|
1
|
Xu X, Fei X, Wang H, Wu X, Zhan Y, Li X, Zhou Y, Shu C, He C, Hu Y, Liu J, Lv N, Li N, Zhu Y. Helicobacter pylori infection induces DNA double-strand breaks through the ACVR1/IRF3/POLD1 signaling axis to drive gastric tumorigenesis. Gut Microbes 2025; 17:2463581. [PMID: 39924917 PMCID: PMC11812335 DOI: 10.1080/19490976.2025.2463581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 01/06/2025] [Accepted: 02/02/2025] [Indexed: 02/11/2025] Open
Abstract
Helicobacter pylori (H. pylori) infection plays a pivotal role in gastric carcinogenesis through inflammation-related mechanisms. Activin A receptor type I (ACVR1), known for encoding the type I receptor for bone morphogenetic proteins (BMPs), has been identified as a cancer diver gene across various tumors. However, the specific role of AVCR1 in H. pylori-induced gastric tumorigenesis remains incompletely understood. We conducted a comprehensive analysis of the clinical relevance of ACVR1 by integrating data from public databases and our local collection of human gastric tissues. In vitro cell cultures, patient-derived gastric organoids, and transgenic INS-GAS mouse models were used for Western blot, qRT-PCR, immunofluorescence, immunohistochemistry, luciferase assays, ChIP, and comet assays. Furthermore, to investigate the therapeutic potential, we utilized the ACVR1 inhibitor DM3189 in our in vivo studies. H. pylori infection led to increased expression of ACVR1 in gastric epithelial cells, gastric organoid and gastric mucosa of INS-GAS mice. ACVR1 activation led to DNA double-strand break (DSB) accumulation by inhibiting POLD1, a crucial DNA repair enzyme. The activation of POLD1 was facilitated by the transcription factor IRF3, with identified binding sites. Additionally, treatment with the ACVR1 inhibitor DM3189 significantly ameliorated H. pylori-induced gastric pathology and reduced DNA damage in INS-GAS mice. Immunohistochemistry analysis showed elevated levels of ACVR1 in H. pylori-positive gastritis tissues, showing a negative correlation with POLD1 expression. This study uncovers a novel signaling axis of AVCR1/IRF3/POLD1 in the pathogenesis of H. pylori infection. The upregulation of ACVR1 and the suppression of POLD1 upon H. pylori infection establish a connection between the infection, genomic instability, and the development of gastric carcinogenesis.
Collapse
Affiliation(s)
- Xinbo Xu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xiao Fei
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Huan Wang
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xidong Wu
- Department of Drug Safety Evaluation, Jiangxi Testing Center of Medical Instruments, Nanchang, China
| | - Yuan Zhan
- Department of Pathology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Xin Li
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yan’an Zhou
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Chunxi Shu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Cong He
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yi Hu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Jianping Liu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Nonghua Lv
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Nianshuang Li
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yin Zhu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| |
Collapse
|
|
2
|
Morris MT, Duncan BC, Piazuelo MB, Olfert IM, Xu X, Hussain S, Peek RM, Busada JT. Chronic Cigarette Smoke Exposure Masks Pathological Features of Helicobacter pylori Infection While Promoting Tumor Initiation. Cancer Prev Res (Phila) 2025; 18:271-281. [PMID: 39789851 PMCID: PMC12045739 DOI: 10.1158/1940-6207.capr-24-0378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 11/26/2024] [Accepted: 01/08/2025] [Indexed: 01/12/2025]
Abstract
Gastric cancer is the fifth most common cancer and the fifth leading cause of cancer deaths worldwide. Chronic infection by the bacterium Helicobacter pylori is the most prominent gastric cancer risk factor, but only 1% to 3% of infected individuals will develop gastric cancer. Cigarette smoking is another independent gastric cancer risk factor, and H. pylori-infected smokers are at a 2- to 11-fold increased risk of gastric cancer development, but the direct impacts of cigarette smoke (CS) on H. pylori pathogenesis remain unknown. In this study, male C57BL/6 mice were infected with H. pylori and began smoking within 1 week of infection. The mice were exposed to CS 5 days/week for 8 weeks. CS exposure had no notable impact on gross gastric morphology or inflammatory status compared with filtered-air (FA) exposed controls in mock-infected mice. However, CS exposure significantly blunted H. pylori-induced gastric inflammatory responses, reducing gastric atrophy and pyloric metaplasia development. Despite blunting these classic pathological features of H. pylori infection, CS exposures increased DNA damage within the gastric epithelial cells and accelerated H. pylori-induced dysplasia onset in the INS-GAS gastric cancer model. These data suggest that cigarette smoking may clinically silence classic clinical symptoms of H. pylori infection but enhance the accumulation of mutations and accelerate gastric cancer initiation. Prevention Relevance: These findings suggest that cigarette smoking suppresses pathophysiological hallmarks of H. pylori infection while accelerating gastric carcinogenesis. Therefore, smokers should receive screening for H. pylori infection to reduce gastric cancer risk. See related Spotlight, p. 257.
Collapse
Affiliation(s)
- Maeve T. Morris
- Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV, 26505, USA
| | - Benjamin C. Duncan
- Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV, 26505, USA
| | - M Blanca Piazuelo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - I. Mark Olfert
- Division of Exercise Physiology West Virginia University West Virginia University, Morgantown, WV, 26505, USA
- Department of Physiology, Pharmacology and Toxicology, West Virginia University, Morgantown, WV, 26505, USA
| | - Xiaojiang Xu
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, United States
| | - Salik Hussain
- Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV, 26505, USA
- Department of Physiology, Pharmacology and Toxicology, West Virginia University, Morgantown, WV, 26505, USA
| | - Richard M. Peek
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jonathan T. Busada
- Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV, 26505, USA
| |
Collapse
|
|
3
|
Huang C, Liu J. Well-differentiated Adenocarcinoma Arising from Gastric Cystica Profunda Treated by Endoscopic Submucosal Dissection: A case report and literature review. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2025; 63:497-501. [PMID: 39965649 DOI: 10.1055/a-1920-4161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2025]
Abstract
Gastritis cystica profunda (GCP) is a rare disease that is often observed at the stoma site of patients undergoing gastric surgery. Specific symptoms are often lacking, making it difficult to diagnose. GCP may develop into cancer. Endoscopic resection is a good method to reduce surgical injury, and the therapeutic effect depends on the status of the primary disease.The patient was a 77-year-old male who was admitted to the hospital for repeated epigastric distention. The man had never undergone gastric surgery and did not have Helicobacter pylori infection. Physical and laboratory tests showed no abnormality. Computed tomography showed no significant abnormality. Endoscopy revealed multiple ulcers on the posterior wall of the gastric body, but biopsy showed no evidence of malignancy. The patient subsequently underwent ESD surgery with a lesion of 1.5 cm×2.3 cm. Pathological results showed the cystic dilatation of gastric glands in the submucosa, with some well-differentiated adenocarcinoma. The final diagnosis was GCP with well-differentiated gastric adenocarcinoma.Herein, we describe a case of ESD therapy for GCP with well-differentiated gastric adenocarcinoma. When gastric mucosal lesions are difficult to diagnose, further treatment and diagnosis with EMR or ESD can be considered. For patients with early gastric cancer, long-term postoperative monitoring should be carried out.
Collapse
Affiliation(s)
- Cao Huang
- Gastroenterology, Huzhou Central Hospital, Huzhou, China
| | - Jiang Liu
- Huzhou Central Hospital, Huzhou, China
| |
Collapse
|
|
4
|
Ge Y, Janson V, Dong Z, Liu H. Role and mechanism of IL-33 in bacteria infection related gastric cancer continuum: From inflammation to tumor progression. Biochim Biophys Acta Rev Cancer 2025; 1880:189296. [PMID: 40058506 DOI: 10.1016/j.bbcan.2025.189296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 03/02/2025] [Accepted: 03/03/2025] [Indexed: 03/22/2025]
Abstract
Gastric cancer, a globally prevalent malignant tumor, is characterized by low early diagnosis rate, high metastasis rate, and poor prognosis, particularly in East Asia, Eastern Europe, and South America. Helicobacter pylori (H. pylori) is recognized as the primary risk factor for gastric cancer. However, the fact that fewer than 3 % of infected individuals develop cancer suggests that other bacteria may also influence gastric carcinogenesis. A diverse community of microorganisms may interact with H. pylori, thereby driving disease progression. Here, the role of the cytokine IL-33, a member of the IL-1 family, is scrutinized. Its production can be induced by H. pylori through the activation of specific signaling pathways, and it contributes to the inflammatory environment by promoting the release of pro-inflammatory cytokines. This article reviews the conflicting evidence regarding IL-33's role in the progression from gastritis to gastric cancer and discusses the potential therapeutic implications of targeting the IL-33/ST2 axis, with various antibodies and inhibitors in development or undergoing clinical trials for inflammatory diseases. However, the role of IL-33 in gastric cancer treatment remains to be fully elucidated, with its effects potentially dependent on the cellular context and stage of cancer progression. In summary, this review provides a comprehensive overview of the intricate relationship between gastric microbiota, IL-33, and gastritis - gastric cancer transition, offering insights into potential therapeutic targets and the development of novel treatment strategies.
