non-canonical NF-κB.
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23
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Chen J, Zhu C, Wang C, Hu C, Czajkowsky DM, Guo Y, Liu B, Shao Z. Evidence for heightened genetic instability in precancerous spasmolytic polypeptide expressing gastric glands. J Med Genet 2019; 57:385-388. [PMID: 30877236 DOI: 10.1136/jmedgenet-2018-105752] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Revised: 02/02/2019] [Accepted: 02/06/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Spasmolytic polypeptide-expressing metaplasia (SPEM) is present in more than 90% of resected gastric cancer tissues. However, although widely regarded as a pre-cancerous tissue, its genetic characteristics have not been well studied. METHODS Immunohistochemistry using Trefoil factor 2 (TFF2) antibodies was used to identify TFF2-positive SPEM cells within SPEM glands in the stomach of Helicobacter felis (H. felis) -infected mice and human clinical samples. Laser microdissection was used to isolate specific cells from both the infected mice and the human samples. The genetic instability in these cells was examined by measuring the lengths of microsatellite (MS) markers using capillary electrophoresis. Also, genome-wide genetic variations in the SPEM cells from the clinical sample was examined using deep whole-exome sequencing. RESULTS SPEM cells indeed exhibit not only heightened MS instability (MSI), but also genetic instabilities that extend genome-wide. Furthermore, surprisingly, we found that morphologically normal, TFF2-negative cells also contain a comparable degree of genomic instabilities as the co-resident SPEM cells within the SPEM glands. CONCLUSION These results, for the first time, clearly establish elevated genetic instability as a critical property of SPEM glands, which may provide a greater possibility for malignant clone selection. More importantly, these results indicate that SPEM cells may not be the sole origin of carcinogenesis in the stomach and strongly suggest the common progenitor of these cells, the stem cells, as the source of these genetic instabilities, and thus, potential key players in carcinogenesis.
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Affiliation(s)
- Jiangrong Chen
- Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Chunchao Zhu
- Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chaojie Wang
- Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chuansheng Hu
- Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Daniel M Czajkowsky
- Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Yan Guo
- Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.,State Key Laboratory for Oncogenes and Related Genes, Shanghai Jiao Tong University, Shanghai, China
| | - Bingya Liu
- Shanghai Key Laboratory of Gastric Neoplasms, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhifeng Shao
- Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.,State Key Laboratory for Oncogenes and Related Genes, Shanghai Jiao Tong University, Shanghai, China
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24
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Chen J, Zhu C, Wang C, Zhang X, Ni J, Czajkowsky DM, Liu B, Guo Y. Discovery and genetic characterization of intestinal metaplasia in the Helicobacter felis-infected mouse model of gastric cancer. Acta Biochim Biophys Sin (Shanghai) 2019; 51:219-222. [PMID: 30576406 DOI: 10.1093/abbs/gmy160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 11/20/2018] [Indexed: 11/12/2022] Open
Affiliation(s)
- Jiangrong Chen
- Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Chunchao Zhu
- Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chaojie Wang
- Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaodan Zhang
- Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Jian Ni
- Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Daniel M Czajkowsky
- Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Bingya Liu
- Shanghai Key Laboratory of Gastric Neoplasms, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Guo
- Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
- State Key Laboratory for Oncogenes & Related Genes, Shanghai Jiao Tong University, Shanghai, China
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25
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Aziz AHAEL, Abdallah HM, Awad SM, EL-Bahr O, Khalil A, Abo Riaa GY. Association of ATG16L1 genetic variant with Helicobacter pylori infection in Egyptian patients with chronic gastritis disease. FRONTIERS IN LABORATORY MEDICINE 2018; 2:134-140. [DOI: https:/doi.org/10.1016/j.flm.2019.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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D'Costa K, Chonwerawong M, Tran LS, Ferrero RL. Mouse Models Of Helicobacter Infection And Gastric Pathologies. J Vis Exp 2018. [PMID: 30394371 DOI: 10.3791/56985] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Helicobacter pylori is a gastric pathogen that is present in half of the global population and is a significant cause of morbidity and mortality in humans. Several mouse models of gastric Helicobacter infection have been developed to study the molecular and cellular mechanisms whereby H. pylori bacteria colonize the stomach of human hosts and cause disease. Herein, we describe protocols to: 1) prepare bacterial suspensions for the in vivo infection of mice via intragastric gavage; 2) determine bacterial colonization levels in mouse gastric tissues, by polymerase chain reaction (PCR) and viable counting; and 3) assess pathological changes, by histology. To establish Helicobacter infection in mice, specific pathogen-free (SPF) animals are first inoculated with suspensions (containing ≥105 colony-forming units, CFUs) of mouse-colonizing strains of either Helicobacter pylori or other gastric Helicobacter spp. from animals, such as Helicobacter felis. At the appropriate time-points post-infection, stomachs are excised and dissected sagittally into two equal tissue fragments, each comprising the antrum and body regions. One of these fragments is then used for either viable counting or DNA extraction, while the other is subjected to histological processing. Bacterial colonization and histopathological changes in the stomach may be assessed routinely in gastric tissue sections stained with Warthin-Starry, Giemsa or Haematoxylin and Eosin (H&E) stains, as appropriate. Additional immunological analyses may also be undertaken by immunohistochemistry or immunofluorescence on mouse gastric tissue sections. The protocols described below are specifically designed to enable the assessment in mice of gastric pathologies resembling those in human-related H. pylori diseases, including inflammation, gland atrophy and lymphoid follicle formation. The inoculum preparation and intragastric gavage protocols may also be adapted to study the pathogenesis of other enteric human pathogens that colonize mice, such as Salmonella Typhimurium or Citrobacter rodentium.
