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Zhou S, Li C, Liu L, Yuan Q, Miao J, Wang H, Ding C, Guan W. Gastric microbiota: an emerging player in gastric cancer. Front Microbiol 2023; 14:1130001. [PMID: 37180252 PMCID: PMC10172576 DOI: 10.3389/fmicb.2023.1130001] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 04/04/2023] [Indexed: 05/16/2023] Open
Abstract
Gastric cancer (GC) is a common cancer worldwide with a high mortality rate. Many microbial factors influence GC, of which the most widely accepted one is Helicobacter pylori (H. pylori) infection. H. pylori causes inflammation, immune reactions and activation of multiple signaling pathways, leading to acid deficiency, epithelial atrophy, dysplasia and ultimately GC. It has been proved that complex microbial populations exist in the human stomach. H. pylori can affect the abundance and diversity of other bacteria. The interactions among gastric microbiota are collectively implicated in the onset of GC. Certain intervention strategies may regulate gastric homeostasis and mitigate gastric disorders. Probiotics, dietary fiber, and microbiota transplantation can potentially restore healthy microbiota. In this review, we elucidate the specific role of the gastric microbiota in GC and hope these data can facilitate the development of effective prevention and therapeutic approaches for GC.
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Affiliation(s)
- Shizhen Zhou
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Chenxi Li
- Laboratory Medicine Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Lixiang Liu
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qinggang Yuan
- Department of General Surgery, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, Nanjing, Jiangsu, China
| | - Ji Miao
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Hao Wang
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Chao Ding
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Wenxian Guan
- Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
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Piazza S, Martinelli G, Fumagalli M, Pozzoli C, Maranta N, Giavarini F, Colombo L, Nicotra G, Vicentini SF, Genova F, De Fabiani E, Sangiovanni E, Dell'Agli M. Ellagitannins from Castanea sativa Mill. Leaf Extracts Impair H. pylori Viability and Infection-Induced Inflammation in Human Gastric Epithelial Cells. Nutrients 2023; 15:nu15061504. [PMID: 36986236 PMCID: PMC10056456 DOI: 10.3390/nu15061504] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 03/15/2023] [Accepted: 03/18/2023] [Indexed: 03/30/2023] Open
Abstract
Helicobacter pylori (H. pylori) is an etiologic factor of peptic ulcer disease and gastric cancer. Virulent strains of H. pylori are correlated with the severity of gastritis, due to NF-κB activation and IL-8 expression at the epithelial level. Ellagitannins have been documented for antibacterial and anti-inflammatory activities, thus suggesting their potential use in gastritis. Recently, several authors, including our group, demonstrated that tannin-rich extracts from chestnut byproducts, at present considered agricultural waste, display promising biological activities. In this work, we detected high levels of polyphenols in hydroalcoholic extracts from chestnut leaves (Castanea sativa L.). Among polyphenols, the ellagitannin isomers castalagin and vescalagin (about 1% w/w of dry extract) were identified as potential bioactive compounds. In GES-1 cells infected by H. pylori, leaf extract and pure ellagitannins inhibited IL-8 release (IC50 ≈ 28 µg/mL and 11 µM, respectively). Mechanistically, the anti-inflammatory activity was partly due to attenuation of NF-κB signaling. Moreover, the extract and pure ellagitannins reduced bacterial growth and cell adhesion. A simulation of the gastric digestion suggested that the bioactivity might be maintained after oral administration. At the transcriptional level, castalagin downregulated genes involved in inflammatory pathways (NF-κB and AP-1) and cell migration (Rho GTPase). To the best of our knowledge, this is the first investigation in which ellagitannins from plant extracts have demonstrated a potential role in the interaction among H. pylori and human gastric epithelium.
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Affiliation(s)
- Stefano Piazza
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, 20133 Milan, Italy
| | - Giulia Martinelli
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, 20133 Milan, Italy
| | - Marco Fumagalli
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, 20133 Milan, Italy
| | - Carola Pozzoli
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, 20133 Milan, Italy
| | - Nicole Maranta
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, 20133 Milan, Italy
| | - Flavio Giavarini
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, 20133 Milan, Italy
| | - Luca Colombo
- Consorzio Castanicoltori di Brinzio, Orino e Castello Cabiaglio, Società Cooperativa Agricola-Varese, 21100 Varese, Italy
| | | | | | - Francesca Genova
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, 20133 Milan, Italy
| | - Emma De Fabiani
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, 20133 Milan, Italy
| | - Enrico Sangiovanni
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, 20133 Milan, Italy
| | - Mario Dell'Agli
- Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, 20133 Milan, Italy
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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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Vitale G, Dicitore A, Barrea L, Sbardella E, Razzore P, Campione S, Faggiano A, Colao A, Albertelli M, Altieri B, Bottiglieri F, De Cicco F, Di Molfetta S, Fanciulli G, Feola T, Ferone D, Ferraù F, Gallo M, Giannetta E, Grillo F, Grossrubatscher E, Guadagno E, Guarnotta V, Isidori AM, Lania A, Lenzi A, Calzo FL, Malandrino P, Messina E, Modica R, Muscogiuri G, Pes L, Pizza G, Pofi R, Puliani G, Rainone C, Rizza L, Rubino M, Ruggieri RM, Sesti F, Venneri MA, Zatelli MC. From microbiota toward gastro-enteropancreatic neuroendocrine neoplasms: Are we on the highway to hell? Rev Endocr Metab Disord 2021; 22:511-525. [PMID: 32935263 PMCID: PMC8346435 DOI: 10.1007/s11154-020-09589-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/04/2020] [Indexed: 02/06/2023]
Abstract
Gut microbiota is represented by different microorganisms that colonize the intestinal tract, mostly the large intestine, such as bacteria, fungi, archaea and viruses. The gut microbial balance has a key role in several functions. It modulates the host's metabolism, maintains the gut barrier integrity, participates in the xenobiotics and drug metabolism, and acts as protection against gastro-intestinal pathogens through the host's immune system modulation. The impaired gut microbiota, called dysbiosis, may be the result of an imbalance in this equilibrium and is linked with different diseases, including cancer. While most of the studies have focused on the association between microbiota and gastrointestinal adenocarcinomas, very little is known about gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). In this review, we provide an overview concerning the complex interplay between gut microbiota and GEP NENs, focusing on the potential role in tumorigenesis and progression in these tumors.
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Affiliation(s)
- Giovanni Vitale
- Istituto Auxologico Italiano IRCCS, Laboratory of Geriatric and Oncologic Neuroendocrinology Research, Cusano Milanino, MI, Italy.
- Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy.
| | - Alessandra Dicitore
- Department of Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy
| | - Luigi Barrea
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Emilia Sbardella
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Paola Razzore
- Endocrinology Unit, A.O. Ordine Mauriziano, Turin, Italy
| | | | | | - Annamaria Colao
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
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Choi JM, Kim SG, Choi J, Park JY, Oh S, Yang HJ, Lim JH, Im JP, Kim JS, Jung HC. Effects of Helicobacter pylori eradication for metachronous gastric cancer prevention: a randomized controlled trial. Gastrointest Endosc 2018; 88:475-485.e2. [PMID: 29800546 DOI: 10.1016/j.gie.2018.05.009] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 05/12/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Whether eradication of Helicobacter pylori reduces the incidence of metachronous gastric cancer (MGC) is still debatable. We aimed to evaluate the long-term effect of H pylori eradication on the development of MGC after endoscopic gastric tumor resection. METHODS We undertook an open-label, prospective, randomized controlled trial at a tertiary hospital in Seoul, Korea. Participants were recruited during April 2005 to February 2011 and followed until December 2016. We assigned 898 patients with H pylori infection treated with endoscopic resection (ER) for gastric dysplasia or early gastric cancer to receive (n =442) or not receive (n =456) eradication therapy using a random-number chart. Eradication group patients received oral omeprazole 20 mg, amoxicillin 1 g, and clarithromycin 500 mg twice daily for a week, whereas control group patients received no H pylori treatment. The primary outcome was the incidence of MGC (intention-to-treat analysis). RESULTS The 877 patients who attended ≥1 follow-up examination (eradication group, 437; control group, 440) were analyzed. Median follow-up was 71.6 months (interquartile range, 42.1-90.0). MGC developed in 18 (4.1%) eradication and 36 (8.2%) control group patients (log-rank test, P = .01). In our yearly analysis, the effect of eradication showed a significant difference in 5 years after allocation (log-rank test, P = .02). The adjusted hazard ratio for the control group was 2.02 (95% CI, 1.14-3.56; P = .02), compared with the eradication group. CONCLUSIONS H pylori eradication significantly reduces the incidence of MGC after ER of gastric tumors and should be considered for H pylori-positive gastric tumor patients treated with ER. (Clinical trial registration number: NCT01510730.).
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Affiliation(s)
- Ji Min Choi
- Department of Internal Medicine, Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea
| | - Sang Gyun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jeongmin Choi
- Department of Internal Medicine, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea
| | - Jae Yong Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Sooyeon Oh
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyo-Joon Yang
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joo Hyun Lim
- Department of Internal Medicine, Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea
| | - Jong Pil Im
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Chae Jung
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Li J, Perez Perez GI. Is There a Role for the Non- Helicobacter pylori Bacteria in the Risk of Developing Gastric Cancer? Int J Mol Sci 2018; 19:E1353. [PMID: 29751550 PMCID: PMC5983810 DOI: 10.3390/ijms19051353] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 04/26/2018] [Accepted: 04/27/2018] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori is the most abundant bacterium in the gastric epithelium, and its presence has been associated with the risk of developing gastric cancer. As of 15 years ago, no other bacteria were associated with gastric epithelial colonization; but thanks to new methodologies, many other non-H. pylori bacteria have been identified. It is possible that non-H. pylori may have a significant role in the development of gastric cancer. Here, we discuss the specific role of H. pylori as a potential trigger for events that may be conducive to gastric cancer, and consider whether or not the rest of the gastric microbiota represent an additional risk in the development of this disease.