Collapse
Affiliation(s)
- Yunxiao Ge
- Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, China
| | - Victor Janson
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Zigang Dong
- Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, China; China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, Zhengzhou, Henan 450008, China
| | - Hui Liu
- Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, Henan 450001, China; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, Zhengzhou, Henan 450008, China.
| |
Collapse
|
|
5
|
Gobert AP, Hawkins CV, McNamara KM, Wilson KT. Alterations in polyamine metabolism induced by the pathogen Helicobacter pylori: Implications for gastric inflammation and carcinogenesis. Methods Enzymol 2025; 715:137-153. [PMID: 40382134 DOI: 10.1016/bs.mie.2025.01.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/20/2025]
Abstract
Helicobacter pylori is a pathogen of the human stomach that infects half of the world's population. The chronicity of the infection is a major risk factor for the development of gastric cancer. Multiple parameters, including the heterogenicity of the virulence factors, the environmental parameters, or the intensity of the host responses, regulate the evolution of the disease. Thus, we have reported that the dysregulation of the polyamine pathway in the infected gastric mucosa represents a major component of the inflammation and the risk for neoplastic transformation. Using different animal models and gastric organoids, we recently highlighted the critical role of spermine oxidase-derived acrolein in the pathogenesis of H. pylori infection and the progression to carcinoma. Herein, we describe the experimental procedures that have been used, from the culture of the bacteria to the various models of infection in vivo and in vitro, and the assessment of acrolein generation.
Collapse
Affiliation(s)
- Alain P Gobert
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, United States; Program in Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Caroline V Hawkins
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Kara M McNamara
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States; Program in Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Keith T Wilson
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, United States; Program in Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, United States; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States; Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, United States.
| |
Collapse
|
|
6
|
Andersen GT, Ianevski A, Resell M, Pojskic N, Rabben HL, Geithus S, Kodama Y, Hiroyuki T, Kainov D, Grønbech JE, Hayakawa Y, Wang TC, Zhao CM, Chen D. Multi-bioinformatics revealed potential biomarkers and repurposed drugs for gastric adenocarcinoma-related gastric intestinal metaplasia. NPJ Syst Biol Appl 2024; 10:127. [PMID: 39496635 PMCID: PMC11535201 DOI: 10.1038/s41540-024-00455-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 10/13/2024] [Indexed: 11/06/2024] Open
Abstract
Biomarkers associated with the progression from gastric intestinal metaplasia (GIM) to gastric adenocarcinoma (GA), i.e., GA-related GIM, could provide valuable insights into identifying patients with increased risk for GA. The aim of this study was to utilize multi-bioinformatics to reveal potential biomarkers for the GA-related GIM and predict potential drug repurposing for GA prevention in patients. The multi-bioinformatics included gene expression matrix (GEM) by microarray gene expression (MGE), ScType (a fully automated and ultra-fast cell-type identification based solely on a given scRNA-seq data), Ingenuity Pathway Analysis, PageRank centrality, GO and MSigDB enrichments, Cytoscape, Human Protein Atlas and molecular docking analysis in combination with immunohistochemistry. To identify GA-related GIM, paired surgical biopsies were collected from 16 GIM-GA patients who underwent gastrectomy, yielding 64 samples (4 biopsies per stomach x 16 patients) for MGE. Co-analysis was performed by including scRNAseq and immunohistochemistry datasets of endoscopic biopsies of 37 patients. The results of the present study showed potential biomarkers for GA-related GIM, including GEM of individual patients, individual genes (such as RBP2 and CD44), signaling pathways, network of molecules, and network of signaling pathways with key topological nodes. Accordingly, potential treatment targets with repurposed drugs were identified including epidermal growth factor receptor, proto-oncogene tyrosine-protein kinase Src, paxillin, transcription factor Jun, breast cancer type 1 susceptibility protein, cellular tumor antigen p53, mouse double minute 2, and CD44.
Collapse
Affiliation(s)
- Gøran Troseth Andersen
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Department of Surgery, St. Olav's Hospital, Trondheim, Norway
- Department of Surgery, Namsos Hospital, Namsos, Norway
| | - Aleksandr Ianevski
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Mathilde Resell
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Naris Pojskic
- Laboratory for Bioinformatics and Biostatistics, University of Sarajevo - Institute for Genetic Engineering and Biotechnology, Sarajevo, Bosnia and Herzegovina
| | - Hanne-Line Rabben
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Synne Geithus
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Yosuke Kodama
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Tomita Hiroyuki
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Denis Kainov
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Jon Erik Grønbech
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Department of Surgery, St. Olav's Hospital, Trondheim, Norway
| | - Yoku Hayakawa
- Department of Gastroenterology, Tokyo University Hospital, Tokyo, Japan
| | - Timothy C Wang
- Department of Digestive and Liver Diseases and Herbert Iring Comprehensive Cancer Center, Columbia University Medical Center, New York, USA
| | - Chun-Mei Zhao
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Duan Chen
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
| |
Collapse
|
|
7
|
Peng C, Xu X, Ouyang Y, Li Y, Lu N, Zhu Y, He C. Spatial Variation of the Gastrointestinal Microbiota in Response to Long-Term Administration of Vonoprazan in Mice With High Risk of Gastric Cancer. Helicobacter 2024; 29:e13117. [PMID: 39086007 DOI: 10.1111/hel.13117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 05/26/2024] [Accepted: 07/17/2024] [Indexed: 08/02/2024]
Abstract
BACKGROUND Vonoprazan, a potassium-competitive acid blocker, is superior to traditional proton pump inhibitor (PPI) in acid suppression and has been approved in the treatment of acid-related disorders. Accumulating evidence suggest associations between PPI use and gut microbiota, yet the effect of vonoprazan on GI microbiota is obscure. METHODS Transgenic FVB/N insulin-gastrin (INS-GAS) mice as a model of gastric cancer (GC) were administered vonoprazan by gavage every other day for 12 weeks. Stomachs were evaluated by histopathology, Ki-67 proliferation index, and inflammatory cytokines. The mucosal and lumen microbiota from stomach, jejunum, ileum, cecum, and feces were detected using 16S rRNA gene sequencing. RESULTS Higher incidence of intestinal metaplasia and epithelial proliferation were observed in the vonoprazan group than that in the control mice. Vonoprazan also elevated the gastric expression of proinflammatory cytokines, including TNF-α, IL-1β, and IL-6. Each mice comprised a unique microbiota composition that was consistent across different niches. The structure of GI microbiota changed dramatically after vonoprazan treatment with the stomach being the most disturbed segment. Vonoprazan administration shifted the gut microbiota toward the enrichment of pathogenic Streptococcus, Staphylococcus, Bilophila, and the loss of commensal Prevotella, Bifidobacterium, and Faecalibacterium. Interestingly, compared to the controls, microbial interactions were weaker in the stomach while stronger in the jejunum of the vonoprazan group. CONCLUSIONS Long-term vonoprazan treatment promoted gastric lesions in male INS-GAS mice, with the disequilibrium of GI microbiome. The clinical application of vonoprazan needs to be judicious particularly among those with high risk of GC.
Collapse
Affiliation(s)
- Chao Peng
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Xinbo Xu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yaobin Ouyang
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yu Li
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Nonghua Lu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Yin Zhu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Cong He
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| |
Collapse
|
|
8
|
Jiang W, Bai L, Zhang S, Cheng R. Endoscopic submucosal dissection (ESD) for gastritis cystica profunda (GCP) with early gastric cancer: A propensity score matching analysis. Heliyon 2024; 10:e29349. [PMID: 38601641 PMCID: PMC11004393 DOI: 10.1016/j.heliyon.2024.e29349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 04/04/2024] [Accepted: 04/05/2024] [Indexed: 04/12/2024] Open
Abstract
Background and aim Cystic dilatation of the gastric glands within the mucosal layer is the hallmark of the rare condition known as gastritis cystica profunda (GCP). Although it has been proved that GCP is the precursor lesion for early gastric cancer (EGC), the management strategy of GCP-related EGC is not well established.The purpose of this research was to determine if ESD is effective and safe for GCP-related EGC. Methods Patients with EGC who had ESD at Beijing Friendship Hospital between January 2015 and May 2023 were retrospectively included. All patients were divided into two groups: those with GCP-related EGC, and those with EGC alone. The two groups were matched 1:1 using the propensity score matching (PSM) method. Curative resection rate, postoperative adverse outcome rate (bleeding, perforation, stricture), and recurrence rate were the primary measures used to evaluate the efficacy and safety of ESD. Results There were a total of 386 participants (44 with GCP and 342 with EGC alone). Following PSM, 44 patients were paired and analyzed separately. Except for the presence of cysts in EUS (multiple/single/none cyst: 12/2/5 versus 1/0/25, P < 0.0001), there was no change in baseline characteristics, EUS appearance, or histology results between groups. Overall, there was no significant difference in curative resection rates between the GCP group (70.5 %) and the control group (81.8 %) (P = 0.211). Postoperative complications were comparative (9/44 vs 5/44, P = 0.244), as were rates of local recurrence (1/44 vs 0/44, P = 1.0), metachronous gastric cancer (1/44 vs 0/44, P = 1.0), and mortality (0/44 vs 0/44, P = 1.0). Conclusions Existence of cysts in EUS is a characteristic presentation to distinguish GCP-related EGC from EGC-alone lesions. ESD might be a safe and effective therapy for patients with GCP-related EGC.