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Affiliation(s)
- Kimberley D'Costa
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
| | - Michelle Chonwerawong
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
| | - Le Son Tran
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
| | - Richard L Ferrero
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research; Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University;
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27
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Kokate SB, Dixit P, Poirah I, Roy AD, Chakraborty D, Rout N, Singh SP, Ashktorab H, Smoot DT, Bhattacharyya A. Testin and filamin-C downregulation by acetylated Siah2 increases invasiveness of Helicobacter pylori-infected gastric cancer cells. Int J Biochem Cell Biol 2018; 103:14-24. [PMID: 30063986 DOI: 10.1016/j.biocel.2018.07.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 07/26/2018] [Accepted: 07/27/2018] [Indexed: 12/15/2022]
Abstract
Helicobacter pylori is the strongest known risk-factor for gastric cancer. However, its role in gastric cancer metastasis remains unclear. Previously we have reported that H. pylori promotes gastric cancer invasiveness by stabilizing the E3 ubiquitin ligase Siah2 which is mediated by Siah2 acetylation at Lys 139 (K139) residue. Here we identify that cell adhesion-related proteins testin (TES) and filamin-C (FLN-C) interact with Siah2 and get proteasomally degraded. The efficiency of TES and FLN-C degradation is significantly potentiated by K139-acetylated Siah2 (ac-K139 Siah2) in infected gastric cancer cells (GCCs). ac-Siah2-mediated downregulation of TES and FLN-C disrupts filopodia structures but promotes lamellipodia formation and enhances invasiveness and migration of infected GCCs. Since H. felis-infected mice as well as human gastric cancer biopsy samples also show high level of ac-K139 Siah2 and downregulated TES and FLN-C, we believe that acetylation of Siah2 is an important checkpoint that can be useful for therapeutic intervention.
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Affiliation(s)
- Shrikant Babanrao Kokate
- School of Biological Sciences, National Institute of Science Education and Research (NISER) Bhubaneswar, Homi Bhabha National Institute (HBNI), P.O. Bhimpur-Padanpur, Via Jatni, Dist. Khurda Jatni, 752050, Odisha, India
| | - Pragyesh Dixit
- School of Biological Sciences, National Institute of Science Education and Research (NISER) Bhubaneswar, Homi Bhabha National Institute (HBNI), P.O. Bhimpur-Padanpur, Via Jatni, Dist. Khurda Jatni, 752050, Odisha, India
| | - Indrajit Poirah
- School of Biological Sciences, National Institute of Science Education and Research (NISER) Bhubaneswar, Homi Bhabha National Institute (HBNI), P.O. Bhimpur-Padanpur, Via Jatni, Dist. Khurda Jatni, 752050, Odisha, India
| | - Arjama Dhar Roy
- School of Biological Sciences, National Institute of Science Education and Research (NISER) Bhubaneswar, Homi Bhabha National Institute (HBNI), P.O. Bhimpur-Padanpur, Via Jatni, Dist. Khurda Jatni, 752050, Odisha, India
| | - Debashish Chakraborty
- School of Biological Sciences, National Institute of Science Education and Research (NISER) Bhubaneswar, Homi Bhabha National Institute (HBNI), P.O. Bhimpur-Padanpur, Via Jatni, Dist. Khurda Jatni, 752050, Odisha, India
| | - Niranjan Rout
- Department of Oncopathology, Acharya Harihar Regional Cancer Centre, Cuttack 753007, Odisha, India
| | | | - Hassan Ashktorab
- Department of Medicine, Howard University, Washington, DC 20060, USA
| | - Duane T Smoot
- Department of Medicine, Meharry Medical Center, Nashville, TN 37208, USA
| | - Asima Bhattacharyya
- School of Biological Sciences, National Institute of Science Education and Research (NISER) Bhubaneswar, Homi Bhabha National Institute (HBNI), P.O. Bhimpur-Padanpur, Via Jatni, Dist. Khurda Jatni, 752050, Odisha, India.
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28
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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. Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial. Gut 2018; 67:1239-1246. [PMID: 28647684 PMCID: PMC5742304 DOI: 10.1136/gutjnl-2016-311685] [Citation(s) in RCA: 133] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 04/17/2017] [Accepted: 04/30/2017] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To evaluate the long-term effect of cumulative time exposed to Helicobacter pylori infection on the progression of gastric lesions. DESIGN 795 adults with precancerous gastric lesions were randomised to receive anti-H. pylori 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 H. pylori 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 H. pylori 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 H. pylori. 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 H. pylori infection was associated with progression of precancerous lesions. Individuals infected with H. pylori 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.
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Affiliation(s)
- Robertino M Mera
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Luis E Bravo
- Department of Pathology, Universidad del Valle School of Medicine, Cali, Colombia
| | - M Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | - Juan C Bravo
- Department of Pathology, Universidad del Valle School of Medicine, Cali, Colombia
| | - Alberto G Delgado
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Judith Romero-Gallo
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Maria C Yepez
- Centro de Estudios en Salud, Universidad de Nariño, Pasto, Colombia
| | - José L Realpe
- Centro de Estudios en Salud, Universidad de Nariño, Pasto, Colombia
| | - Barbara G Schneider
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Douglas R Morgan
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Richard M Peek
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Pelayo Correa
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Keith T Wilson
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee, USA
| | - M Blanca Piazuelo
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Zhang S, Kim W, Pham TT, Rogers AB, Houghton JM, Moss SF. Native and bone marrow-derived cell mosaicism in gastric carcinoma in H. pylori-infected p27-deficient mice. Oncotarget 2018; 7:69136-69148. [PMID: 27655701 PMCID: PMC5342465 DOI: 10.18632/oncotarget.12049] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 09/02/2016] [Indexed: 01/25/2023] Open
Abstract
Objective Chronic Helicobacter pylori (H. pylori) infection promotes non-cardia gastric cancer. Some mouse models suggest that bone marrow derived cells (BMDC) contribute to Helicobacter-associated gastric carcinogenesis. We determined whether this increased susceptibility to Helicobacter-induced gastric carcinogenesis of p27-deficient mice is dependent upon their p27-null BMDC or their p27-null gastric epithelial cells. Design Female mice (recipients) were irradiated and transplanted with BMDC from male donors. Wild type (WT) mice in group 1 (control) received BMDC from male GFP-transgenic mice. Female WT and p27 KO mice were engrafted with male p27KO mice BMDC (Group 2) or GFP-transgenic WT BMDC (Group 3). Recipients were infected with H. pylori SS1 for one year. Results Mice lacking p27 in either the BM pool or gastric epithelium developed significantly more advanced gastric pathology, including high-grade dysplasia. Co-staining of donor BMDC in dysplastic gastric glands was confirmed by immunofluorescence. Gastric expression of IL-1 beta protein was reduced in groups 2 and 3 (p < 0.05 vs control) whereas expression of IFN-γ and chemokines MIP-1 beta, MIG, IP-10 and RANTES in group 2 were significantly higher than group 3. Conclusions Both bone marrow-derived and gastric epithelial cells contribute to the increased gastric cancer susceptibility of p27-deficient H. pylori-infected mice.