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Affiliation(s)
- Jackie Li
- Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
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Park JY, Forman D, Waskito LA, Yamaoka Y, Crabtree JE. Epidemiology of Helicobacter pylori and CagA-Positive Infections and Global Variations in Gastric Cancer. Toxins (Basel) 2018; 10:E163. [PMID: 29671784 PMCID: PMC5923329 DOI: 10.3390/toxins10040163] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 04/10/2018] [Accepted: 04/10/2018] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer is a major health burden and is the fifth most common malignancy and the third most common cause of death from cancer worldwide. Development of gastric cancer involves several aspects, including host genetics, environmental factors, and Helicobacter pylori infection. There is increasing evidence from epidemiological studies of the association of H. pylori infection and specific virulence factors with gastric cancer. Studies in animal models indicate H. pylori is a primary factor in the development of gastric cancer. One major virulence factor in H. pylori is the cytotoxin-associated gene A (cagA), which encodes the CagA protein in the cag pathogenicity island (cag PAI). Meta-analysis of studies investigating CagA seropositivity irrespective of H. pylori status identified that CagA seropositivity increases the risk of gastric cancer (OR = 2.87, 95% CI: 1.95⁻4.22) relative to the risk of H. pylori infection alone (OR = 2.31, 95% CI: 1.58⁻3.39). Eradicating H. pylori is a strategy for reducing gastric cancer incidence. A meta-analysis of six randomised controlled trials (RCTs) suggests that searching for and eradicating H. pylori infection reduces the subsequent incidence of gastric cancer with a pooled relative risk of 0.66 (95% CI: 0.46⁻0.95). The introduction in regions of high gastric cancer incidence of population-based H. pylori screening and treatment programmes, with a scientifically valid assessment of programme processes, feasibility, effectiveness and possible adverse consequences, would impact the incidence of H. pylori-induced gastric cancer. Given the recent molecular understanding of the oncogenic role of CagA, targeting H. pylori screening and treatment programmes in populations with a high prevalence of H. pylori CagA-positive strains, particularly the more oncogenic East Asian H. pylori CagA strains, may be worth further investigation to optimise the benefits of such strategies.
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Affiliation(s)
- Jin Young Park
- International Agency for Research on Cancer, 69372 Lyon, France.
| | - David Forman
- International Agency for Research on Cancer, 69372 Lyon, France.
| | - Langgeng Agung Waskito
- Institute of Tropical Disease, Universitas Airlangga, Surabaya 60113, Indonesia.
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Oita University, Yufu, Oita 879-5503, Japan.
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Faculty of Medicine, Oita University, Yufu, Oita 879-5503, Japan.
- Department of Medicine-Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX 77030, USA.
| | - Jean E Crabtree
- Leeds Institute Biomedical and Clinical Sciences, Wellcome Trust Brenner Building, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
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Ananthamurthy A, Correa M, Patil M. Type 1 Gastric Carcinoid in the Indian Population and Its Association with Multifocal Gastric Atrophy. Euroasian J Hepatogastroenterol 2016; 6:106-110. [PMID: 29201740 PMCID: PMC5578576 DOI: 10.5005/jp-journals-10018-1180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 06/29/2016] [Indexed: 12/21/2022] Open
Abstract
Aim Recent studies have shown an increase in the incidence of gastric neuroendocrine tumors (NETs) (carcinoids). This may be attributable to the frequent employment of endoscopy in clinical practice and the increasing use of proton pump inhibitors. From the literature that is available, it is interesting to note that the profile of patients with gastric carcinoids is different in the Asian population when compared to the western societies. As limited data is available from India, we evaluated retrospectively the clinical profile and pathology of gastric carcinoids presenting to our hospital. Materials and methods A total of 31 patients with gastric carcinoids who presented to our institution from 2006 till 2013 were included in this study. The clinical data were obtained from the case files and the histopathology slides were reviewed. Results Gastric carcinoids constituted about 32% of all gastrointestinal (GI) NETs and were second only to duodenal carcinoids in frequency. Men were more commonly affected (74%) and the majority were of type 1 (90%). Multifocal gastric atrophy with intestinal metaplasia was additional features seen in the majority of cases with type 1 carcinoids. Conclusion This study, one of the largest series reported from India, shows that the frequency and profile of gastric carcinoids is different in this population when compared to the west. It also raises the possibility that Helicobacter pylori induced multifocal gastric atrophy might be a triggering factor for the most common type 1 gastric carcinoid rather than autoimmune gastritis. Clinical significance Eradication of H.pylori may be a potential preventive strategy for the occurrence of gastric carcinoids. How to cite this article Ananthamurthy A, Correa M, Patil M. Type 1 Gastric Carcinoid in the Indian Population and Its Association with Multifocal Gastric Atrophy. Euroasian J Hepato-Gastroenterol 2016;6(2):106-110.
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Affiliation(s)
| | - Marjorie Correa
- Department of Pathology, St. John's Medical College, Bengaluru, Karnataka, India
| | - Mallikarjun Patil
- Department of Gastroenterology, St. John's Medical College, Bengaluru, Karnataka, India
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Helicobacter pylori with high thioredoxin-1 expression promotes stomach carcinogenesis in Mongolian gerbils. Clin Res Hepatol Gastroenterol 2016; 40:480-6. [PMID: 26669590 DOI: 10.1016/j.clinre.2015.11.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Revised: 10/18/2015] [Accepted: 11/02/2015] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Previous studies by this group have shown that Helicobacter pylori with high thioredoxin-1 (Trx1) expression might be involved in stomach carcinogenesis in vitro. To study histopathological changes of the stomach mucosa in vivo, a Mongolian gerbil model infected with H. pylori with high Trx1 expression was established. METHODS Healthy, male Mongolian gerbils (n=75) were randomly divided into 3 groups: controls (n=15), which were not infected with H. pylori, high Trx1 (n=30) which were infected with H. pylori with high Trx1 expression and low Trx1 (n=30) which were infected with low Trx1 expression H. pylori. The animals were sacrificed at 4, 20, 34, 48, 70 and 90 weeks after inoculation. RESULTS The Mongolian gerbil model of H. pylori infection was successfully established. Three animals died during the study, leaving 72 animals (controls, n=14; low Trx1, n=29; high Trx1, n=29) examined on schedule. Histopathological analysis of the stomach mucosa showed gradually increased aggravation over time in the high and low Trx1 groups. Compared with control and low Trx1, the histopathological changes were more serious in the high Trx1 group. At 90 weeks, no abnormal changes were found in the controls, but 62.5% of the high Trx1 group and 33.3% of the low Trx1 showed adenocarcinomas. The H. pylori Trx1 level in gastric cancer tissue was significantly higher than that from gastritis tissue. Within gastric cancer cells, high Trx1 expression in H. pylori significantly upregulated cyclin D1. CONCLUSIONS High Trx1 expression in H. pylori promoted stomach carcinogenesis. More studies are needed to confirm this finding.
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Waldum HL, Hauso Ø, Brenna E, Qvigstad G, Fossmark R. Does long-term profound inhibition of gastric acid secretion increase the risk of ECL cell-derived tumors in man? Scand J Gastroenterol 2016; 51:767-73. [PMID: 26872579 DOI: 10.3109/00365521.2016.1143527] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Since the description of ECL cell-derived tumors in rodents after long-term profound acid inhibition inducing hypergastrinemia, there has been concern that proton pump inhibitors (PPIs) could also do that in man. The recent description of a Spanish family with gastric ECL cell tumors at the age of about 30 years secondary to a defect in the proton pump due to mutation in the ATP4A gene clearly shows that hypergastrinemia alone also is sufficient to induce ECL cell neoplasia in man. The present review aims to evaluate the risk of gastric neoplasia secondary to gastric acid inhibition. METHODS Literature (MEDLINE) was searched for the role of the ECL cell in gastric carcinogenesis in animals and man in general and particularly secondary to long-term inhibition of acid secretion. RESULTS An important proportion of patients treated with PPI develops hypergastrinemia causing ECL cell hyperplasia and the first descriptions of ECL cell carcinoids secondary to PPI have been reported. The role of the ECL cell has hitherto been under estimated in gastric carcinogenesis in man where for instance the signet ring cell type of gastric carcinoma seems to originate from the ECL cell. CONCLUSIONS The first two of three steps in rodent ECL cell carcinogenesis (hyperplasia, carcinoid, and carcinoma) secondary to PPI dosing, have been described for man. It is every reason to believe that the final step, gastric carcinoma, will develop also in man. Clinical decisions should be based not only on so-called evidence based medicine, but also on physiological knowledge and animal studies.