Collapse
Affiliation(s)
| | | | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, PR China
| | - Rui Cheng
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, 100050, PR China
| |
Collapse
|
|
9
|
Privitera G, Williams JJ, De Salvo C. The Importance of Th2 Immune Responses in Mediating the Progression of Gastritis-Associated Metaplasia to Gastric Cancer. Cancers (Basel) 2024; 16:522. [PMID: 38339273 PMCID: PMC10854712 DOI: 10.3390/cancers16030522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 01/19/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Gastric cancer is one of the leading causes of cancer deaths worldwide, with chronic gastritis representing the main predisposing factor initiating the cascade of events leading to metaplasia and eventually progressing to cancer. A widely accepted classification distinguishes between autoimmune and environmental atrophic gastritis, mediated, respectively, by T cells promoting the destruction of the oxyntic mucosa, and chronic H. pylori infection, which has also been identified as the major risk factor for gastric cancer. The original dogma posits Th1 immunity as a main causal factor for developing gastritis and metaplasia. Recently, however, it has become evident that Th2 immune responses play a major role in the events causing chronic inflammation leading to tumorigenesis, and in this context, many different cell types and cytokines are involved. In particular, the activity of cytokines, such as IL-33 and IL-13, and cell types, such as mast cells, M2 macrophages and eosinophils, are intertwined in the process, promoting chronic gastritis-dependent and more diffuse metaplasia. Herein, we provide an overview of the critical events driving the pathology of this disease, focusing on the most recent findings regarding the importance of Th2 immunity in gastritis and gastric metaplasia.
Collapse
Affiliation(s)
- Giuseppe Privitera
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; (G.P.); (J.J.W.)
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, 20142 Milan, Italy
| | - Joseph J. Williams
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; (G.P.); (J.J.W.)
| | - Carlo De Salvo
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; (G.P.); (J.J.W.)
| |
Collapse
|
|
10
|
Ikeda S, Takahashi T, Tandoh T, Ushiyama K, Kida Y. Severe Anemia from Multiple Gastric Hyperplastic Polyps in a Hemodialysis Patient after Long-term Use of a Proton-pump Inhibitor. Intern Med 2024; 63:649-657. [PMID: 38432892 PMCID: PMC10982011 DOI: 10.2169/internalmedicine.2091-23] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 06/04/2023] [Indexed: 03/05/2024] Open
Abstract
A 90-year-old man on maintenance hemodialysis was admitted due to severe symptomatic anemia. Biopsies under esophagogastroduodenoscopy demonstrated that the cause of anemia was intermittent blood oozing from multiple gastric hyperplastic polyps. Even after successful eradication of Helicobacter pylori, he showed hypergastrinemia (480 pg/mL) owing to esomeprazole (proton-pump inhibitor) therapy for the past 4.5 years to treat reflux esophagitis. Seven months after we switched esomeprazole to famotidine (H2-receptor antagonist), those gastric polyps and anemia were remarkably ameliorated with lowered gastrin levels. This case indicates that long-term use of a proton-pump inhibitor triggers chronic hypergastrinemia, leading to gastric hyperplastic polyps and subsequent severe anemia.
Collapse
Affiliation(s)
- Shiyo Ikeda
- Department of Nephrology, Takashimadaira Chūō General Hospital, Japan
- Blood Purification Center, Takashimadaira Chūō General Hospital, Japan
| | - Toshiya Takahashi
- Department of Nephrology, Takashimadaira Chūō General Hospital, Japan
- Blood Purification Center, Takashimadaira Chūō General Hospital, Japan
| | - Toshitsugu Tandoh
- Department of Clinical Engineering, Takashimadaira Chūō General Hospital, Japan
| | - Kaori Ushiyama
- Blood Purification Center, Takashimadaira Chūō General Hospital, Japan
- Department of Nursing, Takashimadaira Chūō General Hospital, Japan
| | - Yujiro Kida
- Department of Nephrology, Takashimadaira Chūō General Hospital, Japan
- Blood Purification Center, Takashimadaira Chūō General Hospital, Japan
| |
Collapse
|
|
11
|
Nguyen TKC, Do HDK, Nguyen TLP, Pham TT, Mach BN, Nguyen TC, Pham TL, Katsande PM, Hong HA, Duong HT, Phan AN, Cutting SM, Vu MT, Nguyen VD. Genomic and vaccine preclinical studies reveal a novel mouse-adapted Helicobacter pylori model for the hpEastAsia genotype in Southeast Asia. J Med Microbiol 2024; 73. [PMID: 38235783 DOI: 10.1099/jmm.0.001786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2024] Open
Abstract
Introduction. Helicobacter pylori infection is a major global health concern, linked to the development of various gastrointestinal diseases, including gastric cancer. To study the pathogenesis of H. pylori and develop effective intervention strategies, appropriate animal pathogen models that closely mimic human infection are essential.Gap statement. This study focuses on the understudied hpEastAsia genotype in Southeast Asia, a region marked by a high H. pylori infection rate. No mouse-adapted model strains has been reported previously. Moreover, it recognizes the urgent requirement for vaccines in developing countries, where overuse of antimicrobials is fuelling the emergence of resistance.Aim. This study aims to establish a novel mouse-adapted H. pylori model specific to the hpEastAsia genotype prevalent in Southeast Asia, focusing on comparative genomic and histopathological analysis of pathogens coupled with vaccine preclinical studies.Methodology. We collected and sequenced the whole genome of clinical strains of H. pylori from infected patients in Vietnam and performed comparative genomic analyses of H. pylori strains in Southeast Asia. In parallel, we conducted preclinical studies to assess the pathogenicity of the mouse-adapted H. pylori strain and the protective effect of a new spore-vectored vaccine candidate on male Mlac:ICR mice and the host immune response in a female C57BL/6 mouse model.Results. Genome sequencing and comparison revealed unique and common genetic signatures, antimicrobial resistance genes and virulence factors in strains HP22 and HP34; and supported clarithromycin-resistant HP34 as a representation of the hpEastAsia genotype in Vietnam and Southeast Asia. HP34-infected mice exhibited gastric inflammation, epithelial erosion and dysplastic changes that closely resembled the pathology observed in human H. pylori infection. Furthermore, comprehensive immunological characterization demonstrated a robust host immune response, including both mucosal and systemic immune responses. Oral vaccination with candidate vaccine formulations elicited a significant reduction in bacterial colonization in the model.Conclusion. Our findings demonstrate the successful development of a novel mouse-adapted H. pylori model for the hpEastAsia genotype in Vietnam and Southeast Asia. Our research highlights the distinctive genotype and pathogenicity of clinical H. pylori strains in the region, laying the foundation for targeted interventions to address this global health burden.
Collapse
Affiliation(s)
- Thi Kim Cuc Nguyen
- Institute of Biotechnology and Environment, Nha Trang University, 2 Nguyen Dinh Chieu Street, Khanh Hoa, Vietnam
| | - Hoang Dang Khoa Do
- NTT Hi-tech Institute, Nguyen Tat Thanh University, 300A Nguyen Tat Thanh, Ho Chi Minh City, Vietnam
| | - Thi Lan Phuong Nguyen
- Institute of Vaccines and Biological Medicals (IVAC), 9 Pasteur Street, Nha Trang, Khanh Hoa, Vietnam
| | - Thu Thuy Pham
- Institute of Biotechnology and Environment, Nha Trang University, 2 Nguyen Dinh Chieu Street, Khanh Hoa, Vietnam
| | - Bao Ngoc Mach
- NTT Hi-tech Institute, Nguyen Tat Thanh University, 300A Nguyen Tat Thanh, Ho Chi Minh City, Vietnam
| | - Thi Chinh Nguyen
- Institute of Biotechnology and Environment, Nha Trang University, 2 Nguyen Dinh Chieu Street, Khanh Hoa, Vietnam
| | - Thi Lan Pham
- Institute of Biotechnology and Environment, Nha Trang University, 2 Nguyen Dinh Chieu Street, Khanh Hoa, Vietnam
| | - Paidamoyo M Katsande
- Department of Biological Sciences, Royal Holloway University of London, Egham, Surrey, TW20 0EX, UK
| | - Huynh Anh Hong
- Department of Biological Sciences, Royal Holloway University of London, Egham, Surrey, TW20 0EX, UK
| | - Huu Thai Duong
- Institute of Vaccines and Biological Medicals (IVAC), 9 Pasteur Street, Nha Trang, Khanh Hoa, Vietnam
| | - Anh N Phan
- School of Engineering, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
| | - Simon M Cutting
- Department of Biological Sciences, Royal Holloway University of London, Egham, Surrey, TW20 0EX, UK
| | - Minh Thiet Vu
- NTT Hi-tech Institute, Nguyen Tat Thanh University, 300A Nguyen Tat Thanh, Ho Chi Minh City, Vietnam
| | - Van Duy Nguyen
- Institute of Biotechnology and Environment, Nha Trang University, 2 Nguyen Dinh Chieu Street, Khanh Hoa, Vietnam
- School of Engineering, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
| |
Collapse
|
|
12
|
Brackman LC, Jung MS, Green EH, Joshi N, Revetta FL, McClain MS, Markham NO, Piazuelo MB, Scott Algood HM. IL-17 signaling protects against Helicobacter pylori-induced gastric cancer. Gut Microbes 2024; 16:2430421. [PMID: 39588838 PMCID: PMC11639209 DOI: 10.1080/19490976.2024.2430421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 09/19/2024] [Accepted: 11/12/2024] [Indexed: 11/27/2024] Open
Abstract
Helicobacter pylori infection is the predominant risk factor for the development of gastric cancer. Risk is enhanced by specific H. pylori virulence factors, diet, and the inflammatory response. Chronic activation of T helper (Th) 1 and Th17 pathways contributes to prolonged inflammation; yet, higher expression of IL-17 receptor (IL-17RA) is a favorable prognostic marker for survival after gastric cancer diagnosis. The protective impact of IL-17RA signaling is not understood. To investigate if IL-17RA signaling protects during H. pylori-induced carcinogenesis, the transgenic InsGAStg/tg mouse, which is prone to H. pylori-induced gastric cancer, was utilized. InsGAStg/tg mice and InsGAStg/tgIl17ra-/- mice were infected with a cag type 4 secretion system (T4SS) positive H. pylori strain for up to 6 months. Six weeks post-infection, IL-17RA deficiency led to increased bacterial burden, increased gastritis, and development of lymphoid follicles. Increased inflammation was associated with heightened cellular proliferation and earlier loss of parietal and chief cells in InsGAStg/tgIl17ra-/- mice. Gastric cancers developed more frequently by 3- and 6-months post-infection in H. pylori-infected InsGAStg/tgIl17ra-/- mice compared to InsGAStg/tg mice. Chronic inflammation was exacerbated with IL-17RA deficiency, characterized by elevated Th1/Th17 cytokines, increased B cell infiltration, and enhanced IgA production, despite reduced expression of the polymeric immunoglobulin receptor. Further, paragastric lymph nodes of InsGAStg/tgIl17ra-/- mice were enlarged relative to controls and displayed altered gene expression profiles. Increased inflammation was accompanied by a significant increase in Cybb expression, which encodes NADPH oxidase 2, suggesting that increased oxidative damage may occur in the absence of IL-17RA. Further, there is increased phosphorylation of histone 2AX in IL-17RA deficient mice, indicating that the DNA damage response is highly activated. These data suggest that IL-17RA signaling activates a protective pathway to prevent excessive inflammation which otherwise can lead to increased oxidative stress, DNA damage, and drive gastric carcinogenesis after H. pylori infection.