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Affiliation(s)
- Songhua Zhang
- Division of Gastroenterology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Woojin Kim
- Division of Gastroenterology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Tu T Pham
- Division of Gastroenterology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Arlin B Rogers
- Department of Biomedical Sciences, Tufts Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA, USA
| | - Jean Marie Houghton
- Department of Medicine and Cancer Biology, Division of Gastroenterology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Steven F Moss
- Division of Gastroenterology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA
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Shibata W, Sue S, Tsumura S, Ishii Y, Sato T, Kameta E, Sugimori M, Yamada H, Kaneko H, Sasaki T, Ishii T, Tamura T, Kondo M, Maeda S. Helicobacter-induced gastric inflammation alters the properties of gastric tissue stem/progenitor cells. BMC Gastroenterol 2017; 17:145. [PMID: 29212456 PMCID: PMC5719643 DOI: 10.1186/s12876-017-0706-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 11/24/2017] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Although Helicobacter-induced gastric inflammation is the major predisposing factor for gastric carcinogenesis, the precise mechanism by which chronic gastritis causes gastric cancer remains unclear. Intestinal and spasmolytic polypeptide-expressing metaplasia (SPEM) is considered as precancerous lesions, changes in epithelial tissue stem/progenitor cells after chronic inflammation has not been clarified yet. In this study, we utilized three-dimensional gastric epithelial cell culture systems that could form organoids, mimicking gastric epithelial layer, and characterized the changes in epithelial cells after chronic Helicobacter felis infection. METHODS We used three mice model; 1) long-term H. felis infection, 2) H. felis eradication, and 3) MNU chemical carcinogenesis model. We performed cRNA microarray analysis after organoid culture, and analyzed the effects of chronic gastric inflammation on tissue stem cells, by the size of organoid, mRNA expression profile and immunohistochemical analysis. RESULTS The number of organoids cultured from gastric epithelial cells was significantly higher in organoids isolated from H. felis-infected mice compared with those from uninfected gastric mucosa. Based on the mRNA expression profile, we found that possible stem cell markers such as Cd44, Dclk1, and genes associated with the intestinal phenotype, such as Villin, were increased in organoids isolated from H. felis-infected mucosa compared with the control. The upregulation of these genes were cancelled after H. felis eradication. In a xenograft model, tumors were generated only from organoids cultured from carcinogen-treated gastric mucosa, not from H. felis infected mucosa or control organoids. CONCLUSIONS Our results suggested that, as a possible mechanism of gastric carcinogenesis, chronic inflammation induced by H. felis infection increased the number of tissue stem/progenitor cells and the expression of stem cell markers. These findings suggest that chronic inflammation may alter the direction of differentiation toward undifferentiated state and that drawbacks may enable cells to redifferentiate to intestinal metaplasia or neoplasia.
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Affiliation(s)
- Wataru Shibata
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Division of Translational Research, Advanced Medical Research Center, Yokohama City University, Yokohama, Japan
| | - Soichiro Sue
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Sachiko Tsumura
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- School of Medicine, Yokohama City University, Yokohama, Japan
| | - Yasuaki Ishii
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takeshi Sato
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Eri Kameta
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Makoto Sugimori
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hiroaki Yamada
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hiroaki Kaneko
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Tomohiko Sasaki
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Tomohiro Ishii
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Toshihide Tamura
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Masaaki Kondo
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
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Floch P, Izotte J, Guillemaud J, Sifré E, Costet P, Rousseau B, Laur AM, Giese A, Korolik V, Mégraud F, Dubus P, Hahne M, Lehours P. A New Animal Model of Gastric Lymphomagenesis. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:1473-1484. [DOI: 10.1016/j.ajpath.2017.03.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 02/27/2017] [Accepted: 03/09/2017] [Indexed: 12/29/2022]
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Membrane-bound β-catenin degradation is enhanced by ETS2-mediated Siah1 induction in Helicobacter pylori-infected gastric cancer cells. Oncogenesis 2017; 6:e327. [PMID: 28481365 PMCID: PMC5523059 DOI: 10.1038/oncsis.2017.26] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 02/16/2017] [Accepted: 03/20/2017] [Indexed: 12/12/2022] Open
Abstract
β-catenin has two different cellular functions: intercellular adhesion and transcriptional activity. The E3 ubiquitin ligase Siah1 causes ubiquitin-mediated degradation of the cytosolic β-catenin and therefore, impairs nuclear translocation and oncogenic function of β-catenin. However, the effect of Siah1 on the cell membrane bound β-catenin has not been studied. In this study, we identified that the carcinogenic bacterium H. pylori increased ETS2 transcription factor-mediated Siah1 protein expression in gastric cancer cells (GCCs) MKN45, AGS and Kato III. Siah1 protein level was also noticeably higher in gastric adenocarcinoma biopsy samples as compared to non-cancerous gastric epithelia. Siah1 knockdown significantly decreased invasiveness and migration of H. pylori-infected GCCs. Although, Siah1 could not increase degradation of the cytosolic β-catenin and its nuclear translocation, it enhanced degradation of the membrane-bound β-catenin in the infected GCCs. This loss of membrane-bound pool of β-catenin was not associated with the proteasomal degradation of E-cadherin. Thus, this work delineated the role of Siah1 in increasing invasiveness of H. pylori-infected GCCs.