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Affiliation(s)
- Helge L Waldum
- a Department of Cancer Research and Molecular Medicine , Norwegian University of Science and Technology , Trondheim , Norway ;,b Department of Gastroenterology and Hepatology , St. Olavs Hospital , Trondheim , Norway
| | - Øyvind Hauso
- a Department of Cancer Research and Molecular Medicine , Norwegian University of Science and Technology , Trondheim , Norway ;,b Department of Gastroenterology and Hepatology , St. Olavs Hospital , Trondheim , Norway
| | - Eiliv Brenna
- a Department of Cancer Research and Molecular Medicine , Norwegian University of Science and Technology , Trondheim , Norway ;,b Department of Gastroenterology and Hepatology , St. Olavs Hospital , Trondheim , Norway
| | - Gunnar Qvigstad
- a Department of Cancer Research and Molecular Medicine , Norwegian University of Science and Technology , Trondheim , Norway ;,b Department of Gastroenterology and Hepatology , St. Olavs Hospital , Trondheim , Norway
| | - Reidar Fossmark
- a Department of Cancer Research and Molecular Medicine , Norwegian University of Science and Technology , Trondheim , Norway ;,b Department of Gastroenterology and Hepatology , St. Olavs Hospital , Trondheim , Norway
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Fossmark R, Calvete O, Mjønes P, Benitez J, Waldum HL. ECL-cell carcinoids and carcinoma in patients homozygous for an inactivating mutation in the gastric H(+) K(+) ATPase alpha subunit. APMIS 2016; 124:561-6. [PMID: 27150581 DOI: 10.1111/apm.12546] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 03/30/2016] [Indexed: 02/07/2023]
Abstract
A family with a missense variant of the ATP4A gene encoding the alpha subunit of the gastric proton pump (H(+) K(+) ATPase) has recently been described. Homozygous siblings were hypergastrinemic (median gastrin 486 pM) and had gastric tumours diagnosed at a median age of 33 years. In the current histopathological study, we further characterized the tumours found in the gastric corpus. The tumours had the histological appearance of carcinoids (NET G1 or G2) and were immunoreactive for the general neuroendocrine markers chromogranin A (CgA) and synaptophysin as well as the ECL-cell markers vesicular monoamine transporter 2 (VMAT2) and histidine decarbozylase (HDC). One of the tumours consisted of a NET G2 component, but also had a component with glandular growth, which morphologically was classified as an intestinal type adenocarcinoma. Many glands of the adenocarcinoma contained a large proportion of cells positive for neuroendocrine markers, especially the small vesicle marker synaptophysin and the cytoplasmic enzyme HDC. In conclusion, patients homozygous for an inactivating ATP4A mutation develop gastric ECL-cell carcinoids in their 3rd or 4th decade. The adenocarcinoma may be classified as neuroendocrine with ECL-cell differentiation.
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Affiliation(s)
- Reidar Fossmark
- Department of Gastroenterology and Hepatology, St. Olav's Hospital, Trondheim, Norway.,Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Oriol Calvete
- Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.,Network of Research on Rare Diseases (CIBERER), Madrid, Spain
| | - Patricia Mjønes
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Pathology, St. Olav's Hospital, Trondheim, Norway
| | - Javier Benitez
- Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.,Network of Research on Rare Diseases (CIBERER), Madrid, Spain
| | - Helge L Waldum
- Department of Gastroenterology and Hepatology, St. Olav's Hospital, Trondheim, Norway.,Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
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12
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Molecular Mechanism of Gastric Carcinogenesis in Helicobacter pylori-Infected Rodent Models. Diseases 2014. [DOI: 10.3390/diseases2020168] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
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13
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Sørdal Ø, Waldum H, Nordrum IS, Boyce M, Bergh K, Munkvold B, Qvigstad G. The gastrin receptor antagonist netazepide (YF476) prevents oxyntic mucosal inflammation induced by Helicobacter pylori infection in Mongolian gerbils. Helicobacter 2013; 18:397-405. [PMID: 23865485 DOI: 10.1111/hel.12066] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVE Long-term Helicobacter pylori infection causes gastritis leading to hypergastrinemia and predisposes to gastric cancer. Our aim was to assess the role of gastrin in oxyntic mucosal inflammation in H. pylori-infected Mongolian gerbils by means of the gastrin receptor antagonist netazepide (YF476). DESIGN We studied 60 gerbils for 18 months and left five animals uninfected (control group), inoculated 55 with H. pylori, and treated 28 of the infected animals with netazepide (Hp+YF476 group). Twenty-seven infected animals were given no treatment (Hp group). We measured plasma gastrin and intraluminal pH. H. pylori detection and histologic evaluations of the stomach were carried out. RESULTS All 55 inoculated animals were H. pylori positive at termination. Eighteen animals in the Hp group had gastritis. There was a threefold increase in mucosal thickness in the Hp group compared to the Hp+YF476 group, and a threefold increase in oxyntic neuroendocrine cells in the Hp group compared to the Hp+YF476 group (p < .05). All animals in the Hp+YF476 group had macro- and microscopically normal findings in the stomach. Plasma gastrin was higher in the Hp group than in the control group (172 ± 16 pmol/L vs 124 ± 5 pmol/L, p < .05) and highest in the Hp+YF476 group (530 ± 36 pmol/L). Intraluminal pH was higher in the Hp group than in the Hp+YF476 group (2.51 vs 2.30, p < .05). CONCLUSION The gastrin antagonist netazepide prevents H. pylori-induced gastritis in Mongolian gerbils. Thus, gastrin has a key role in the inflammatory reaction of the gastric mucosa to H. pylori infection in this species.
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Affiliation(s)
- Øystein Sørdal
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
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14
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Cho YT, Kuo CH, Wang SS, Chen YS, Weng BC, Lee YC, Cheng CN, Shiea J, Wu DC. Differentiation of virulence of Helicobacter pylori by matrix-assisted laser desorption/ionization mass spectrometry and multivariate analyses. Clin Chim Acta 2013; 424:123-30. [DOI: 10.1016/j.cca.2013.05.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2012] [Revised: 05/18/2013] [Accepted: 05/20/2013] [Indexed: 02/01/2023]
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15
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Helicobacter pylori infection and gastric carcinogenesis in rodent models. Semin Immunopathol 2012; 35:177-90. [PMID: 23111700 DOI: 10.1007/s00281-012-0357-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2012] [Accepted: 10/15/2012] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori infection is an important factor for gastric carcinogenesis in human. In carcinogen-treated Mongolian gerbils, H. pylori infection enhances stomach carcinogenesis, while infection alone induced severe hyperplasia called heterotopic proliferative glands. A high-salt diet or early acquisition of the bacteria exacerbates inflammation and carcinogenesis. Oxygen radical scavengers or anti-inflammatory chemicals as well as eradication of H. pylori are effective to prevent carcinogenesis. H. pylori-associated inflammation induces intestinal metaplasia and intestinalization of stomach cancers independently. It is necessary to control cancer development not only in H. pylori-positive cases but also in H. pylori-negative metaplastic gastritis.
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16
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Abstract
Animal models are essential for in vivo analysis of Helicobacter-related diseases. Transgenic mice and Mongolian gerbil models have been the corner stone of present research focusing on both bacterial virulence factors and host response to infection. Establishing a reproducible rodent model of persistent Helicobacter pylori infection that resembles the H. pylori-associated gastritis observed in humans was a considerable challenge until Lee et al. (Gastroenterology 112:1386-1397, 1997) successfully adapted a clinical Cag A- and Vac A-expressing strain for the mouse stomach. This so-called SS1 (Sydney) strain has since been extensively used for H. pylori research; other rodent-adapted Helicobacter strains have subsequently been developed and utilized in wild-type and genetically engineered rodent models. These bacteria include both H. pylori and the larger but related species H. felis (originally isolated from cats). In this chapter we focus mainly on these two Helicobacter strains and review the rodent models that have been employed to investigate how Helicobacter species induce gastric inflammation and disease.
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Liu YE, Yuan Y. Gastric diseases in Mongolian gerbils infected with different strains of Helicobacter pylori. Shijie Huaren Xiaohua Zazhi 2011; 19:2467-2472. [DOI: 10.11569/wcjd.v19.i23.2467] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H.pylori) is a bacterium responsible for one of the most widespread infections found in humans. It colonizes the gastric mucosa and can result in chronic gastritis and gastric cancer. The incidence of spontaneous gastric gastritis is low in Mongolian gerbils, and spontaneous H.pylori infection can not be detected in this animal. Since H.pylori-related gastric diseases in Mongolian gerbils are very similar to those in humans, they have been considered as ideal animals to establish H.pylori infection models. However, different strains of H.pylori may induce different types of pathologic changes in Mongolian gerbils. Clarification of the pathogenic mechanisms of different strains of H.pylori may provide a theoretical basis for screening appropriate H.pylori strains and directing individualized treatment in patients with H.pylori-related gastric diseases. In this paper, we review the recent progress in research of gastric diseases in Mongolian gerbils infected with different strains of H.pylori.
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Animal models to study the role of long-term hypergastrinemia in gastric carcinogenesis. J Biomed Biotechnol 2010; 2011:975479. [PMID: 21127707 PMCID: PMC2992820 DOI: 10.1155/2011/975479] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2010] [Accepted: 10/28/2010] [Indexed: 01/16/2023] Open
Abstract
Patients with chronic hypergastrinemia due to chronic atrophic gastritis or gastrinomas have an increased risk of developing gastric malignancy, and it has been questioned whether also patients with hypergastrinemia caused by long-term use of acid inhibiting drugs are at risk. Gastric carcinogenesis in humans is affected by numerous factors and progresses slowly over years. When using animal models with the possibility of intervention, a complex process can be dissected by studying the role of hypergastrinemia in carcinogenesis within a relatively short period of time. We have reviewed findings from relevant models where gastric changes in animal models of long-term hypergastrinemia have been investigated. In all species where long-term hypergastrinemia has been induced, there is an increased risk of gastric malignancy. There is evidence that hypergastrinemia is a common causative factor in carcinogenesis in the oxyntic mucosa, while other cofactors may vary in the different models.