Collapse
Affiliation(s)
- Lee C. Brackman
- Department of Medicine, Division of Infectious Disease, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Matthew S. Jung
- Department of Medicine, Division of Infectious Disease, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Emily H. Green
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Vanderbilt Institute of Infection, Immunity, and Inflammation (VI4), Vanderbilt University Medical Center, Nashville, TN, USA
| | - Nikhita Joshi
- Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, USA
- School of Biological Sciences, Vanderbilt University, Nashville, TN, USA
| | - Frank L. Revetta
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Mark S. McClain
- Department of Medicine, Division of Infectious Disease, Vanderbilt University School of Medicine, Nashville, TN, USA
- Vanderbilt Institute of Infection, Immunity, and Inflammation (VI4), Vanderbilt University Medical Center, Nashville, TN, USA
| | - Nicholas O. Markham
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Vanderbilt Institute of Infection, Immunity, and Inflammation (VI4), Vanderbilt University Medical Center, Nashville, TN, USA
- Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, USA
- Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - M. Blanca Piazuelo
- Department of Medicine, Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Holly M. Scott Algood
- Department of Medicine, Division of Infectious Disease, Vanderbilt University School of Medicine, Nashville, TN, USA
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Vanderbilt Institute of Infection, Immunity, and Inflammation (VI4), Vanderbilt University Medical Center, Nashville, TN, USA
- Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, USA
| |
Collapse
|
|
13
|
Noto JM, Piazuelo MB, Romero-Gallo J, Delgado AG, Suarez G, Akritidou K, Girod Hoffman M, Roa JC, Taylor CT, Peek RM. Targeting hypoxia-inducible factor-1 alpha suppresses Helicobacter pylori-induced gastric injury via attenuation of both cag-mediated microbial virulence and proinflammatory host responses. Gut Microbes 2023; 15:2263936. [PMID: 37828903 PMCID: PMC10578190 DOI: 10.1080/19490976.2023.2263936] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 09/24/2023] [Indexed: 10/14/2023] Open
Abstract
Helicobacter pylori-induced inflammation is the strongest known risk factor for gastric adenocarcinoma. Hypoxia-inducible factor-1 (HIF-1α) is a key transcriptional regulator of immunity and carcinogenesis. To examine the role of this mediator within the context of H. pylori-induced injury, we first demonstrated that HIF-1α levels were significantly increased in parallel with the severity of gastric lesions in humans. In interventional studies targeting HIF-1α, H. pylori-infected mice were treated ± dimethyloxalylglycine (DMOG), a prolyl hydroxylase inhibitor that stabilizes HIF-1α. H. pylori significantly increased proinflammatory chemokines/cytokines and inflammation in vehicle-treated mice; however, this was significantly attenuated in DMOG-treated mice. DMOG treatment also significantly decreased function of the H. pylori type IV secretion system (T4SS) in vivo and significantly reduced T4SS-mediated NF-κB activation and IL-8 induction in vitro. These results suggest that prolyl hydroxylase inhibition protects against H. pylori-mediated pathologic responses, and is mediated, in part, via attenuation of H. pylori cag-mediated virulence and suppression of host proinflammatory responses.
Collapse
Affiliation(s)
- Jennifer M. Noto
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - M. Blanca Piazuelo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Judith Romero-Gallo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Alberto G. Delgado
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Giovanni Suarez
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | | | - Juan Carlos Roa
- Department of Pathology, School of Medicine, Center for Cancer Prevention and Control (CECAN), Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Cormac T. Taylor
- School of Medicine, Systems Biology Ireland and The Conway Institute, University College Dublin, Dublin, Ireland
| | - Richard M. Peek
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| |
Collapse
|
|
14
|
Waldum H, Mjønes P. The central role of gastrin in gastric cancer. Front Oncol 2023; 13:1176673. [PMID: 37941554 PMCID: PMC10628637 DOI: 10.3389/fonc.2023.1176673] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 09/19/2023] [Indexed: 11/10/2023] Open
Abstract
The prevalence of gastric cancer has markedly declined, but due to the high mortality rates associated with gastric cancer, it is still a serious disease. The preferred classification of gastric cancer is according to Lauren into either the intestinal type, which has a glandular growth pattern, or the diffuse type, which does not have glandular structures. Both types have been classified as adenocarcinomas, with the latter type based on periodic acid-Schiff (PAS) positivity presumed to reflect mucin. However, the presence of mucin in the diffuse type, in contrast to neuroendocrine/enterochromaffin-like (ECL) cell markers, has not been confirmed by immunohistochemistry and in situ hybridization. The ECL cells are probably prone to becoming cancerous because they do not express E-cadherin. Gastric cancer is unique in that a bacterium, Helicobacter pylori, is thought to be its main cause. H. pylori predisposes infected individuals to cancer only after having caused oxyntic atrophy leading to gastric hypoacidity and hypergastrinemia. No single H. pylori factor has been convincingly proved to be carcinogenic. It is probable that gastrin is the pathogenetic factor for gastric cancer due to H. pylori, autoimmune gastritis, and long-term prolonged inhibition of gastric acid secretion. Hypergastrinemia induces ECL cell hyperplasia, which develops into neuroendocrine tumors (NETs) and then into neuroendocrine carcinomas in rodents, a sequence that has also been described in humans. During carcinogenesis, the tumor cells lose specific traits, requiring that sensitive methods be used to recognize their origin. Gastric cancer occurrence may hopefully be prevented by H. pylori eradication at a young age, and by the reduced use of inhibitors of acid secretion and use of a gastrin antagonist in those with previous long-term H. pylori infection and those with autoimmune gastritis.
Collapse
Affiliation(s)
- Helge Waldum
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Patricia Mjønes
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Pathology, St. Olav’s Hospital – Trondheim University Hospital, Trondheim, Norway
| |
Collapse
|
|
15
|
Gašenko E, Bogdanova I, Sjomina O, Aleksandraviča I, Kiršners A, Ancāns G, Rudzīte D, Vangravs R, Sīviņš A, Škapars R, Tzivian L, Polaka I, Folkmanis V, Leja M. Assessing the utility of pepsinogens and gastrin-17 in gastric cancer detection. Eur J Cancer Prev 2023; 32:478-484. [PMID: 36912185 DOI: 10.1097/cej.0000000000000791] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2023]
Abstract
OBJECTIVES The aim of the study was to determine the proportion of gastric cancer patients with decreased levels of pepsinogen and gastrin-17 in plasma, with the goal of providing indirect evidence of the sensitivity of these biomarkers when applied in a cancer screening setting. METHODS The levels of pepsinogens I and II, gastrin-17, and Helicobacter pylori immunoglobulin antibodies in plasma samples of gastric cancer patients were evaluated using the GastroPanel test system (Biohit Oyj, Helsinki, Finland). A decreased level of the pepsinogen I/II ratio was defined as less than three, while a decrease in gastrin-17 was defined as less than 1 pmol/L. Univariate analysis using non-parametric tests was used to investigate differences between normal and low concentrations of biomarkers. RESULTS In total, 481 plasma samples from patients (59.9% male) with a median age of 64 years (ranging from 27 to 88 years) were analyzed. Out of the 400 cases of gastric cancer (83.2% of the total), 182 were categorized as the intestinal type, 141 as the diffuse type, 60 as the mixed type, and 17 as indeterminate according to the Lauren classification system. The H. pylori immunoglobulin test was positive in 74.0% of the patients. Pepsinogen I/II ratio was decreased in 32.4% (36.8% of the intestinal type); gastrin-17 in 12.3% (10.1% of the antral region) of all cases. CONCLUSION The majority of gastric cancer patients had normal levels of pepsinogen and gastrin-17, suggesting that these biomarkers have limited application as screening tools in the Caucasian population.