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Goldenring JR. The AGA/Funderburg Award in Gastric Cancer: Twenty-five Years of Advances in Gastric Cancer Research. Gastroenterology 2017; 152:1262-1266. [PMID: 28327368 DOI: 10.1053/j.gastro.2017.03.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- James R Goldenring
- Nashville VA Medical Center and Vanderbilt University Medical Center, Nashville, Tennessee
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MIFTAHUSSURUR MUHAMMAD, YAMAOKA YOSHIO, GRAHAM DAVIDY. Helicobacter pylori as an oncogenic pathogen, revisited. Expert Rev Mol Med 2017; 19:e4. [PMID: 28322182 PMCID: PMC6905048 DOI: 10.1017/erm.2017.4] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Gastric cancer is an inflammation-associated malignancy aetiologically related to infection with the bacterium, Helicobacter pylori, which is considered a necessary but insufficient cause. Unless treated, H. pylori causes life-long acute and chronic gastric inflammation resulting in progressive gastric mucosal damage that may result in gastric cancer. The rate of progression from superficial gastritis, to an atrophic metaplastic mucosa, and ultimately to cancer relates to the virulence of the infecting H. pylori as well as host and environmental factors. H. pylori virulence is a reflection of its propensity to cause severe gastric inflammation. Both mucosal inflammation and H. pylori can cause host genomic instability, including dysregulation of DNA mismatch repair, stimulation of expression of activation-induced cytidine deaminase, abnormal DNA methylation and dysregulation of micro RNAs, which may result in an accumulation of mutations and loss of normal regulation of cell growth. The difference in cancer risk between the most and least virulent H. pylori strain is only approximately 2-fold. Overall, none of the putative virulence factors identified to date have proved to be disease-specific. The presence, severity, extent and duration of inflammation appear to be the most important factors and current evidence suggests that any host, environmental or bacterial factor that reliably enhances the inflammatory response to the H. pylori infection increases the risk of gastric cancer.
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Affiliation(s)
- MUHAMMAD MIFTAHUSSURUR
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, Texas 77030, USA
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu 879-5593, Japan
- Gastroentero-Hepatology Division, Department of Internal Medicine, Faculty of Medicine – Dr Soetomo Teaching Hospital – Institute of Tropical Disease, Universitas Airlangga, Surabaya 60115, Indonesia
| | - YOSHIO YAMAOKA
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, Texas 77030, USA
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu 879-5593, Japan
| | - DAVID Y. GRAHAM
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, Texas 77030, USA
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Abstract
The approvals and provisions of the Management of Helicobacter pylori infection-the Maastricht V/ Florence Consensus Report and those of the Kyoto Global Consensus Conference on H. pylori-associated gastritis, concerning with the primary and secondary prevention of gastric cancer (GC), unambiguously suggest that H. pylori infection is the most important risk factor of GC. Accordingly, the basis for the primary and secondary prevention of GC is the optimization of H. pylori eradication therapy. The clear direct relationship of the risk of GC to the severity and extent of atrophic gastritis, intestinal metaplasia and dysplasia and no reversal of intestinal metaplasia and dysplasia in the presence of H. pylori eradication presume that gastroprotective agents should be used for primary and secondary prevention. Experimental and clinical findings can lead to the conclusion that rebamipide is a highly effective and safe agent for the primary and secondary prevention of GC in patients with and without H. pylori infection, by optimizing anti-Helicobacter therapy, its anti-inflammatory effect and ability to restore the cellular structure of the gastric epithelium.
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Affiliation(s)
- I G Maev
- A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia, Moscow, Russia
| | - A N Kazyulin
- A.I. Evdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia, Moscow, Russia
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Bessède E, Molina S, Amador LA, Dubus P, Staedel C, Chambonnier L, Buissonnière A, Sifré E, Giese A, Bénéjat L, Rousseau B, Costet P, Sacks DB, Mégraud F, Varon C. Deletion of IQGAP1 promotes Helicobacter pylori-induced gastric dysplasia in mice and acquisition of cancer stem cell properties in vitro. Oncotarget 2016; 7:80688-80699. [PMID: 27729612 PMCID: PMC5340252 DOI: 10.18632/oncotarget.12486] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 07/18/2016] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori infection is responsible for gastric carcinogenesis but host factors are also implicated. IQGAP1, a scaffolding protein of the adherens junctions interacting with E-cadherin, regulates cellular plasticity and proliferation. In mice, IQGAP1 deficiency leads to gastric hyperplasia. The aim of this study was to elucidate the consequences of IQGAP1 deletion on H. pylori-induced gastric carcinogenesis.Transgenic mice deleted for iqgap1 and WT littermates were infected with Helicobacter sp., and histopathological analyses of the gastric mucosa were performed. IQGAP1 and E-cadherin expression was evaluated in gastric tissues and in gastric epithelial cell lines in response to H. pylori infection. The consequences of IQGAP1 deletion on gastric epithelial cell behaviour and on the acquisition of cancer stem cell (CSC)-like properties were evaluated. After one year of infection, iqgap1+/- mice developed more preneoplastic lesions and up to 8 times more gastro-intestinal neoplasia (GIN) than WT littermates. H. pylori infection induced IQGAP1 and E-cadherin delocalization from cell-cell junctions. In vitro, knock-down of IQGAP1 favoured the acquisition of a mesenchymal phenotype and CSC-like properties induced by H. pylori infection.Our results indicate that alterations in IQGAP1 signalling promote the emergence of CSCs and gastric adenocarcinoma development in the context of an H. pylori infection.