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Kato M, Asaka M. Recent knowledge of the relationship between Helicobacter pylori and gastric cancer and recent progress of gastroendoscopic diagnosis and treatment for gastric cancer. Jpn J Clin Oncol 2010; 40:828-37. [PMID: 20736219 DOI: 10.1093/jjco/hyq119] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer is a multi-step process and multi-factorial disease. However, Helicobacter pylori plays the most important role in gastric carcinogenesis because most gastric cancers including both intestinal type and diffuse type arise from mucosa infected by H. pylori. The relationship between H. pylori infection and gastric cancer has been proved in epidemiological studies, animal experiments with Mongolian gerbils, and clinical prospective studies. Significant preventive effect of H. pylori eradication was reported in Japanese randomized study for secondary gastric cancer after endoscopic resection of primary gastric cancer and meta-analysis of randomized studies. The Japanese Society for Helicobacter Research has published a guideline recommending that H. pylori infection should be treated by eradication therapy to suppress the incidence of gastric cancer. The development of endoscopic technology has advanced the diagnosis and treatment of gastric cancer. In the diagnosis of gastric cancer, image enhancement endoscopy including magnifying observation with narrow-band imaging system and microscopic magnifying observation opens the possibility of optical biopsy. Endoscopic resection for early stage of gastric cancer has been established as proper treatment of early gastric cancer. Recently endoscopic submucosal dissection had made en bloc resection possible for mucosal cancers >2 cm in diameter. Because of endoscopic submucosal dissection, endoscopic resection is indicated in a greater number of cases. Although the use of endoscopic treatment for gastric cancer has been increasing steadily, long-term outcome data is necessary.
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Affiliation(s)
- Mototsugu Kato
- Division of Endoscopy, Hokkaido University Hospital North 14, Sapporo, Hokkaido 060-8468, Japan.
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20
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Castillo-Juarez I, Rangel-Vega A, Romero I. Rapid paper disk test for identification of Helicobacter pylori in mixed cultures of gerbil gastric homogenates. J Microbiol Methods 2010; 83:20-5. [PMID: 20624429 DOI: 10.1016/j.mimet.2010.07.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2010] [Accepted: 07/06/2010] [Indexed: 01/27/2023]
Abstract
A method denominated rapid paper disk test (RPDT) was developed to identify H. pylori colonies in complex cultures obtained from gerbil gastric homogenates. Identification is based on a characteristic reaction pattern (RP) for H. pylori colonies given by the combination of the urease-oxidase activities on a paper disk. Compared to the RPs obtained from gerbil's intestinal tract isolated bacteria, H. pylori RP is completely distinguishable, even from those of bacteria that share one or both activities as are Aerococcus urinae, Bacillus sphaericus, Bacillus brevis, Corynebacterium pseudogenitalium, and Staphylococcus simulans, as well as from those produced by collection strains Proteus vulgaris and Pseudomonas aeruginosa. This method allows the practical quantification of H. pylori colonies in highly contaminated plates. RPDT has the following advantages over other methodologies that use indicators in the medium: it employs two of the three routinely used H. pylori biochemical identification tests, the reagents do not interfere with bacterial viability, there are no restrictions in relation to the medium used, and it is a simple, fast, and low-cost method.
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Affiliation(s)
- Israel Castillo-Juarez
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad Universitaria, C.P. 04510, México, D.F., México
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21
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Chiba T, Marusawa H, Seno H, Watanabe N. H. pyloriInfection – The Route from Inflammation to Cancer. BACTERIAL VIRULENCE 2010:31-41. [DOI: 10.1002/9783527629664.ch3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Malfertheiner P, Bornschein J, Selgrad M. Role of Helicobacter pylori infection in gastric cancer pathogenesis: a chance for prevention. J Dig Dis 2010; 11:2-11. [PMID: 20132425 DOI: 10.1111/j.1751-2980.2009.00408.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Gastric cancer in the absence of strategies implemented for early detection continues to have a dismal prognosis. There are limited options for a curative therapy once patients present with clinical manifestations of this malignant disease. Helicobacter pylori (H. pylori) infection plays a key role in gastric carcinogenesis, supported by epidemiological, preclinical and clinical studies. The recognition of H. pylori infection as a critical risk factor in the development of gastric cancer opens the chance for new venues in prevention strategies.
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Affiliation(s)
- Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University of Magdeburg, Leipziger, Magdeburg, Germany.
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23
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Yanaoka K, Oka M, Ohata H, Yoshimura N, Deguchi H, Mukoubayashi C, Enomoto S, Inoue I, Iguchi M, Maekita T, Ueda K, Utsunomiya H, Tamai H, Fujishiro M, Iwane M, Takeshita T, Mohara O, Ichinose M. Eradication of Helicobacter pylori prevents cancer development in subjects with mild gastric atrophy identified by serum pepsinogen levels. Int J Cancer 2009; 125:2697-703. [PMID: 19610064 DOI: 10.1002/ijc.24591] [Citation(s) in RCA: 107] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A longitudinal cohort study was conducted in Helicobactor pylori-infected middle-aged Japanese males to evaluate the preventive effects of H. pylori eradication on the development of gastric cancer according to the extent of chronic atrophic gastritis (CAG). The extent of CAG was monitored by baseline serum pepsinogen (PG) levels. We followed 3,656 subjects with persistent H. pylori infection and 473 subjects with successful H. pylori eradication for cancer development for a mean (SD) of 9.3 (0.7) years. Groups with and without extensive CAG were categorized based on PG test-positive criteria to detect extensive CAG of PG I <or= 70 ng/ml and PG I/II ratio <or= 3.0. During the study period, 5 and 55 gastric cancers developed in H. pylori-eradicated and the noneradicated subjects, respectively, indicating no significant reduction in cancer incidence after H. pylori eradication. Among the noneradicated subjects, 1,329 were PG test-positive and 2,327 were PG test-negative. Gastric cancer was confirmed in 30 and 25 subjects, respectively. Among subjects whose infection was eradicated, 155 were PG test-positive and 318 were PG test-negative. Of these subjects, gastric cancer was confirmed in 3 and 2 subjects, respectively. Significant reduction in cancer incidence after eradication was observed only in PG test-negative subjects (p < 0.05; log-rank test). The results of this study strongly indicate that cancer development after eradication depends on the presence of extensive CAG before eradication and that H. pylori eradication is beneficial to most PG test-negative subjects with mild CAG as defined by the aforementioned criteria.
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Affiliation(s)
- Kimihiko Yanaoka
- Department of Gastroenterology, School of Medicine, Wakayama Medical University, Wakayama-city, Wakayama, Japan
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Mabe K, Takahashi M, Oizumi H, Tsukuma H, Shibata A, Fukase K, Matsuda T, Takeda H, Kawata S. Does Helicobacter pylori eradication therapy for peptic ulcer prevent gastric cancer? World J Gastroenterol 2009; 15:4290-7. [PMID: 19750572 PMCID: PMC2744185 DOI: 10.3748/wjg.15.4290] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2009] [Revised: 07/29/2009] [Accepted: 08/05/2009] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effects of Helicobacter pylori (H pylori) eradication therapy for treatment of peptic ulcer on the incidence of gastric cancer. METHODS A multicenter prospective cohort study was conducted between November 2000 and December 2007 in Yamagata Prefecture, Japan. The study included patients with H pylori-positive peptic ulcer who decided themselves whether to receive H pylori eradication (eradication group) or conventional antacid therapy (non-eradication group). Incidence of gastric cancer in the two groups was determined based on the results of annual endoscopy and questionnaire surveys, as well as Yamagata Prefectural Cancer Registry data, and was compared between the two groups and by results of H pylori therapy. RESULTS A total of 4133 patients aged between 13 and 91 years (mean 52.9 years) were registered, and 56 cases of gastric cancer were identified over a mean follow-up of 5.6 years. The sex- and age-adjusted incidence ratio of gastric cancer in the eradication group, as compared with the non-eradication group, was 0.58 (95% CI: 0.28-1.19) and ratios by follow-up period (< 1 year, 1-3 years, > 3 years) were 1.16 (0.27-5.00), 0.50 (0.17-1.49), and 0.34 (0.09-1.28), respectively. Longer follow-up tended to be associated with better prevention of gastric cancer, although not to a significant extent. No significant difference in incidence of gastric cancer was observed between patients with successful eradication therapy (32/2451 patients, 1.31%) and those with treatment failure (11/639 patients, 1.72%). Among patients with duodenal ulcer, which is known to be more prevalent in younger individuals, the incidence of gastric cancer was significantly less in those with successful eradication therapy (2/845 patients, 0.24%) than in those with treatment failure (3/216 patients, 1.39%). CONCLUSION H pylori eradication therapy for peptic ulcer patients with a mean age of 52.9 years at registration did not significantly decrease the incidence of gastric cancer.
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Abstract
Helicobacter pylori (H. pylori) infection plays a crucial role in the development of gastric cancer. There are two major pathways for the development of gastric cancer by H. pylori infection: the indirect action of H. pylori on gastric epithelial cells through inflammation, and the direct action of the bacteria on epithelial cells through the induction of protein modulation and gene mutation. Both pathways work together to promote gastric carcinogenesis.