Collapse
Affiliation(s)
| | | | - Olga Sjomina
- Department of Internal Medicine, Riga East University Hospital
| | - Ilona Aleksandraviča
- Faculty of Medicine, Institute of Clinical and Preventive Medicine, University of Latvia, Riga
| | - Arnis Kiršners
- Faculty of Medicine, Institute of Clinical and Preventive Medicine, University of Latvia, Riga
| | - Guntis Ancāns
- Department of Surgery, Jēkabpils Regional Hospital, Jēkabpils
| | | | - Reinis Vangravs
- Faculty of Medicine, Institute of Clinical and Preventive Medicine, University of Latvia, Riga
| | - Armands Sīviņš
- Department of Abdominal and Soft Tissue Surgery, Clinic of Oncological Surgery
| | - Roberts Škapars
- Department of Abdominal and Soft Tissue Surgery, Clinic of Oncological Surgery
| | - Lilian Tzivian
- Faculty of Medicine, Institute of Clinical and Preventive Medicine, University of Latvia, Riga
| | - Inese Polaka
- Faculty of Medicine, Institute of Clinical and Preventive Medicine, University of Latvia, Riga
| | - Valdis Folkmanis
- Faculty of Medicine, Institute of Clinical and Preventive Medicine, University of Latvia, Riga
| | - Mārcis Leja
- Department of Research, Riga East University Hospital, Riga, Latvia
| |
Collapse
|
|
16
|
Bugaytsova JA, Piddubnyi A, Tkachenko I, Rakhimova L, Edlund JO, Thorell K, Marcotte H, Lundquist A, Schön K, Lycke N, Suerbaum S, Schulz C, Malfertheiner P, Hansen LM, Solnick JV, Moskalenko R, Hammarström L, Borén T. Vaccination with Helicobacter pylori attachment proteins protects against gastric cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.25.542131. [PMID: 37461695 PMCID: PMC10349987 DOI: 10.1101/2023.05.25.542131] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/24/2023]
Abstract
Most cases of gastric cancer are caused by chronic Helicobacter pylori infection, but the lack of early onco-diagnostics and a high risk for antibiotic resistance hampers early intervention through eradication of H. pylori infection by antibiotics. We reported on a protective mechanism where H. pylori gastric mucosal attachment can be reduced by natural antibodies that block the binding of its attachment protein BabA. Here we show that challenge infection with H. pylori induced response of such blocking antibodies in both human volunteers and in rhesus macaques, that mucosal vaccination with BabA protein antigen induced blocking antibodies in rhesus macaques, and that vaccination in a mouse model induced blocking antibodies that reduced gastric mucosal inflammation, preserved the gastric juice acidity, and fully protected the mice from gastric cancer caused by H. pylori.
Collapse
Affiliation(s)
- Jeanna A. Bugaytsova
- Department Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, 40022 Sumy, Ukraine
| | - Artem Piddubnyi
- Department Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, 40022 Sumy, Ukraine
- Department of Pathology, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Iryna Tkachenko
- Department Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Department of Public Health, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Lena Rakhimova
- Department Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Present address: Department of Odontology, Umea University, SE90187 Umeå, Sweden
| | - Johan Olofsson Edlund
- Department Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- The Biochemical Imaging Center Umeå (BICU), Umeå University, SE90187 Umeå, Sweden
| | - Kaisa Thorell
- Department of Chemistry and Molecular Biology, University of Gothenburg, SE40530, Gothenburg, Sweden
| | - Harold Marcotte
- Department Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- Department of Biosciences and Nutrition, Karolinska Institutet, SE14183, Huddinge, Sweden
| | - Anders Lundquist
- Department of Statistics, USBE, Umeå University, SE90187 Umeå, Sweden
- Umeå Center for Functional Brain Imaging, Umeå University, SE90187 Umeå, Sweden
| | - Karin Schön
- Department of Microbiology & Immunology, University of Gothenburg, Gothenburg, Sweden
| | - Nils Lycke
- Department of Microbiology & Immunology, University of Gothenburg, Gothenburg, Sweden
- Deceased, December 2022
| | - Sebastian Suerbaum
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, 30625 Hannover, Germany
- German Center for Infection Research (DZIF), Hannover-Braunschweig Site, 30625 Hannover, Germany
- Max von Pettenkofer Institute of Hygiene and Medical Microbiology, LMU Munich, 80336 Munich, Germany
- German Center for Infection Research (DZIF), Munich Site, 80336 Munich, Germany
| | - Christian Schulz
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Lori M. Hansen
- Departments of Medicine and Microbiology and Immunology, Center for Immunology and Infectious Disease, University of California Davis, Davis, CA 95616, USA
| | - Jay V. Solnick
- Departments of Medicine and Microbiology and Immunology, Center for Immunology and Infectious Disease, University of California Davis, Davis, CA 95616, USA
- California National Primate Research Center, University of California Davis School of Medicine, Davis, CA 95616, USA
| | - Roman Moskalenko
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, 40022 Sumy, Ukraine
- Department of Pathology, Medical Institute, Sumy State University, 40007 Sumy, Ukraine
| | - Lennart Hammarström
- Department of Biosciences and Nutrition, Karolinska Institutet, SE14183, Huddinge, Sweden
| | - Thomas Borén
- Department Medical Biochemistry and Biophysics, Umeå University, SE90187 Umeå, Sweden
- SUMEYA, The Ukrainian-Swedish Research Center, Sumy State University, 40022 Sumy, Ukraine
- Lead contact
| |
Collapse
|
|
17
|
Li ML, Hong XX, Zhang WJ, Liang YZ, Cai TT, Xu YF, Pan HF, Kang JY, Guo SJ, Li HW. Helicobacter pylori plays a key role in gastric adenocarcinoma induced by spasmolytic polypeptide-expressing metaplasia. World J Clin Cases 2023; 11:3714-3724. [PMID: 37383139 PMCID: PMC10294147 DOI: 10.12998/wjcc.v11.i16.3714] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 03/01/2023] [Accepted: 04/23/2023] [Indexed: 06/02/2023] Open
Abstract
Heliobacter pylori (H. pylori), a group 1 human gastric carcinogen, is significantly associated with chronic gastritis, gastric mucosal atrophy, and gastric cancer. Approximately 20% of patients infected with H. pylori develop precancerous lesions, among which metaplasia is the most critical. Except for intestinal metaplasia (IM), which is characterized by goblet cells appearing in the stomach glands, one type of mucous cell metaplasia, spasmolytic polypeptide-expressing metaplasia (SPEM), has attracted much attention. Epidemiological and clinicopathological studies suggest that SPEM may be more strongly linked to gastric adenocarcinoma than IM. SPEM, characterized by abnormal expression of trefoil factor 2, mucin 6, and Griffonia simplicifolia lectin II in the deep glands of the stomach, is caused by acute injury or inflammation. Although it is generally believed that the loss of parietal cells alone is a sufficient and direct cause of SPEM, further in-depth studies have revealed the critical role of immunosignals. There is controversy regarding whether SPEM cells originate from the transdifferentiation of mature chief cells or professional progenitors. SPEM plays a functional role in the repair of gastric epithelial injury. However, chronic inflammation and immune responses caused by H. pylori infection can induce further progression of SPEM to IM, dysplasia, and adenocarcinoma. SPEM cells upregulate the expression of whey acidic protein 4-disulfide core domain protein 2 and CD44 variant 9, which recruit M2 macrophages to the wound. Studies have revealed that interleukin-33, the most significantly upregulated cytokine in macrophages, promotes SPEM toward more advanced metaplasia. Overall, more effort is needed to reveal the specific mechanism of SPEM malignant progression driven by H. pylori infection.
Collapse
Affiliation(s)
- Mian-Li Li
- Department of Gastroenterology, Shenzhen Hospital of Integrated, Traditional Chinese and Western Medicine, Shenzhen 518033, Guangdong Province, China
| | - Xin-Xin Hong
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Wei-Jian Zhang
- Science and Technology Innovation Center, Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Yi-Zhong Liang
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Tian-Tian Cai
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Yi-Fei Xu
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Hua-Feng Pan
- Science and Technology Innovation Center, Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Jian-Yuan Kang
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Shao-Ju Guo
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Hai-Wen Li
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| |
Collapse
|
|
18
|
Development of amplified luminescent proximity homogeneous assay for quantitation of gastrin-17. Anal Biochem 2023; 662:115016. [PMID: 36502889 DOI: 10.1016/j.ab.2022.115016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022]
Abstract
A highly sensitive and convenient amplified luminescent proximity homogeneous assay (AlphaLISA) method with high throughput and automation potential was developed for quantitation of serum Gastrin-17 (G-17) levels, which can facilitate the early diagnosis of atrophic gastritis in people at high risk of gastric cancer using a non-invasive approach. In this study, donor and acceptor beads with modified carboxyl groups on the surface were directly coupled to anti-G-17 antibodies through activation was proposed for application in the development of the new AlphaLISA, which can effectively simplify the steps and shorten the reaction time to achieve faster detection. Therefore, the G-17-AlphaLISA only needs to react for 15 min to obtain good analysis results. The proposed method has a wider detection range than commercial enzyme-linked immunosorbent assay (ELISA) kits (0.12-112.8 pmol/L > 0.5-40 pmol/L). In addition, results of G-17-AlphaLISA and ELISA had good correlation and agreement (ρ = 0.936). Importantly, the developed method may be more suitable for the large-scale screening of people at high risk for gastric cancer than traditional ELISA and provides a novel solution for other biomarkers that require accurate, highly sensitive, and high throughput detection.