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Affiliation(s)
- Emilie Bessède
- Bacteriology Laboratory, University of Bordeaux, Bordeaux, France
- INSERM, U853, Bordeaux, France
| | - Silvia Molina
- Bacteriology Laboratory, University of Bordeaux, Bordeaux, France
- INSERM, U853, Bordeaux, France
| | - Luis Acuña Amador
- Bacteriology Laboratory, University of Bordeaux, Bordeaux, France
- INSERM, U853, Bordeaux, France
| | - Pierre Dubus
- EA2406 Histologie et pathologie moléculaire des tumeurs, University of Bordeaux, Bordeaux, France
| | - Cathy Staedel
- ‘RNA: Natural and Artificial Regulation’ (ARNA) Laboratory, University of Bordeaux, Bordeaux, France
- INSERM, U869, Bordeaux, France
| | - Lucie Chambonnier
- Bacteriology Laboratory, University of Bordeaux, Bordeaux, France
- INSERM, U853, Bordeaux, France
| | - Alice Buissonnière
- Bacteriology Laboratory, University of Bordeaux, Bordeaux, France
- INSERM, U853, Bordeaux, France
| | - Elodie Sifré
- Bacteriology Laboratory, University of Bordeaux, Bordeaux, France
- INSERM, U853, Bordeaux, France
| | - Alban Giese
- EA2406 Histologie et pathologie moléculaire des tumeurs, University of Bordeaux, Bordeaux, France
- Experimental Pathology Platform, SIRIC BRIO, University of Bordeaux, Bordeaux, France
| | - Lucie Bénéjat
- Bacteriology Laboratory, University of Bordeaux, Bordeaux, France
- INSERM, U853, Bordeaux, France
| | - Benoît Rousseau
- Service Commun des Animaleries, Animalerie A2, University of Bordeaux, Bordeaux, France
| | - Pierre Costet
- Service Commun des Animaleries, Animalerie Transgénique, University of Bordeaux, Bordeaux, France
| | - David B. Sacks
- Department of Laboratory Medicine, National Institutes of Health, Bethesda, MD, USA
| | - Francis Mégraud
- Bacteriology Laboratory, University of Bordeaux, Bordeaux, France
- INSERM, U853, Bordeaux, France
| | - Christine Varon
- Bacteriology Laboratory, University of Bordeaux, Bordeaux, France
- INSERM, U853, Bordeaux, France
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Chonwerawong M, Avé P, Huerre M, Ferrero RL. Interferon-γ promotes gastric lymphoid follicle formation but not gastritis in Helicobacter-infected BALB/c mice. Gut Pathog 2016; 8:61. [PMID: 27895717 PMCID: PMC5117576 DOI: 10.1186/s13099-016-0142-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 11/14/2016] [Indexed: 12/13/2022] Open
Abstract
Background Mouse infection studies have shown that interferon-γ (IFN-γ), a T helper 1 (Th1) cytokine, is required for the development of severe pathology induced by chronic Helicobacter infection. This finding is largely based on studies performed using mice that have polarised Th1 responses i.e. C57BL/6 animals. The current work aims to investigate the role of IFN-γ in Helicobacter-induced inflammation in BALB/c mice which have Th2-polarised immune responses. Results At 7 months post-infection with Helicobacter felis, IFN-γ deficiency in BALB/c mice had no significant effect on H. felis colonisation levels in the gastric mucosa, nor on humoral responses, or gastritis severity. Ifng−/− animals with chronic H. felis infection did, however, develop significantly fewer lymphoid follicle lesions, as well as increased IL-4 splenocyte responses, when compared with infected Ifng+/+ mice (P = 0.015 and P = 0.0004, respectively). Conclusions The work shows that in mice on a BALB/c background, IFN-γ is not required for bacterial clearance, antibody responses, nor gastric inflammation. Conversely, IFN-γ appears to play a role in the development of gastric lymphoid follicles, which are precursor lesions to mucosa-associated lymphoid tissue (MALT) lymphoma. This study highlights the importance of mouse host background on the susceptibility to Helicobacter-induced pathologies.
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Affiliation(s)
- Michelle Chonwerawong
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, VIC 3123 Australia
| | - Patrick Avé
- Unité de Recherche et d'Expertise Histotechnologie et Pathologie, Institut Pasteur, 25-28 Rue du Dr Roux, 75724 Paris, France ; Unité de Histopathologie Humaine et Modèles Animaux, Institut Pasteur, 25-28 Rue du Dr Roux, 75724 Paris, France
| | - Michel Huerre
- Unité de Recherche et d'Expertise Histotechnologie et Pathologie, Institut Pasteur, 25-28 Rue du Dr Roux, 75724 Paris, France ; Département de Pathologie, Institut Curie, 26 Rue d'Ulm, 75248 Paris, France
| | - Richard L Ferrero
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, VIC 3123 Australia ; Department of Microbiology, Monash University, Clayton, VIC Australia
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Lee JY, Kim N, Choi YJ, Nam RH, Choi YJ, Lee S, Choi D, Lee HS, Kim JW, Lee DH. Effect of N-Methyl-N-Nitrosourea on Helicobacter-induced Gastric Carcinogenesis in C57BL/6 Mice. J Cancer Prev 2016; 21:182-186. [PMID: 27722144 PMCID: PMC5051592 DOI: 10.15430/jcp.2016.21.3.182] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 09/11/2016] [Accepted: 09/13/2016] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND The aim of this study was to investigate the effect of N-methyl-N-nitrosourea (MNU) treatment followed by chronic Helicobacter pylori SS1 and H. felis colonization on the stomachs of C57BL/6 mice. The role of MNU and Helicobacter species in gastric carcinogenesis was also elucidated. METHODS A total of 69 C57BL/6 mice at 4 weeks of age were divided into 6 groups according to MNU treatment and H. pylori SS1 or H. felis infection. The mice were sacrificed at 21 and 50 weeks. The degree of inflammation was determined by histopathology. The levels of gastric mucosal myeloperoxidase, TNF-α, and interleukin-1β (IL-1β) were measured by ELISA. RESULTS In the H. felis groups with or without MNU, the incidence of gastric tumors was 21.1% and 35.0% at 21 and 50 weeks, respectively. No gastric tumors were observed in all control mice. At 50 weeks, 37.5% of gastric adenoma cases were observed in the H. felis alone and MNU + H. felis groups. Furthermore, 12.5% of gastric adenocarcinoma cases were observed in the MNU alone and MNU + H. felis groups. The gastric mucosal IL-1β level was significantly higher in the MNU + H. felis group at 21 weeks and H. felis group at 50 weeks, respectively, than that for control mice (P < 0.05). However, the effect of MNU on H. pylori SS1-induced gastric carcinogenesis was low compared to that on H. felis. CONCLUSIONS Administration of MNU before H. felis infection provokes severe inflammation through IL-1β, and eventually induces gastric cancer. However, the role of MNU in H. pylori SS1-induced gastric carcinogenesis model is minor.