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Fossmark R, Qvigstad G, Waldum HL. Gastric cancer: Animal studies on the risk of hypoacidity and hypergastrinemia. World J Gastroenterol 2008; 14:1646-51. [PMID: 18350594 PMCID: PMC2695903 DOI: 10.3748/wjg.14.1646] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastric hypoacidity and hypergastrinaemia are seen in several conditions associated with an increased risk of gastric malignancy. Hypoacidity and hypergastrinaemia are closely related and their long-term effects are difficult to study separately in patients. Studies using animal models can provide valuable information about risk factors and mechanisms in gastric cancer development as the models allow a high degree of intervention when introducing or eliminating factors possibly affecting carcinogenesis. In this report, we briefly review findings from relevant animal studies on this topic. Animal models of gastric hypoacidity and hypergastrinaemia provide evidence hypergastrinaemia is a common causative factor in many otherwise diverse settings. In all species where sufficient hypoacidity and hypergastrinaemia have been induced, a proportion of the animals develop malignant lesions in the gastric oxyntic mucosa.
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Abstract
Although incidences of stomach cancer have decreased over the past several decades, the disease remains an important public health problem. To identify pathological and molecular biochemical mechanisms, various experimental animal models have been established in rats and mice with chemical carcinogens including N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-methyl-N-nitrosourea (MNU). Helicobacter pylori(H. pylori) is one of the most important factors for human stomach disorders, including neoplasia, and the H. pylori-infected and carcinogen-treated Mongolian gerbil (MG) has proven very useful for analyses of underlying processes. The findings with this model support the hypothesis that intestinal metaplasia is important not as a precancerous lesion but rather as a paracancerous condition and that intestinalization of stomach cancer progresses with chronic inflammation. Furthermore, dose-dependent enhancing effects of salt on stomach carcinogenesis could be demonstrated in MGs treated with MNU and H. pylori modifying surface mucous gel layer. H. pylori itself only causes chronic inflammation and acts as a promoter of stomach carcinogenesis in experimental models. Based on the precise pathological diagnosis of stomach lesions such as noncancerous heterotopic proliferative glands (HPG) and adenocarcinomas, a basis for understanding mechanisms of carcinogenesis has been established on which chemoprevention can be modeled.
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Affiliation(s)
- Tetsuya Tsukamoto
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
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Chen D, Stenström B, Zhao CM, Wadström T. Does Helicobacter pylori infection per se cause gastric cancer or duodenal ulcer? Inadequate evidence in Mongolian gerbils and inbred mice. ACTA ACUST UNITED AC 2007; 50:184-9. [PMID: 17567281 DOI: 10.1111/j.1574-695x.2007.00249.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
A role for Helicobacter pylori infection in the development of gastric cancer in humans is well established; however, evidence for its carcinogenicity in animals remains inadequate. Mongolian gerbils and mice are commonly used to investigate the carcinogenicity of H. pylori, yet it is unclear whether H. pylori infection per se causes gastric cancer or duodenal ulcers in these animal models. Gastric adenocarcinoma in the gerbils was reported over 10 years ago, but this species has proved an unreliable model for studying H. pylori infection-associated gastric cancer. Helicobacter pylori infection alone appears insufficient to induce gastric cancer in these animals; additional carcinogenic insult is required. The development of invasive adenocarcinoma in inbred mice is rare regardless of the mouse or bacterial strain, and many long-term studies have failed to induce gastric cancer in these animals. Helicobacter pylori infection is also an established causative factor for duodenal ulcer in humans. However, few studies have attempted to develop animal models of H. pylori infection-induced duodenal ulcer. We therefore conclude that both Mongolian gerbils and inbred mice may be inadequate models for studying H. pylori infection-associated gastric cancer and that there is no animal model of H. pylori infection-induced duodenal ulcer.
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Affiliation(s)
- Duan Chen
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
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Kawazoe T, Sakagami T, Nakajima K, Hori K, Fukuda Y, Matsumoto T, Miwa H. Role of bacterial strain diversity of Helicobacter pylori in gastric carcinogenesis induced by N-methyl-N-nitrosourea in Mongolian gerbils. Helicobacter 2007; 12:213-23. [PMID: 17493001 DOI: 10.1111/j.1523-5378.2007.00491.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
AIM Helicobacter pylori is known to enhance gastric carcinogenesis induced by chemical carcinogens. We previously demonstrated that infection with H. pylori strain SS1 did not enhance such carcinogenesis in C57BL/6 mice. Whether this result was due to the bacterial strain SS1 or to the experimental host, C57BL/6 mice, should be addressed. Therefore, we examined whether H. pylori strains introduced to the same host (Mongolian gerbils) differed in carcinogenicity. MATERIALS AND METHODS H. pylori TN2GF4 strain (CagA(+), VacA(+)) and SS1 strain (CagA functionally(-), VacA(-)) were infected to Mongolian gerbils (n = 126). In the first experiment (induction of gastritis), histologic change in gastric mucosa of gerbils infected by H. pylori (TN2GF4, SS1, vehicle) without N-methyl-N-nitrosourea (MNU) at 1 month or 6 months was assessed. In the second experiment (experimental carcinogenesis), H. pylori (TN2GF4, SS1, vehicle) was inoculated to the gerbils after administration of MNU for 10 weeks, and the number of cancers and histopathologic changes at week 54 were assessed. RESULTS In the first experiment, activity and inflammation in the TN2GF4 group were significantly greater than in the SS1 group at 1 month, while no significant difference was noted at 6 months. On the other hand, intestinal metaplasia and atrophy were significantly greater with TN2GF4 than with SS1 at 6 months but not at 1 month. In studies on experimental carcinogenesis, microscopically, 47.8% (11/23), 26% (7/26), and 0% (0/26), of animals had gastric adenocarcinoma in the MNU + TN2GF4 group, MNU + SS1 group, and MNU alone group, respectively. CONCLUSION Both H. pylori strains, TN2GF4 and SS1, promoted carcinogenesis in Mongolian gerbils. The severity of gastritis and destruction and restoration of gastric mucosa may be related to gastric carcinogenesis. That the SS1 strain significantly accelerated carcinogenesis only in Mongolian gerbils and not in C57BL/6 mice suggests the crucial role of host factors in carcinogenesis by H. pylori infection.
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Affiliation(s)
- Tomotaro Kawazoe
- Division of Upper Gastroenterology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
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Gamboa-Dominguez A, Ubbelohde T, Saqui-Salces M, Romano-Mazzoti L, Cervantes M, Domínguez-Fonseca C, de la Luz Estreber M, Ruíz-Palacios GM. Salt and stress synergize H. pylori-induced gastric lesions, cell proliferation, and p21 expression in Mongolian gerbils. Dig Dis Sci 2007; 52:1517-26. [PMID: 17404882 DOI: 10.1007/s10620-006-9524-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2006] [Accepted: 07/17/2006] [Indexed: 12/13/2022]
Abstract
Our aim was to determine if salt and stress enhance Helicobacter pylori (Hp) lesions in Meriones unguiculatus. Two hundred seventy-eight pathogen-free gerbils were allocated to seven groups: Hp-Sydney strain (45), 8% higher-salt diet (38), stress (60% space reduction/water immersion; 36), Hp + salt (33), Hp + stress (34), N-methyl-N-nitro-N-nitrosoguanidine (34), and sham (58). Gerbils were sacrificed at 1 week (67), 12 weeks (73), 52 weeks (65), and 68 weeks (73). Sydney, Padova, and Lauren classifications were blindly used. Proliferation, p53, p21, and apoptosis were assessed. Follicular active gastritis (grade 2/3) was observed in 10% of Hp gerbils, 38% of Hp + salt gerbils, and 29% of Hp + stress gerbils at 52 weeks and 67%, 83%, and 43% at 68 weeks (P < 0.05). Heterotopic proliferative glands were identified in synergy groups from 52 weeks, with increases in their number and size by 68 weeks. Higher proliferative rates were observed in Hp+salt gerbils (P < 0.0001), and p21 overexpression in Hp+salt and Hp+stress gerbils (both P's < 0.0001), by 68 weeks, without p53 increases. We conclude that salt and stress synergize Hp damage and increase pseudo-invasive gland foci.
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Affiliation(s)
- Armando Gamboa-Dominguez
- Department of Pathology, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Tlalpan, Mexico City, DF, Mexico.
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31
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Tatematsu M, Tsukamoto T, Toyoda T. Effects of eradication of Helicobacter pylori on gastric carcinogenesis in experimental models. J Gastroenterol 2007; 42 Suppl 17:7-9. [PMID: 17238018 DOI: 10.1007/s00535-006-1927-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Helicobacter pylori infection enhances glandular stomach carcinogenesis in Mongolian gerbils (MGs) treated with N-methyl-N'-nitro-N-nitrosoguanidine and N-methyl-N-nitrosourea. A high-salt diet has been revealed to synergistically enhance development of stomach cancer with H. pylori infection; the latter exerts stronger promoting effects than the former. Eradication of H. pylori with antibiotics diminishes their enhancing effects. The earlier the eradication of H. pylori is undergone, the more effective is the prevention of gastric carcinogenesis in MGs. To explore whether the role of H. pylori infection is a cause of stomach carcinogenesis (initiator) or just a supporting actor (promoter), we established an experimental model of long-term (2 years) H. pylori infection and eradication in MGs without chemical carcinogens. Long-term H. pylori infection stimulated development of highly proliferative and dilated glands containing a large amount of mucin, called heterotopic proliferative glands (HPGs), resembling mucinous adenocarcinomas. However, no gastric carcinomas were found in MGs after 2 years of H. pylori infection in our system. After eradication of the bacteria, HPGs were obviously reduced, and gastric lesions were mostly alleviated. These findings showed that H. pylori infection is related to severe gastritis and that HPGs are frequently induced reversible lesions rather than being malignant in character. Helicobacter pylori infection thus appears to have a strong promotional influence but not to initiate gastric carcinogenesis.