Collapse
|
|
19
|
Karpiński TM, Ożarowski M, Stasiewicz M. Carcinogenic microbiota and its role in colorectal cancer development. Semin Cancer Biol 2022; 86:420-430. [PMID: 35090978 DOI: 10.1016/j.semcancer.2022.01.004] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 12/30/2021] [Accepted: 01/13/2022] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of the most common malignancies worldwide. The main risk factors for CRC are family history of colon or rectal cancer, familial polyposis syndrome or hereditary nonpolyposis, and chronic inflammatory bowel diseases (ulcerative colitis and Crohn's disease). Recent studies show that the gastrointestinal microbiota play a significant role in colorectal carcinogenesis. In this review we present the microorganisms, whose influence on the development of CRC has been proven: Bacteroides fragilis, Clostridioides and Clostridium spp., Enterococcus faecalis, Escherichia coli, Fusobacterium nucleatum, Helicobacter pylori, Peptostreptococcus anaerobius, Streptococcus bovis group, and sulfate-reducing bacteria. Moreover, the carcinogenic mechanisms of action mediated by the above bacteria are laid out.
Collapse
Affiliation(s)
- Tomasz M Karpiński
- Chair and Department of Medical Microbiology, Poznań University of Medical Sciences, Wieniawskiego 3, 61-712 Poznań, Poland.
| | - Marcin Ożarowski
- Department of Biotechnology, Institute of Natural Fibres and Medicinal Plants - National Research Institute, Wojska Polskiego 71b, 60-630 Poznań, Poland.
| | - Mark Stasiewicz
- Research Group of Medical Microbiology, Chair and Department of Medical Microbiology, Poznań University of Medical Sciences, Wieniawskiego 3, 61-712 Poznań, Poland.
| |
Collapse
|
|
20
|
Zeng Y, Jin RU. Molecular pathogenesis, targeted therapies, and future perspectives for gastric cancer. Semin Cancer Biol 2022; 86:566-582. [PMID: 34933124 DOI: 10.1016/j.semcancer.2021.12.004] [Citation(s) in RCA: 93] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 11/29/2021] [Accepted: 12/11/2021] [Indexed: 01/27/2023]
Abstract
Gastric cancer is a major source of global cancer mortality with limited treatment options and poor patient survival. As our molecular understanding of gastric cancer improves, we are now beginning to recognize that these cancers are a heterogeneous group of diseases with incredibly unique pathogeneses and active oncogenic pathways. It is this molecular diversity and oftentimes lack of common oncogenic driver mutations that bestow the poor treatment responses that oncologists often face when treating gastric cancer. In this review, we will examine the treatments for gastric cancer including up-to-date molecularly targeted therapies and immunotherapies. We will then review the molecular subtypes of gastric cancer to highlight the diversity seen in this disease. We will then shift our discussion to basic science and gastric cancer mouse models as tools to study gastric cancer molecular heterogeneity. Furthermore, we will elaborate on a molecular process termed paligenosis and the cyclical hit model as key events during gastric cancer initiation that impart nondividing mature differentiated cells the ability to re-enter the cell cycle and accumulate disparate genomic mutations during years of chronic inflammation and injury. As our basic science understanding of gastric cancer advances, so too must our translational and clinical efforts. We will end with a discussion regarding single-cell molecular analyses and cancer organoid technologies as future translational avenues to advance our understanding of gastric cancer heterogeneity and to design precision-based gastric cancer treatments. Elucidation of interpatient and intratumor heterogeneity is the only way to advance future cancer prevention, diagnoses and treatment.
Collapse
Affiliation(s)
- Yongji Zeng
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, USA
| | - Ramon U Jin
- Section of Hematology/Oncology, Department of Medicine, Baylor College of Medicine, Houston, USA.
| |
Collapse
|
|
21
|
Baranovskiy AY, Tcvetkova TL. Risk factors of gastric cancer as a basis for the development of a prognostic questionnaire for the register of patients with precancerous gastroduodenal diseases. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2022:29-38. [DOI: 10.31146/1682-8658-ecg-205-9-29-38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
The article is a critical analysis of the world scientific literature devoted to the search for risk factors for stomach cancer for the timely prognosis of this disease and the implementation of cancer prevention measures. The paper presents data from numerous studies to determine the role of environmental factors, including unfavorable ecology, as well as gender, age, smoking, alcohol abuse. The authors’ opinions are presented on the essential role of the alimentary factor in the genesis of neoplasms in the stomach, including the predominance of animal fats in food, the abuse of overcooked, pickled foods rich in nitrosoamines, foods saturated with spices, the use of too hot food, the use of foods infected with mycotoxins in nutrition. The role of environmental factors in the prognosis of gastric cancer is noted: the state of secretory activity of the stomach, the dynamics of inflammatory and atrophic processes in the mucous membrane. A special role for the prognosis of stomach cancer is assigned by many authors to the pyloric helicobacter, as well as the quantitative indicator of glycated blood hemoglobin and its dynamics. The significance of genetic changes in the genesis of gastric cancer and their role as prognostic factors of the disease is ambiguous. The article draws attention to the multidirectional results of many authors in understanding a large number of factors they have studied that could be used as prognostic witnesses of stomach cancer. The expediency of searching for the most significant regional factors for the prognosis of gastric cancer is substantiated, on the basis of which it is very important to create registers of patients with precancerous diseases of the stomach for the organization and implementation of personalized and effective measures of cancer prevention.
Collapse
|
|
22
|
Occurrences and phenotypes of RIPK3-positive gastric cells in Helicobacter pylori infected gastritis and atrophic lesions. Dig Liver Dis 2022; 54:1342-1349. [PMID: 35514018 DOI: 10.1016/j.dld.2022.04.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 04/20/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND Research evidences suggest that diverse forms of programmed cell death (PCD) are involved in the helicobacter pylori (H. pylori)-induced gastric inflammation and disorders. AIMS To characterize occurrences and phenotypes of necroptosis in gastric cells in H. pylori infected gastritis and atrophic specimens. METHODS Occurrences and phenotypes of necroptosis in gastric cells were immunohistochemically characterized with receptor-interacting protein kinase 3 (RIPK3) antibody in both human H. pylori infected gastric gastritis, atrophic specimens, and transgenic mice. RESULTS Increased populations of RIPK3-positive cells were observed in both gastric glands and lamina propria in H. pylori infected human oxyntic gastritis and atrophic specimens. Phenotypic analysis revealed that many RIPK3-positive cells were H + K+ ATPase-positive parietal cells in the gastric glands and were predominantly CD3-positive T lymphocytes, CD68-positive macrophages, and SMA-alpha-positive stromal cells in the lamina propria. Furthermore, we found an increased expression of RIPK3-positive gastric glandular cells along with the histological process of hyperplasia-atrophy-dysplasia progression in hypergastrinemic INS-GAS mice. CONCLUSIONS An increased population of RIPK3-positive cells was observed in several types of gastric cells, future studies that define the effects and mechanisms of PCD implicated in the development of H. pylori induced gastric disorders are needed.
Collapse
|
|
23
|
Mommersteeg MC, Yu BT, van den Bosch TPP, von der Thüsen J, Kuipers EJ, Doukas M, Spaander M, Peppelenbosch MP, Fuhler GM. Constitutive programmed death ligand 1 expression protects gastric G-cells from Helicobacter pylori-induced inflammation. Helicobacter 2022; 27:e12917. [PMID: 35899973 PMCID: PMC9542424 DOI: 10.1111/hel.12917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 05/20/2022] [Accepted: 06/23/2022] [Indexed: 12/09/2022]
Abstract
INTRODUCTION Gastric intestinal metaplasia (GIM) is a premalignant lesion, highly associated with Helicobacter pylori infection. Previous studies have shown that H. pylori is able to induce the expression of programmed death ligand 1 (PD-L1), an inhibitory immune modulator, in gastric cells. Our aim was to investigate whether tissues from GIM patients may exploit PD-L1 expression upon H. pylori infection to evade immunosurveillance. METHODS Immunohistochemistry was performed for PD-L1 and enteroendocrine markers somatostatin and gastrin on samples derived from a cohort of patients with known GIM, both before and after H. pylori eradication. To determine the identity of any observed PD-L1-positive cells, we performed multiplex immunofluorescent staining and analysis of single-cell sequencing data. RESULTS GIM tissue was rarely positive for PD-L1. In normal glands from GIM patients, PD-L1 was mainly expressed by gastrin-positive G-cells. While the D-cell and G-cell compartments were both diminished 2-fold (p = .015 and p = .01, respectively) during H. pylori infection in the normal antral tissue of GIM patients, they were restored 1 year after eradication. The total number of PD-L1-positive cells was not affected by H. pylori, but the percentage of PD-L1-positive G-cells was 30% higher in infected subjects (p = .011), suggesting that these cells are preferentially rescued from destruction. CONCLUSIONS Antral G-cells frequently express PD-L1 during homeostasis. G-cells seem to be protected from H. pylori-induced immune destruction by PD-L1 expression. GIM itself does not express PD-L1 and is unlikely to escape immunosurveillance via expression of PD-L1.