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Affiliation(s)
- Ju Yup Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea; Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Yoon Jeong Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ryoung Hee Nam
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Yoon Jin Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Seonmin Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Daeun Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jin-Wook Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
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Poh AR, O'Donoghue RJJ, Ernst M, Putoczki TL. Mouse models for gastric cancer: Matching models to biological questions. J Gastroenterol Hepatol 2016; 31:1257-72. [PMID: 26809278 PMCID: PMC5324706 DOI: 10.1111/jgh.13297] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Revised: 01/12/2016] [Accepted: 01/14/2016] [Indexed: 02/06/2023]
Abstract
Gastric cancer is the third leading cause of cancer-related mortality worldwide. This is in part due to the asymptomatic nature of the disease, which often results in late-stage diagnosis, at which point there are limited treatment options. Even when treated successfully, gastric cancer patients have a high risk of tumor recurrence and acquired drug resistance. It is vital to gain a better understanding of the molecular mechanisms underlying gastric cancer pathogenesis to facilitate the design of new-targeted therapies that may improve patient survival. A number of chemically and genetically engineered mouse models of gastric cancer have provided significant insight into the contribution of genetic and environmental factors to disease onset and progression. This review outlines the strengths and limitations of current mouse models of gastric cancer and their relevance to the pre-clinical development of new therapeutics.
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Affiliation(s)
- Ashleigh R Poh
- Department of Medical BiologyUniversity of MelbourneMelbourneVictoriaAustralia
- The Walter and Eliza Hall Institute of Medical ResearchMelbourneVictoriaAustralia
| | - Robert J J O'Donoghue
- School of Cancer MedicineLa Trobe University, Olivia Newton‐John Cancer Research InstituteMelbourneVictoriaAustralia
| | - Matthias Ernst
- School of Cancer MedicineLa Trobe University, Olivia Newton‐John Cancer Research InstituteMelbourneVictoriaAustralia
| | - Tracy L Putoczki
- Department of Medical BiologyUniversity of MelbourneMelbourneVictoriaAustralia
- The Walter and Eliza Hall Institute of Medical ResearchMelbourneVictoriaAustralia
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Li H, Jasper H. Gastrointestinal stem cells in health and disease: from flies to humans. Dis Model Mech 2016; 9:487-99. [PMID: 27112333 PMCID: PMC4892664 DOI: 10.1242/dmm.024232] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The gastrointestinal tract of complex metazoans is highly compartmentalized. It is lined by a series of specialized epithelia that are regenerated by specific populations of stem cells. To maintain tissue homeostasis, the proliferative activity of stem and/or progenitor cells has to be carefully controlled and coordinated with regionally distinct programs of differentiation. Metaplasias and dysplasias, precancerous lesions that commonly occur in the human gastrointestinal tract, are often associated with the aberrant proliferation and differentiation of stem and/or progenitor cells. The increasingly sophisticated characterization of stem cells in the gastrointestinal tract of mammals and of the fruit fly Drosophila has provided important new insights into these processes and into the mechanisms that drive epithelial dysfunction. In this Review, we discuss recent advances in our understanding of the establishment, maintenance and regulation of diverse intestinal stem cell lineages in the gastrointestinal tract of Drosophila and mice. We also discuss the field's current understanding of the pathogenesis of epithelial dysfunctions.
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Affiliation(s)
- Hongjie Li
- Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA Department of Biology, University of Rochester, River Campus Box 270211, Rochester, NY 14627, USA
| | - Heinrich Jasper
- Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA
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Recapitulating Human Gastric Cancer Pathogenesis: Experimental Models of Gastric Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 908:441-78. [PMID: 27573785 DOI: 10.1007/978-3-319-41388-4_22] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
This review focuses on the various experimental models to study gastric cancer pathogenesis, with the role of genetically engineered mouse models (GEMMs) used as the major examples. We review differences in human stomach anatomy compared to the stomachs of the experimental models, including the mouse and invertebrate models such as Drosophila and C. elegans. The contribution of major signaling pathways, e.g., Notch, Hedgehog, AKT/PI3K is discussed in the context of their potential contribution to foregut tumorigenesis. We critically examine the rationale behind specific GEMMs, chemical carcinogens, dietary promoters, Helicobacter infection, and direct mutagenesis of relevant oncogenes and tumor suppressor that have been developed to study gastric cancer pathogenesis. Despite species differences, more efficient and effective models to test specific genes and pathways disrupted in human gastric carcinogenesis have yet to emerge. As we better understand these species differences, "humanized" versions of mouse models will more closely approximate human gastric cancer pathogenesis. Towards that end, epigenetic marks on chromatin, the gut microbiota, and ways of manipulating the immune system will likely move center stage, permitting greater overlap between rodent and human cancer phenotypes thus providing a unified progression model.
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Gastric Metaplasia Induced by Helicobacter pylori Is Associated with Enhanced SOX9 Expression via Interleukin-1 Signaling. Infect Immun 2015; 84:562-72. [PMID: 26644382 DOI: 10.1128/iai.01437-15] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 11/28/2015] [Indexed: 12/19/2022] Open
Abstract
Histopathological changes of the gastric mucosa after Helicobacter pylori infection, such as atrophy, metaplasia, and dysplasia, are considered to be precursors of gastric cancer, yet the mechanisms of histological progression are unknown. The aim of this study was to analyze the histopathological features of the gastric mucosa in mice infected with H. pylori strain PMSS1 in relation to gastric stem cell marker expression. C57BL/6J mice infected with PMSS1 were examined for histopathological changes, levels of proinflammatory cytokines, and expression of stem cell markers. Histopathological gastritis scores, such as atrophy and metaplasia, and levels of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β), were increased after PMSS1 infection. Expression levels of the cell proliferation and stem cell markers CD44 and SOX9 were also significantly increased in PMSS1-infected mice. Importantly, almost all metaplastic cells induced by PMSS1 infection expressed SOX9. When IL-1 receptor (IL-1R) knockout mice were infected with PMSS1, metaplastic changes and expression levels of stem cell markers were significantly decreased compared with those in wild-type (WT) mice. In conclusion, H. pylori infection induced the expression of cytokines and stem cell markers and histopathological metaplasia in the mouse gastric mucosa. SOX9 expression, in particular, was strongly associated with metaplastic changes, and these changes were dependent on IL-1 signaling. The results suggested the importance of SOX9 in gastric carcinogenesis.