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Affiliation(s)
- Masae Tatematsu
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan
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32
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Kato M, Asaka M, Ono S, Nakagawa M, Nakagawa S, Shimizu Y, Chuma M, Kawakami H, Komatsu Y, Hige S, Takeda H. Eradication of Helicobacter pylori for primary gastric cancer and secondary gastric cancer after endoscopic mucosal resection. J Gastroenterol 2007; 42 Suppl 17:16-20. [PMID: 17238020 DOI: 10.1007/s00535-006-1928-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Because most gastric cancers develop from a background of Helicobacter pylori-infected gastric mucosa, H. pylori plays an important role in gastric carcinogenesis. Therefore, eradication of H. pylori may inhibit the incidence of gastric cancers. In experimental studies, H. pylori eradication has proved to act as a prophylaxis against gastric cancer. However, the results of recent randomized controlled studies are absolutely contradictory. In Japan, mucosal gastric cancer is usually resected by endoscopic treatment. As only a small part of the gastric mucosa is resected, secondary gastric cancer after endoscopic resection of the primary gastric cancer often develops at another site in the stomach. A nonrandomized Japanese study involving 132 early gastric cancer patients reported that eradication of H. pylori after endoscopic resection tended to reduce the development of secondary gastric cancer. Also, a retrospective multicenter survey indicated that the incidence rate of secondary gastric cancer in H. pylori-eradicated patients was about one-third that among patients in the non eradication group. We conducted a large-scale multicenter randomized trial to confirm the effect of H. pylori eradication on secondary and residual gastric cancer after endoscopic resection. This study was begun in 2003 and is ongoing at present. Diagnosis of a new carcinoma at another site of the stomach is defined as the primary end point, and recurrence of tumors at the resection site as a secondary end point. A total of 542 subjects have been enrolled in the study. This study will have the statistical power to demonstrate whether H. pylori eradication decreases the incidence and recurrence of gastric cancer.
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Affiliation(s)
- Motosugu Kato
- Division of Endoscopy, Hokkaido University Hospital, North 14, West 5, Kita-Ku, Sapporo, 060-8638, Japan
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33
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Takenaka Y, Tsukamoto T, Mizoshita T, Cao X, Ban H, Ogasawara N, Kaminishi M, Tatematsu M. Helicobacter pylori infection stimulates intestinalization of endocrine cells in glandular stomach of Mongolian gerbils. Cancer Sci 2006; 97:1015-22. [PMID: 16984375 PMCID: PMC11158682 DOI: 10.1111/j.1349-7006.2006.00273.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Intestinal metaplasia has been investigated extensively as a possible premalignant condition for stomach cancer but its pathogenesis is still not fully understood. In the present study, we examined the relationship between endocrine and mucous cell marker expression periodically after Helicobacter pylori infection in the Mongolian gerbil model. The numbers of chromogranin A (CgA)-positive, gastrin-positive and gastric inhibitory polypeptide (GIP)-positive cells in H. pylori-infected groups was increased significantly compared with the non-infected case. However, CgA-positive and gastrin-positive cells then decreased from 50 through 100 experimental weeks after H. pylori infection, whereas GIP-positive cells increased. Coexistence of gastrin-positive and GIP-positive cells was detected in the same gastric and intestinal mixed phenotypic glandular-type glands. In conclusion, the endocrine cell phenotype is in line with that of the mucous counterpart in the glands of H. pylori-infected Mongolian gerbil stomach, supporting the concept that development of intestinal metaplasia is due to the abnormal differentiation of a stem cell.
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Affiliation(s)
- Yoshiharu Takenaka
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa, Nagoya, Japan
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Abstract
Infection with H pylori is the most important known etiological factor associated with gastric cancer. While colonization of the gastric mucosa with H pylori results in active and chronic gastritis in virtually all individuals infected, the likelihood of developing gastric cancer depends on environmental, bacterial virulence and host specific factors. The majority of all gastric cancer cases are attributable to H pylori infection and therefore theoretically preventable. There is evidence from animal models that eradication of H pylori at an early time point can prevent gastric cancer development. However, randomized clinical trials exploring the prophylactic effect of H pylori eradication on the incidence of gastric cancer in humans remain sparse and have yielded conflicting results. Better markers for the identification of patients at risk for H pylori induced gastric malignancy are needed to allow the development of a more efficient public eradication strategy. Meanwhile, screening and treatment of H pylori in first-degree relatives of gastric cancer patients as well as certain high-risk populations might be beneficial.
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35
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Otaka M, Konishi N, Odashima M, Jin M, Wada I, Matsuhashi T, Horikawa Y, Ohba R, Watanabe S. Is Mongolian gerbil really adequate host animal for study of Helicobacter pylori infection-induced gastritis and cancer? Biochem Biophys Res Commun 2006; 347:297-300. [PMID: 16815296 DOI: 10.1016/j.bbrc.2006.06.094] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2006] [Accepted: 06/15/2006] [Indexed: 10/24/2022]
Abstract
BACKGROUND Many researches have been published to understand the pathogenesis and mechanism of Helicobacter pylori (Hp)-associated diseases, including gastritis followed by gastric cancer, using Mongolian gerbil (MG) model because Hp could be hardly inoculated in other animal species. The aim of this study was to evaluate the induction ability of heat shock protein (HSP70) and protective ability in the gastric mucosa of MG comparing with those of Sprague-Dawley (SD) rats, since HSP70 is a key molecule known to be involved in important biological activities such as apoptosis, carcinogenesis, and cytoprotection from cytotoxic damage. MATERIALS AND METHODS Basal expression level and induction ability of gastric mucosal HSP70 were evaluated by immunoblotting and densitometric analysis in MG and SD rats before and after HSP-induction by zinc l-carnosine, gastric HSP70 inducer, administration. Mucosal protective ability against water-immersion stress-induced mucosal lesion was also compared. RESULTS Basal expression level of HSP70 was not significantly different between MG and SD rats. However, HSP70-induction by zinc derivatives was not observed in MG. Mucosal lesion induced by water-immersion stress was significantly severe in MG compared with SD rats. CONCLUSIONS MG might be special (not ordinary) animal, in which HSP70-induction was absent and has extremely poor mucosal protective ability in view of HSP-dependent cytoprotection in the gastric mucosa. Our results may suggest that MG is not an adequate animal to evaluate the effect of Hp-infection-associated gastric inflammation followed by development of gastric cancer.
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Affiliation(s)
- Michiro Otaka
- Department of Internal Medicine and Gastroenterology, Akita University School of Medicine, Japan.
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36
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Eslick GD. Helicobacter pylori infection causes gastric cancer? A review of the epidemiological, meta-analytic, and experimental evidence. World J Gastroenterol 2006; 12:2991-2999. [PMID: 16718777 PMCID: PMC4124371 DOI: 10.3748/wjg.v12.i19.2991] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2005] [Revised: 01/08/2006] [Accepted: 01/14/2006] [Indexed: 02/06/2023] Open
Abstract
Since the discovery of Campylobacter-like organisms Helicobacter pylori (H pylori) more than two decades ago the possibility of a relationship with gastric cancer has been postulated, tested and supposedly proven. There have been numerous human studies of various designs from many countries around the world. Several meta-analyses have been published and more recently a small number of experimental animal studies were reported looking at the association between H pylori infection and gastric cancer. Over the years, the human epidemiological studies have produced conflicting results; the meta-analyses have as one would expect produced similar pooled estimates; while the early experimental animal studies require replication. The exact mechanisms by which H pylori might cause gastric cancer are still under investigation and remain to be elucidated.
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Affiliation(s)
- Guy-D Eslick
- School of Public Health, The University of Sydney, Sydney, New South Wales, Australia.
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37
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Miyazawa M, Utsunomiya H, Inada KI, Yamada T, Okuno Y, Tanaka H, Tatematsu M. Inhibition of Helicobacter pylori motility by (+)-Syringaresinol from unripe Japanese apricot. Biol Pharm Bull 2006; 29:172-3. [PMID: 16394533 DOI: 10.1248/bpb.29.172] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
A methanol extract from unripe Japanese apricot showed inhibitory activity of Helicobacter pylori motility. Inhibitory compound 1 was isolated and identified as (+)-syringaresinol (1) by spectoroscopic means. (+)-Syringaresinol (1) inhibited >90% of the H. pylori motility at a concentration of 500 microg/ml and the IC50 value was 50 microg/ml.
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Affiliation(s)
- Mitsuo Miyazawa
- Department of Applied Chemistry, Faculty of Science and Engineering, Kinki University.