Collapse
Affiliation(s)
- Michiel C. Mommersteeg
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | - Bing Ting Yu
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | | | | | - Ernst J. Kuipers
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | - Michael Doukas
- Department of PathologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | - Manon C. W. Spaander
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | - Maikel P. Peppelenbosch
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamThe Netherlands
| | - Gwenny M. Fuhler
- Department of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamThe Netherlands
| |
Collapse
|
|
24
|
Kwon SK, Park JC, Kim KH, Yoon J, Cho Y, Lee B, Lee JJ, Jeong H, Oh Y, Kim SH, Lee SD, Hwang BR, Chung Y, Kim JF, Nam KT, Lee YC. Human gastric microbiota transplantation recapitulates premalignant lesions in germ-free mice. Gut 2022; 71:1266-1276. [PMID: 34389621 DOI: 10.1136/gutjnl-2021-324489] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 07/28/2021] [Indexed: 12/26/2022]
Abstract
OBJECTIVE Gastric cancer (GC) is a leading cause of cancer-related mortality. Although microbes besides Helicobacter pylori may also contribute to gastric carcinogenesis, wild-type germ-free (GF) mouse models investigating the role of human gastric microbiota in the process are not yet available. We aimed to evaluate the histopathological features of GF mouse stomachs transplanted with gastric microbiota from patients with different gastric disease states and their relationships with the microbiota. DESIGN Microbiota profiles in corpus and antrum tissues and gastric fluid from 12 patients with gastric dysplasia or GC were analysed. Thereafter, biopsied corpus and antrum tissues and gastric fluid from patients (n=15 and n=12, respectively) with chronic superficial gastritis, intestinal metaplasia or GC were inoculated into 42 GF C57BL/6 mice. The gastric microbiota was analysed by amplicon sequencing. Histopathological features of mouse stomachs were analysed immunohistochemically at 1 month after inoculation. An independent set of an additional 15 GF mice was also analysed at 1 year. RESULTS The microbial community structures of patients with dysplasia or GC in the corpus and antrum were similar. The gastric microbiota from patients with intestinal metaplasia or GC selectively colonised the mouse stomachs and induced premalignant lesions: loss of parietal cells and increases in inflammation foci, in F4/80 and Ki-67 expression, and in CD44v9/GSII lectin expression. Marked dysplastic changes were noted at 1 year post inoculation. CONCLUSION Major histopathological features of premalignant changes are reproducible in GF mice transplanted with gastric microbiota from patients with intestinal metaplasia or GC. Our results suggest that GF mice are useful for analysing the causality of associations reported in human gastric microbiome studies.
Collapse
Affiliation(s)
- Soon-Kyeong Kwon
- Department of Systems Biology, Division of Life Sciences, and Institute for Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.,Division of Applied Life Science (Brain Korea 21), Gyeongsang National University, Jinju, Republic of Korea
| | - Jun Chul Park
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kwang H Kim
- Severance Biomedical Science Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jaekyung Yoon
- Department of Systems Biology, Division of Life Sciences, and Institute for Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Yejin Cho
- Severance Biomedical Science Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Buhyun Lee
- Severance Biomedical Science Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jin-Jae Lee
- Severance Biomedical Science Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.,Department of Life Science, Hallym University, Chuncheon, Republic of Korea
| | - Haengdueng Jeong
- Severance Biomedical Science Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yeseul Oh
- Severance Biomedical Science Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung-Hee Kim
- Severance Biomedical Science Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - So Dam Lee
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Bo Ram Hwang
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yusook Chung
- Department of Systems Biology, Division of Life Sciences, and Institute for Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
| | - Jihyun F Kim
- Department of Systems Biology, Division of Life Sciences, and Institute for Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea .,Strategic Initiative for Microbiomes in Agriculture and Food, Yonsei University, Seoul, Republic of Korea
| | - Ki Taek Nam
- Severance Biomedical Science Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong Chan Lee
- Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| |
Collapse
|
|
25
|
Vartanoglu Aktokmakyan T, Tokocin M, Bugdayci N, Tokocin O, Cay T, Gunes A, Solmaz A, Gulcicek OB, Celik A, Celebi F. Metabolic and Histopathological Effects of Mini Gastric By-Pass: An Experimental Animal Model. Bariatr Surg Pract Patient Care 2022. [DOI: 10.1089/bari.2021.0116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
| | - Merve Tokocin
- Department of General Surgery, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Nihat Bugdayci
- Department of General Surgery, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Onur Tokocin
- Department of Emergency Surgery, Kagithane State Hospital, Istanbul, Turkey
| | - Tugce Cay
- Department of Pathology, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Aysegul Gunes
- Department of Biochemistry, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Ali Solmaz
- Department of General Surgery, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Osman Bilgin Gulcicek
- Department of General Surgery, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Atilla Celik
- Department of General Surgery, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkey
| | - Fatih Celebi
- Department of General Surgery, Istanbul Bagcilar Training and Research Hospital, Istanbul, Turkey
| |
Collapse
|
|
26
|
Puri P, Grimmett G, Faraj R, Gibson L, Gilbreath E, Yoder BK. Elevated Protein Kinase A Activity in Stomach Mesenchyme Disrupts Mesenchymal-epithelial Crosstalk and Induces Preneoplasia. Cell Mol Gastroenterol Hepatol 2022; 14:643-668.e1. [PMID: 35690337 PMCID: PMC9421585 DOI: 10.1016/j.jcmgh.2022.06.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 05/31/2022] [Accepted: 06/01/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Mesenchymal-epithelial crosstalk (MEC) in the stomach is executed by pathways such as bone morphogenetic protein (BMP) and extracellular signal-regulated kinase (ERK). Mis-regulation of MEC disrupts gastric homeostasis and causes tumorigenesis. Protein Kinase A (PKA) crosstalks with BMP and ERK signaling; however, PKA function(s) in stomach development and homeostasis remains undefined. METHODS We generated a novel Six2-Cre+/-PKAcαRfl/wt (CA-PKA) mouse in which expression of constitutive-active PKAcαR was induced in gastric mesenchyme progenitors. Lineage tracing determined spatiotemporal activity of Six2-Cre in the stomach. For phenotyping CA-PKA mice histological, co-immunofluorescence, immunoblotting, mRNA sequencing, and bioinformatics analyses were performed. RESULTS Lineage tracing showed that Six2-Cre activity in the stomach is restricted to the mesenchymal compartment. CA-PKA mice showed disruption of gastric homeostasis characterized by aberrant mucosal development and epithelial hyperproliferation; ultimately developing multiple features of gastric corpus preneoplasia including decreased parietal cells, mucous cell hyperplasia, spasmolytic peptide expressing metaplasia with intestinal characteristics, and dysplastic and invasive cystic glands. Furthermore, mutant corpus showed marked chronic inflammation characterized by infiltration of lymphocytes and myeloid-derived suppressor cells along with the upregulation of innate and adaptive immune system components. Striking upregulation of inflammatory mediators and STAT3 activation was observed. Mechanistically, we determined there is an activation of ERK1/2 and downregulation of BMP/SMAD signaling characterized by marked upregulation of BMP inhibitor gremlin 1. CONCLUSIONS We report a novel role of PKA signaling in gastric MEC execution and show that PKA activation in the gastric mesenchyme drives preneoplasia by creating a proinflammatory and proproliferative microenvironment associated with the downregulation of BMP/SMAD signaling and activation of ERK1/2.
Collapse
Affiliation(s)
- Pawan Puri
- Department of Biomedical Sciences, Tuskegee University College of Veterinary Medicine, Tuskegee, Alabama,Correspondence Address correspondence to: Pawan Puri, DVM, PhD, Department of Biomedical Sciences, Tuskegee University College of Veterinary Medicine, A310 Patterson Hall, Tuskegee, AL 36088; tel. (334) 724-4486; fax: (334) 727-8177.
| | - Garfield Grimmett
- Department of Biomedical Sciences, Tuskegee University College of Veterinary Medicine, Tuskegee, Alabama
| | - Rawah Faraj
- Department of Biomedical Sciences, Tuskegee University College of Veterinary Medicine, Tuskegee, Alabama
| | - Laurielle Gibson
- Department of Biomedical Sciences, Tuskegee University College of Veterinary Medicine, Tuskegee, Alabama
| | - Ebony Gilbreath
- Department of Pathobiology, College of Veterinary Medicine, Tuskegee University, Tuskegee, Alabama
| | - Bradley K. Yoder
- Department of Cell, Developmental, and Integrative Biology, Heersink School of Medicine, University of Alabama, Birmingham, Alabama
| |
Collapse
|
|
27
|
Ansari S, Yamaoka Y. Animal Models and Helicobacter pylori Infection. J Clin Med 2022; 11:jcm11113141. [PMID: 35683528 PMCID: PMC9181647 DOI: 10.3390/jcm11113141] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 05/25/2022] [Accepted: 05/25/2022] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori colonize the gastric mucosa of at least half of the world’s population. Persistent infection is associated with the development of gastritis, peptic ulcer disease, and an increased risk of gastric cancer and gastric-mucosa-associated lymphoid tissue (MALT) lymphoma. In vivo studies using several animal models have provided crucial evidence for understanding the pathophysiology of H. pylori-associated complications. Numerous animal models, such as Mongolian gerbils, transgenic mouse models, guinea pigs, and other animals, including non-human primates, are being widely used due to their persistent association in causing gastric complications. However, finding suitable animal models for in vivo experimentation to understand the pathophysiology of gastric cancer and MALT lymphoma is a complicated task. In this review, we summarized the most appropriate and latest information in the scientific literature to understand the role and importance of H. pylori infection animal models.