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Duckworth CA, Burkitt MD, Williams JM, Parsons BN, Tang JMF, Pritchard DM. Murine Models of Helicobacter (pylori or felis)-associated Gastric Cancer. ACTA ACUST UNITED AC 2015; 69:14.34.1-14.34.35. [PMID: 26344212 DOI: 10.1002/0471141755.ph1434s69] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Gastric adenocarcinoma is the fifth most common cancer and third most common cause of cancer-related death in the world. The majority of these cancers develop in genetically susceptible individuals who are chronically infected with the Gram-negative bacterium Helicobacter pylori. Often these individuals have also been exposed to certain environmental factors that increase susceptibility, such as dietary components. Murine models of Helicobacter-induced gastric cancer are valuable tools for investigating the mechanisms responsible for the stepwise pathological changes of chronic atrophic gastritis, intestinal metaplasia, dysplasia and gastric adenocarcinoma. Helicobacter felis colonization greatly accelerates the development of gastric neoplasia in mice, and causes pathologies similar to those observed with Helicobacter pylori-associated gastric carcinogenesis in humans. These mouse models are therefore useful for investigating genetic and environmental factors that may be involved in the pathogenesis and treatment of gastric cancer. Detailed in these protocols are procedures for inducing Helicobacter-associated carcinogenesis in mice as well as the histological analysis and interpretation of gastric pathology in these animals.
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Affiliation(s)
- Carrie A Duckworth
- Department of Cellular and Molecular Physiology, Gastroenterology Research Unit, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.,Authors share first authorship
| | - Michael D Burkitt
- Department of Cellular and Molecular Physiology, Gastroenterology Research Unit, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.,Authors share first authorship
| | - Jonathan M Williams
- Department of Cellular and Molecular Physiology, Gastroenterology Research Unit, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Bryony N Parsons
- Department of Cellular and Molecular Physiology, Gastroenterology Research Unit, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Joseph M F Tang
- Department of Cellular and Molecular Physiology, Gastroenterology Research Unit, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - D Mark Pritchard
- Department of Cellular and Molecular Physiology, Gastroenterology Research Unit, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.,Correspondence: Prof D. Mark Pritchard, Department of Cellular and Molecular Physiology, Gastroenterology Research Unit, Institute of Translational Medicine, University of Liverpool, Ashton St, Liverpool, L69 3GE. Tel: 0151 794 5772; e-mail:
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Abstract
Humans depend on our commensal bacteria for nutritive, immune-modulating, and metabolic contributions to maintenance of health. However, this commensal community exists in careful balance that, if disrupted, enters dysbiosis; this has been shown to contribute to the pathogenesis of colon, gastric, esophageal, pancreatic, laryngeal, breast, and gallbladder carcinomas. This development is closely tied to host inflammation, which causes and is aggravated by microbial dysbiosis and increases vulnerability to pathogens. Advances in sequencing technology have increased our ability to catalog microbial species associated with various cancer types across the body. However, defining microbial biomarkers as cancer predictors presents multiple challenges, and existing studies identifying cancer-associated bacteria have reported inconsistent outcomes. Combining metabolites and microbiome analyses can help elucidate interactions between gut microbiota, metabolism, and the host. Ultimately, understanding how gut dysbiosis impacts host response and inflammation will be critical to creating an accurate picture of the role of the microbiome in cancer.
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Zhang S, Lee DS, Morrissey R, Aponte-Pieras JR, Rogers AB, Moss SF. Early or late antibiotic intervention prevents Helicobacter pylori-induced gastric cancer in a mouse model. Cancer Lett 2015; 359:345-51. [PMID: 25853150 DOI: 10.1016/j.canlet.2015.01.028] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
H. pylori infection causes gastritis, peptic ulcers and gastric cancer. Eradicating H. pylori prevents ulcers, but to what extent this prevents cancer remains unknown, especially if given after intestinal metaplasia has developed. H. pylori infected wild-type (WT) mice do not develop cancer, but mice lacking the tumor suppressor p27 do so, thus providing an experimental model of H. pylori-induced cancer. We infected p27-deficient mice with H. pylori strain SS1 at 6-8 weeks of age. Persistently H. pylori-infected WT C57BL/6 mice served as controls. Mice in the eradication arms received antimicrobial therapy (omeprazole, metronidazole and clarithromycin) either "early" (at 15 weeks post infection, WPI) or "late" at 45 WPI. At 70 WPI, mice were euthanized for H. pylori determination, histopathology and cytokine/chemokine expression. Persistently infected mice developed premalignant lesions including high-grade dysplasia, whereas those given antibiotics did not. Histologic activity scores in the eradication groups were similar to each other, and were significantly decreased compared with controls for inflammation, epithelial defects, hyperplasia, metaplasia, atrophy and dysplasia. IP-10 and MIG levels in groups that received antibiotics were significantly lower than controls. There were no significant differences in expression of IFN-γ, TNF-α, IL-1β, RANTES, MCP-1, MIP-1α or MIP-1β among the three groups. Thus, H. pylori eradication given either early or late after infection significantly attenuated gastric inflammation, gastric atrophy, hyperplasia, and dysplasia in the p27-deficient mice model of H. pylori-induced gastric cancer, irrespective of the timing of antibiotic administration. This was associated with reduced expression of IP-10 and MIG.
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Bento-Miranda M, Figueiredo C. Helicobacter heilmannii sensu lato: An overview of the infection in humans. World J Gastroenterol 2014; 20:17779-17787. [PMID: 25548476 PMCID: PMC4273128 DOI: 10.3748/wjg.v20.i47.17779] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Revised: 06/27/2014] [Accepted: 07/30/2014] [Indexed: 02/06/2023] Open
Abstract
Helicobacter heilmannii sensu lato (H. heilmannii s.l.) is a group of gastric non-Helicobacter pylori Helicobacter species that are morphologically indistinguishable from each other. H. heilmannii s.l. infect the stomach of several animals and may have zoonotic potential. Although the prevalence of these infections in humans is low, they are associated with gastric pathology, including mucosa-associated lymphoid tissue lymphoma, making them a significant health issue. Here, the taxonomy, epidemiology, microbiology, diagnosis, and treatment of these infections will be reviewed. The gastric pathology associated with H. heilmannii s.l. infections in humans will also be addressed. Finally, the features of the complete bacterial genomes available and studies on species-specific pathogenesis will be reviewed. The understanding of the mechanisms that underlie gastric disease development mediated by the different bacterial species that constitute H. heilmannii s.l. is essential for developing strategies for prevention and treatment of these infections.