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38
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Brzozowski T, Konturek PC, Mierzwa M, Drozdowicz D, Bielanski W, Kwiecien S, Konturek SJ, Stachura J, Pawlik WW, Hahn EG. Effect of probiotics and triple eradication therapy on the cyclooxygenase (COX)-2 expression, apoptosis, and functional gastric mucosal impairment in Helicobacter pylori-infected Mongolian gerbils. Helicobacter 2006; 11:10-20. [PMID: 16423085 DOI: 10.1111/j.0083-8703.2006.00373.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Helicobacter pylori infection in Mongolian gerbils is an established experimental model of gastric carcinogenesis that mimics H. pylori-positive patients developing gastric ulcer and gastric cancer, but the effect of probiotic therapy on functional aspects of this infection remains unknown. METHODS We compared the effects of intragastric inoculation of gerbils with H. pylori strain (cagA+ vacA+, 5 x 10(6) colony forming units/ml) with or without triple therapy including omeprazole, amoxicillin, and tinidazol or probiotic bacteria Lacidofil. Histology of glandular mucosa, the viable H. pylori, and density of H. pylori colonization were evaluated. The gastric blood flow was measured by H2-gas clearance method; the plasma gastrin and gastric luminal somatostatin were determined by RIA and expression of cyclooxygenase (COX)-2 and apoptotic Bax and Bcl-2 proteins were evaluated by Western blot. RESULTS The gastric H. pylori infection was detected in all animals by histology and H. pylori culture. Basal gastric acid was significantly reduced in H. pylori-infected animals but not in those with triple therapy or Lacidofil. Early lesions were seen already 4 weeks upon H. pylori inoculation and consisted of chronic gastritis and glandular atypia associated with typical regenerative hyperplasia and increased mitotic activity and formation of apoptotic bodies. The H. pylori infection was accompanied by the fall in gastric blood flow, the marked increase in plasma gastrin, the significant fall in gastric somatostatin levels and Bcl-2 protein expression, and the rise in expression of COX-2 and Bax proteins. These mucosal changes were counteracted by the triple therapy and Lacidofil. CONCLUSIONS H. pylori infection in gerbils, associated with regenerative hyperplasia of glandular structure, results in the suppression of gastric secretion, overexpression of COX-2, and enhancement in apoptosis and impairment of both, gastric blood flow and gastrin-somatostatin link that were reversed by anti-H. pylori triple therapy and attenuated by probiotics.
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Affiliation(s)
- Tomasz Brzozowski
- Department of Physiology Jagiellonian University School of Medicine, Cracow, Poland
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39
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Malfertheiner P, Fry LC, Mönkemüller K. Can gastric cancer be prevented by Helicobacter pylori eradication? Best Pract Res Clin Gastroenterol 2006; 20:709-19. [PMID: 16997155 DOI: 10.1016/j.bpg.2006.04.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Helicobacter pylori infection always causes chronic gastritis and triggers several gastroduodenal pathologies ranging from peptic ulcer disease to gastric cancer. It is well established that H. pylori eradication decreases the incidence of gastroduodenal ulcer and its recurrence. However, despite being accepted as the critical risk factor for gastric cancer, there is no conclusive evidence that H. pylori eradication decreases the incidence of gastric cancer. Bacterial virulence characteristics, as well as genetic predisposition of the host in conjunction with certain environmental conditions, are the major factors which influence the development of gastric cancer. Preclinical and clinical data suggest that reversibility of precancerous lesions (atrophic gastritis and intestinal metaplasia) is possible in some patients after H. pylori eradication. Since neoplastic lesions do not progress - or even regress in some cases - after H. pylori eradication, eradication therapy should be considered even in patients with precancerous lesions. Nonetheless, progression of atrophic gastritis and intestinal metaplasia into cancer has been also demonstrated in patients after H. pylori eradication, suggesting that there might be a point of no return where genetic changes have already happened and are irreversible despite elimination of the triggering carcinogen (H. pylori). At the present time the clinical decision to treat a patient is based on established risk profiles. A general screen-and-treat policy, although desirable, currently awaits a less complex treatment regimen.
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Affiliation(s)
- Peter Malfertheiner
- Division of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Universitätsklinikum Magdeburg, Leipziger Strasse 44, Magdeburg, Germany.
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40
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Seo JK. Helicobacter pylori infection and abdominal pain in children. KOREAN JOURNAL OF PEDIATRICS 2006. [DOI: 10.3345/kjp.2006.49.2.136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Jeong Kee Seo
- Department of Pediatrics, College of Medicine, Seoul National University Children's Hospital, Seoul, Korea
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41
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Tatematsu M, Tsukamoto T, Mizoshita T. Significant Factors on Gastric Carcinogenesis Revealed by Experimental Animal Models. J Toxicol Pathol 2006. [DOI: 10.1293/tox.19.75] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Masae Tatematsu
- Division of Oncological Pathology, Aichi Cancer Center Research Institute
| | - Tetsuya Tsukamoto
- Division of Oncological Pathology, Aichi Cancer Center Research Institute
| | - Tsutomu Mizoshita
- Division of Oncological Pathology, Aichi Cancer Center Research Institute
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42
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Kodama M, Murakami K, Sato R, Okimoto T, Nishizono A, Fujioka T. Helicobacter pylori-infected animal models are extremely suitable for the investigation of gastric carcinogenesis. World J Gastroenterol 2005; 11:7063-71. [PMID: 16437649 PMCID: PMC4725077 DOI: 10.3748/wjg.v11.i45.7063] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2005] [Revised: 06/23/2005] [Accepted: 06/24/2005] [Indexed: 02/06/2023] Open
Abstract
Although various animal models have been developed to clarify gastric carcinogenesis, apparent mechanism of gastric cancer was not clarified in recent years. Since the recognition of the pathogenicity of Helicobacter pylori (H pylori), several animal models with H pylori infection have been developed to confirm the association between H pylori and gastric cancer. Nonhuman primate and rodent models were suitable for this study. Japanese monkey model revealed atrophic gastritis and p53 mutation after long-term infection of H pylori. Mongolian gerbil model showed the development of gastric carcinoma with H pylori infection alone, as well as with combination of chemical carcinogens, such as N-methyl-N-nitrosourea and N-methyl-N-nitro-N'-nitrosoguanidine. The histopathological changes of these animal models after H pylori inoculation are closely similar to those in human beings with H pylori infection. Eradication therapy attenuated the development of gastric cancer in H pylori-infected Mongolian gerbil. Although several features of animal models differ from those seen in human beings, these experimental models provide a starting point for further studies to clarify the mechanism of gastric carcinogenesis as a result of H pylori infection and assist the planning of eradication therapy to prevent gastric carcinoma.
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Affiliation(s)
- Masaaki Kodama
- Department of Gastroenterology, Oita University, Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Oita-gun, Oita 879-55, Japan.
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43
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Elfvin A, Bölin I, Von Bothmer C, Stolte M, Watanabe H, Fändriks L, Vieth M. Helicobacter pylori induces gastritis and intestinal metaplasia but no gastric adenocarcinoma in Mongolian gerbils. Scand J Gastroenterol 2005; 40:1313-20. [PMID: 16334441 DOI: 10.1080/00365520510023611] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The Mongolian gerbil is considered as the model of choice when studying adenocarcinoma related to Helicobacter pylori infection. The purpose of this study was to compare two different H. pylori strains and elucidate whether adenocarcinomas developed in gerbils. MATERIAL AND METHODS Male gerbils were separated into three groups: one control and two groups infected with two different strains of H. pylori, TN2GF4 and SS1. At 3, 6, 12 or 18 months after inoculation 5 animals from each group were sacrificed. The stomach was used for culture, and for histology. RESULTS Inflammation was seen after 3 months in all the infected animals. In the controls no pathology was found at any time. Intestinal metaplasia was found in both the infected groups. Glands buried in the submucusal layer, changes that might be misinterpreted as adenocarcinoma, were found in 10% of the SS1 and in 65% of the TN2GF4 animals. Adenocarcinoma was not found in any of the gerbils. CONCLUSIONS All studies claiming to have found H. pylori-induced adenocarcinomas in gerbils describe atypical glands penetrating into the muscularis propria and interpret these as invasive growths due to cancer. An alternative interpretation is that the deranged glandular structures grow in and below the submucosa. It is suggested that atypical glands in the muscularis layer are not enough as a diagnostic criterion for gastric adenocarcinoma. It is concluded that adenocarcinoma has not yet been shown convincingly to develop in Mongolian gerbils infected with H. pylori. Nevertheless, it is a model well suited for studying gastritis, gastric ulcer and premalignant changes such as metaplasia.
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Affiliation(s)
- Anders Elfvin
- Department of Gastrosurgical Research, Sahlgrenska Academy, Göteborg University, Sahlgrensky University Hospital. Box 75038, SE-400 36 Gothenburg, Sweden.
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44
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Talley NJ, Vakil NB, Moayyedi P. American gastroenterological association technical review on the evaluation of dyspepsia. Gastroenterology 2005; 129:1756-80. [PMID: 16285971 DOI: 10.1053/j.gastro.2005.09.020] [Citation(s) in RCA: 261] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Nicholas J Talley
- Division of Gastroenterology and Hepatology and Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota
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45
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Siomek A, Rytarowska A, Szaflarska-Poplawska A, Gackowski D, Rozalski R, Dziaman T, Czerwionka-Szaflarska M, Olinski R. Helicobacter pylori infection is associated with oxidatively damaged DNA in human leukocytes and decreased level of urinary 8-oxo-7,8-dihydroguanine. Carcinogenesis 2005; 27:405-8. [PMID: 16219635 DOI: 10.1093/carcin/bgi238] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Helicobacter pylori infection is responsible for inflammation, increased production of reactive oxygen species and oxidatively damaged DNA in the gastric mucosa. There is also evidence which suggests that H.pylori infection may lead to the development of several extragastroduodenal pathologies with reactive oxygen species involvement. In order to assess whether the infection may impose oxidatively damaged DNA not only in the target organ (stomach) but in other organs as well we decided, for the first time, to analyse the two kinds of oxidatively damaged DNA biomarkers: urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanine (8-oxoGua) as well as the level of oxidatively damaged DNA in leukocytes. Using high performance liquid chromatography prepurification/gas chromatography with isotope dilution mass detection methodology, we examined the amount of oxidatively damaged DNA products excreted into urine and the amount of 8-oxodG in the DNA of leukocytes' (with the the HPLC/EC technique) in three groups of children: (i) control group, (ii) H.pylori infected children and (iii) children with gastritis where H.pylori infection was excluded. The levels of 8-oxodG in DNA isolated from leukocytes of H.pylori infected patients and in the group with gastritis without H.pylori infection were significantly higher than in DNA isolated from the control group. The mean level of 8-oxoGua in urine samples of children infected with H.pylori was significantly lower than in the urine of the group with gastritis without H.pylori infection. The data suggest that inflammation itself, not just H.pylori infection, is responsible for the observed rise of 8-oxodG level in leukocytes. However, the observed decrease in the level of modified base in urine seems to be specific for H.pylori infection and possibly linked with nitric oxide mediated inhibition of a key base excision repair enzyme (human 8-oxo-7, 8-dihydroguanine glycosylase) responsible for the repair of 8-oxo-7,8-dihydroguanine.
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Affiliation(s)
- Agnieszka Siomek
- Department of Clinical Biochemistry, Nicolaus Copernicus University, Collegium Medicum in Bydgoszcz, Karlowicza 24, 85-092 Poland
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Waldum HL, Gustafsson B, Fossmark R, Qvigstad G. Antiulcer drugs and gastric cancer. Dig Dis Sci 2005; 50 Suppl 1:S39-44. [PMID: 16184420 DOI: 10.1007/s10620-005-2805-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2005] [Accepted: 06/07/2005] [Indexed: 01/05/2023]
Abstract
Inhibitors of gastric acid secretion are efficient drugs in the treatment of acid-related diseases. However, by reducing gastric acidity, hypergastrinemia develops. Gastrin regulates its target cell, the enterochromaffin (ECL) cell, both functionally and tropicaly. Long-term hypergastrinemia in whatever species studied, has been shown to induce tumors originating from the ECL cell. In man, at least 10 years of hypergastrinemia, accompanied by high or reduced gastric acidity is necessary to induce ECL cell carcinoids. There are reports indicating development of ECL cell carcinoids after long-term treatment with proton pump inhibitors. Moreover, the ECL cell may give rise to gastric carcinomas of diffuse type, which have increased during the last decades. Furthermore, most of the carcinomas developing in patients with long-lasting hypergastrinemia are of ECL cell origin. Therefore, long-lasting iatrogenic hypergastrinemia induced by potent inhibitors of acid secretion may be expected to increase the occurrence of gastric carcinomas in the future.
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Affiliation(s)
- Helge L Waldum
- Norwegian University of Science and Technology, Department of Cancer Research and Molecular Medicine, Trondheim University Hospital, N-7006 Trondheim, Norway.
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Malfertheiner P, Sipponen P, Naumann M, Moayyedi P, Mégraud F, Xiao SD, Sugano K, Nyrén O. Helicobacter pylori eradication has the potential to prevent gastric cancer: a state-of-the-art critique. Am J Gastroenterol 2005; 100:2100-15. [PMID: 16128957 DOI: 10.1111/j.1572-0241.2005.41688.x] [Citation(s) in RCA: 146] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Helicobacter pylori infection continues to play a key role in gastric diseases. Colonization of the gastric mucosa with the bacterium invariably results in the development of chronic gastritis and subsets of patients have a progression of the chronic gastritis to either ulcer or cancer. Epidemiological evidence indicates that the proportion of all gastric cancers attributable to H. pylori infection, and hence potentially preventable upon elimination of this risk factor, is somewhere in the range of 60% to 90%. This portends significant benefit in terms of morbidity and mortality, not least in populations with high prevalence of H. pylori infection coupled with high incidence of gastric cancer. The effect of prophylactic H. pylori eradication on gastric cancer incidence in humans remains unknown, however. Results from randomized trials are eagerly awaited, but availability of strong conclusive results may take many years. A growing number of studies show considerable variation in risk for gastric cancer development, depending on H. pylori strain type and the genetic predisposition of the host. There is also a remote possibility that elimination of the infection may have adverse health implications (e.g., antibiotic resistance), and therefore "simple" risk stratification and targeted chemoprevention is required. Based on "in depth" evidence presented at this workshop, the majority of the scientific task force favored a search-and-treat strategy in first-degree relatives of gastric cancer patients and an overwhelming majority felt that a more general screen-and-treat strategy should be focused in the first instance on a population with a high incidence of H. pylori-associated diseases.
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Affiliation(s)
- Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
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Fossmark R, Zhao CM, Martinsen TC, Kawase S, Chen D, Waldum HL. Dedifferentiation of enterochromaffin-like cells in gastric cancer of hypergastrinemic cotton rats. APMIS 2005; 113:436-49. [PMID: 15996161 DOI: 10.1111/j.1600-0463.2005.apm_134.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The role of enterochromaffin-like (ECL) cells in gastric carcinogenesis is not fully understood. Spontaneous tumours developing in hypergastrinemic female cotton rats have an adenocarcinoma phenotype, but numerous cells in the dysplastic mucosa as well as in the carcinomas are positive for neuroendocrine markers. In the present study of female cotton rats with 2 and 8 months' hypergastrinemia, the oxyntic mucosa of the stomach was examined histologically and immunolabelled for histidine decarboxylase (HDC) and pancreastatin, and hyperplastic and neoplastic ECL cells were evaluated by electron microscopy. These animals developed hyperplasia of the oxyntic mucosa in general and of the ECL cells in particular after 2 months and dysplasia and carcinomas after 8 months. The immunoreactivity of the ECL cells in the oxyntic mucosa was increased at 2 months and declined at 8 months. These histological changes were associated with progressive loss of secretory vesicles and granules in ECL cells. We suggest that ECL cells in hypergastrinemic cotton rats dedifferentiate with time and that the gastric carcinomas may develop from ECL cells.
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Affiliation(s)
- Reidar Fossmark
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
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Tatematsu M, Tsukamoto T, Mizoshita T. Role of Helicobacter pylori in gastric carcinogenesis: the origin of gastric cancers and heterotopic proliferative glands in Mongolian gerbils. Helicobacter 2005; 10:97-106. [PMID: 15810939 DOI: 10.1111/j.1523-5378.2005.00305.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Helicobacter pylori infection is well accepted to be a very important factor for the development of gastric carcinogenesis in the human stomach. In Mongolian gerbils treated with chemical carcinogens, H. pylori infection enhances glandular stomach carcinogenesis, and eradication of infection and results in curtailment of enhancing effects, particularly at early stages of associated inflammation. A high-salt diet exacerbates the effects of H. pylori infection on gastric carcinogenesis, and these two factors act synergistically to promote the development of gastric cancers in this animal model. However, the bacterium exerts the greater effects. Early acquisition significantly increases gastric chemical carcinogenesis in Mongolian gerbils, as compared to later infection. While heterotopic proliferative glands, hyperplastic and dilated glands localized beneath the muscularis mucosae, frequently develop with H. pylori infection alone in this animal model, they obviously regress on eradication, suggesting a relation to severe gastritis, rather than a malignant character. Furthermore, endocrine cells, positive for chromogranin A, are observed in the heterotopic proliferative glands, in contrast to cancerous lesions which lack endocrine elements. In conclusion, H. pylori is not an initiator, but rather a strong promoter of gastric carcinogenesis, whose eradication, together with reduction in salt intake, might effectively prevent gastric cancer development.
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Affiliation(s)
- Masae Tatematsu
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
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Nakagawa S, Osaki T, Fujioka Y, Yamaguchi H, Kamiya S. Long-term infection of Mongolian gerbils with Helicobacter pylori: microbiological, histopathological, and serological analyses. CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY 2005; 12:347-53. [PMID: 15699432 PMCID: PMC549302 DOI: 10.1128/cdli.12.2.347-353.2005] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2004] [Revised: 08/19/2004] [Accepted: 10/21/2004] [Indexed: 12/18/2022]
Abstract
The effects of long-term infection with Helicobacter pylori on the gastric mucosa of Mongolian gerbils were examined. Colonization by H. pylori was evaluated by both microaerobic cultivation and real-time reverse transcriptase PCR (RT-PCR). Persistent infection with H. pylori in gastric mucosa was detected by real-time RT-PCR during 6 months after infection, but no H. pylori was isolated 4 months after infection by cultivation. Infiltration with neutrophils and mononuclear cells was observed from 2 months after infection. Both intestinal metaplasia and gastric atrophy were also detected from 2 months after infection. The results by enzyme-linked immunosorbent assay indicated that antibody titers against whole H. pylori antigens, H. pylori heat shock protein 60 (HSP60), and Escherichia coli GroEL were significantly higher in the infected gerbils than in noninfected gerbils. After long-term infection with H. pylori for 18 months, marked atrophy of gastric mucosa and multiple cysts in the submucosa were observed in the glandular stomach of the infected gerbils. In addition, squamous cell papilloma with hyperkeratosis was observed in cardia of all the infected gerbils. These results indicate that evaluation of bacterial colonization during long-term infection can be done by real-time RT-PCR and that mucosal damage might be induced by host immune response against whole H. pylori antigen.
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Affiliation(s)
- Shigehito Nakagawa
- Department of Infectious Diseases, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan
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