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Lee JY, Kim N, Choi YJ, Nam RH, Choi YJ, Kwon YH, Yoon K, Suh JH, Lee SM, Lee HS, Lee DH. Histologic Findings and Inflammatory Reactions After Long-term Colonization of Helicobacter felis in C57BL/6 Mice. J Cancer Prev 2014; 19:224-30. [PMID: 25337592 PMCID: PMC4189513 DOI: 10.15430/jcp.2014.19.3.224] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 08/20/2014] [Indexed: 12/20/2022] Open
Abstract
Background: The Helicobacter felis (H. felis) mouse model has been developed for the research regarding pathogenesis of chronic gastritis and gastric cancer. The aim of this study was to investigate long-term H. felis colonization in the stomachs of C57BL/6 mice and subsequent histologic findings and inflammatory reactions including pro-inflammatory cytokines. Methods: Twenty-three female C57BL/6 mice at 4 weeks of age were gavaged with H. felis, and 13 control mice served as vehicle only. The mice were sacrificed at 4, 24, and 52 weeks after inoculation. The infection status and degree of inflammation were determined by culture and histopathology. The level of gastric mucosal myeloperoxidase (MPO), tumor necrosis factor alpha (TNF-α), and interleukin-1beta (IL-1β) were measured by ELISA. Results: The overall infection rate was 100%, as determined by the culture and histology. At 4, 24, and 52 weeks, the neutrophil and monocyte scores were significantly higher in infected mice than in control mice. At 24 weeks after inoculation, most of the infected mice showed mucosal atrophy with or without metaplasia, and a few showed focal dysplasia. Adenocarcinoma was observed in one mouse at 52 week post-infection. Gastric mucosal MPO and IL-1β levels were significantly higher in infected mice than those in control mice at 24 and 52 weeks. However, the expression of gastric mucosal TNF-α was not significantly different between the infected and control mice at any time-point. Conclusions: Long-term H. felis-infection in C57BL/6 mice provoked a severe inflammatory reaction and it progressed into atrophy, metaplasia, dysplasia and cancer. IL-1β might play an important role in the inflammatory response of mice to Helicobacter species.
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Affiliation(s)
- Ju Yup Lee
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, Korea
| | - Nayoung Kim
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, Korea
| | - Yoon Jeong Choi
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, Korea
| | - Ryoung Hee Nam
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, Korea
| | - Yoon Jin Choi
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, Korea
| | - Yong Hwan Kwon
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, Korea
| | - Kichul Yoon
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, Korea
| | - Ji Hyung Suh
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, Korea
| | - Seon Min Lee
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, Korea
| | - Hye Seung Lee
- Pathology, Seoul National University Bundang Hospital, Seoungnam, Korea
| | - Dong Ho Lee
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, Korea
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Zhang S, Lee DS, Morrissey R, Aponte-Pieras JR, Rogers AB, Moss SF. Early or late antibiotic intervention prevents Helicobacter pylori-induced gastric cancer in a mouse model. Cancer Lett 2014; 355:106-12. [PMID: 25218349 DOI: 10.1016/j.canlet.2014.09.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 09/01/2014] [Accepted: 09/04/2014] [Indexed: 02/08/2023]
Abstract
H. pylori infection causes gastritis, peptic ulcers and gastric cancer. Eradicating H. pylori prevents ulcers, but to what extent this prevents cancer remains unknown, especially if given after intestinal metaplasia has developed. H. pylori infected wild-type (WT) mice do not develop cancer, but mice lacking the tumor suppressor p27 do so, thus providing an experimental model of H. pylori-induced cancer. We infected p27-deficient mice with H. pylori strain SS1 at 6-8 weeks of age. Persistently H. pylori-infected WT C57BL/6 mice served as controls. Mice in the eradication arms received antimicrobial therapy (omeprazole, metronidazole and clarithromycin) either "early" (at 15 weeks post infection, WPI) or "late" at 45 WPI. At 70 WPI, mice were euthanized for H. pylori determination, histopathology and cytokine/chemokine expression. Persistently infected mice developed premalignant lesions including high-grade dysplasia, whereas those given antibiotics did not. Histologic activity scores in the eradication groups were similar to each other, and were significantly decreased compared with controls for inflammation, epithelial defects, hyperplasia, metaplasia, atrophy and dysplasia. IP-10 and MIG levels in groups that received antibiotics were significantly lower than controls. There were no significant differences in expression of IFN-γ, TNF-α, IL-1β, RANTES, MCP-1, MIP-1α or MIP-1β among the three groups. Thus, H. pylori eradication given either early or late after infection significantly attenuated gastric inflammation, gastric atrophy, hyperplasia, and dysplasia in the p27-deficient mice model of H. pylori-induced gastric cancer, irrespective of the timing of antibiotic administration. This was associated with reduced expression of IP-10 and MIG.
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Affiliation(s)
- Songhua Zhang
- Division of Gastroenterology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
| | - Dong Soo Lee
- Department of Gastroenterology, The Catholic University of Korea, Seoul 137-701, Republic of Korea
| | - Rhiannon Morrissey
- Department of Biology and Biomedical Sciences, Salve Regina University, Newport, RI 02840, USA
| | - Jose R Aponte-Pieras
- Division of Gastroenterology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
| | - Arlin B Rogers
- Department of Biomedical Sciences, Tufts Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA
| | - Steven F Moss
- Division of Gastroenterology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
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Bessède E, Dubus P, Mégraud F, Varon C. Helicobacter pylori infection and stem cells at the origin of gastric cancer. Oncogene 2014; 34:2547-55. [DOI: 10.1038/onc.2014.187] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2014] [Revised: 05/08/2014] [Accepted: 05/23/2014] [Indexed: 02/06/2023]
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