Collapse
Affiliation(s)
- Shamshul Ansari
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu 879-5593, Oita, Japan;
| | - Yoshio Yamaoka
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu 879-5593, Oita, Japan;
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX 77030, USA
- Institute of Tropical Disease, Universitas Airlangga, Surabaya 60115, Indonesia
- Correspondence: ; Tel.: +81-97-586-5740
| |
Collapse
|
|
28
|
Noto JM, Piazuelo MB, Shah SC, Romero-Gallo J, Hart JL, Di C, Carmichael JD, Delgado AG, Halvorson AE, Greevy RA, Wroblewski LE, Sharma A, Newton AB, Allaman MM, Wilson KT, Washington MK, Calcutt MW, Schey KL, Cummings BP, Flynn CR, Zackular JP, Peek RM. Iron deficiency linked to altered bile acid metabolism promotes Helicobacter pylori-induced inflammation-driven gastric carcinogenesis. J Clin Invest 2022; 132:e147822. [PMID: 35316215 PMCID: PMC9106351 DOI: 10.1172/jci147822] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 03/16/2022] [Indexed: 12/24/2022] Open
Abstract
Gastric carcinogenesis is mediated by complex interactions among Helicobacter pylori, host, and environmental factors. Here, we demonstrate that H. pylori augmented gastric injury in INS-GAS mice under iron-deficient conditions. Mechanistically, these phenotypes were not driven by alterations in the gastric microbiota; however, discovery-based and targeted metabolomics revealed that bile acids were significantly altered in H. pylori-infected mice with iron deficiency, with significant upregulation of deoxycholic acid (DCA), a carcinogenic bile acid. The severity of gastric injury was further augmented when H. pylori-infected mice were treated with DCA, and, in vitro, DCA increased translocation of the H. pylori oncoprotein CagA into host cells. Conversely, bile acid sequestration attenuated H. pylori-induced injury under conditions of iron deficiency. To translate these findings to human populations, we evaluated the association between bile acid sequestrant use and gastric cancer risk in a large human cohort. Among 416,885 individuals, a significant dose-dependent reduction in risk was associated with cumulative bile acid sequestrant use. Further, expression of the bile acid receptor transmembrane G protein-coupled bile acid receptor 5 (TGR5) paralleled the severity of carcinogenic lesions in humans. These data demonstrate that increased H. pylori-induced injury within the context of iron deficiency is tightly linked to altered bile acid metabolism, which may promote gastric carcinogenesis.
Collapse
Affiliation(s)
- Jennifer M Noto
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M Blanca Piazuelo
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Shailja C Shah
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Judith Romero-Gallo
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | | | - Chao Di
- Division of Protective Immunity, and
- Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - James D Carmichael
- Department of Biochemistry, Mass Spectrometry Research Center Laboratory, Vanderbilt University, Nashville, Tennessee, USA
| | - Alberto G Delgado
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Alese E Halvorson
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Robert A Greevy
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Lydia E Wroblewski
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Ayushi Sharma
- Creighton University School of Medicine, Omaha, Nebraska, USA
| | | | - Margaret M Allaman
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Keith T Wilson
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M Kay Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - M Wade Calcutt
- Department of Biochemistry, Mass Spectrometry Research Center Laboratory, Vanderbilt University, Nashville, Tennessee, USA
| | - Kevin L Schey
- Department of Biochemistry, Mass Spectrometry Research Center Laboratory, Vanderbilt University, Nashville, Tennessee, USA
| | - Bethany P Cummings
- Department of Surgery, University of California, Davis, Davis, California, USA
| | - Charles R Flynn
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Joseph P Zackular
- Division of Protective Immunity, and
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Richard M Peek
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| |
Collapse
|
|
29
|
Ness-Jensen E, Bringeland EA, Mjønes P, Lagergren J, Grønbech JE, Waldum H, Fossmark R. Hypergastrinemia and mortality in gastric adenocarcinoma: a population-based cohort study, the HUNT study. Scand J Gastroenterol 2022; 57:558-565. [PMID: 35068320 DOI: 10.1080/00365521.2022.2026462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Purpose: Hypergastrinemia increases the risk of developing proximal gastric adenocarcinoma. However, it is unclear if hypergastrinemia affects the survival in patients with gastric adenocarcinoma. This study aimed to examine the hypothesis that hypergastrinemia is associated with increased risk of mortality in patients with gastric adenocarcinoma.Materials and methods: This prospective population-based cohort study based on the Trøndelag Health Study (HUNT) included 78,962 adult individuals (≥20 years). During the baseline assessment period (1995-2008) of these participants, serum samples were collected and frozen. All participants with a newly diagnosed gastric adenocarcinoma in the cohort in 1995-2015 were identified and their gastrin levels were measured in the pre-diagnostic serum samples. Gastrin levels were analysed in relation to all-cause mortality until year 2020 using multivariable Cox regression providing hazard ratios (HRs) with 95% confidence intervals (CIs), adjusted for sex, age, body mass index (BMI), tobacco smoking, tumour stage, completeness of surgical resection, and peri-operative chemotherapy.Results: Among 172 patients with gastric adenocarcinoma, 81 (47%) had hypergastrinemia (serum gastrin >60 pmol/L) and 91 (53%) had normal gastrin level. The tumour location was proximal in 83 patients (43%) and distal in 78 (41%). Hypergastrinemia was not associated with any increased risk of all-cause mortality in all patients (adjusted HR 0.8, 95% CI 0.5-1.1), or in sub-groups of patients with proximal tumour location (HR 0.9, 95% CI 0.4-2.2) or distal tumour location (HR 0.9, 95% CI 0.5-1.7).Conclusion: This population-based cohort study indicates that hypergastrinemia may not increase the risk of mortality in patients with gastric adenocarcinoma.
Collapse
Affiliation(s)
- Eivind Ness-Jensen
- HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway.,Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.,Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Erling Audun Bringeland
- Department of Gastrointestinal Surgery, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.,Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
| | - Patricia Mjønes
- Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Pathology, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Jesper Lagergren
- Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.,School of Cancer and Pharmaceutical Sciences, King's College London, London, UK
| | - Jon Erik Grønbech
- Department of Gastrointestinal Surgery, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.,Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
| | - Helge Waldum
- Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
| | - Reidar Fossmark
- Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Gastroenterology and Hepatology, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway
| |
Collapse
|
|
30
|
Chinzon D, Domingues G, Tosetto N, Perrotti M. SAFETY OF LONG-TERM PROTON PUMP INHIBITORS: FACTS AND MYTHS. ARQUIVOS DE GASTROENTEROLOGIA 2022; 59:219-225. [PMID: 35830032 DOI: 10.1590/s0004-2803.202202000-40] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 01/06/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are one of the most prescribed drugs in the world. Frequent use and long-term maintenance of these drugs drew the attention of researchers for sporadic adverse effects reports. OBJECTIVE The purpose of this narrative review is to discuss appropriate data and causality related to these adverse events and PPIs. METHODS A narrative review was conducted by systematizing information about safety and adverse events on PPIs from 2015 to 2020. A structured search on Pubmed was performed to identify systematic reviews and meta-analysis investigating the following situations: a) gastric cancer; b) micronutrients deficiency; c) acid rebound; d) infections; e) fractures; f) dementia; g) kidney disease; and h) sudden death and cardiovascular changes. RESULTS Recent studies have potentially associated PPIs with some adverse events as osteoporosis-related fractures. There are also reports of intestinal infections, including Clostridium difficile, besides poor vitamins absorption and minerals such as vitamin B12, magnesium, and iron. Furthermore, there are some dementia, pneumonia, kidney disease, myocardial infarction, and stroke reports. For kidney diseases, studies consistently suggest that the use of PPI may be associated with an increased risk of adverse kidney events, especially in the elderly, with long-term PPI use and pre-existing kidney disease. Another additional question is whether chronic PPI use would also lead to the onset of gastric cancer. The abrupt discontinuation of PPIs is also related to increased gastric acid production above pre-PPI treatment levels; this phenomenon is called acid rebound. CONCLUSION The key to mitigate adverse effects is the rational use of PPIs at the lowest effective dose and in the shortest possible duration. Although these adverse effects have a potential clinical impact, their causal association is still subject to validation.
Collapse
Affiliation(s)
- Decio Chinzon
- Faculdade de Medicina da Universidade de São Paulo, Departamento de Gastroenterologia, São Paulo, SP, Brasil
| | - Gerson Domingues
- Faculdade de Medicina da Universidade do Estado do Rio Janeiro, Departamento de Gastroenterologia, Rio de Janeiro, RJ, Brasil
| | | | | |
Collapse
|
|
31
|
Yu YN, Wang XW, Chen YQ, Cui Z, Tian ZB, Zhao QX, Mao T, Xie M, Yin XY. A retrospective analysis of 13 cases of gastritis cystica profunda treated by endoscopic resection and surgery. J Dig Dis 2022; 23:186-190. [PMID: 35150051 DOI: 10.1111/1751-2980.13086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 12/26/2021] [Accepted: 02/10/2022] [Indexed: 12/11/2022]
Affiliation(s)
- Ya Nan Yu
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Xiao Wei Wang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Yun Qing Chen
- Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Zheng Cui
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Zi Bin Tian
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Qing Xi Zhao
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Tao Mao
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Man Xie
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| | - Xiao Yan Yin
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
| |
Collapse
|
|
32
|
Goldenring JR, Mills JC. Cellular Plasticity, Reprogramming, and Regeneration: Metaplasia in the Stomach and Beyond. Gastroenterology 2022; 162:415-430. [PMID: 34728185 PMCID: PMC8792220 DOI: 10.1053/j.gastro.2021.10.036] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 10/21/2021] [Accepted: 10/24/2021] [Indexed: 02/03/2023]
Abstract
The mucosa of the body of the stomach (ie, the gastric corpus) uses 2 overlapping, depth-dependent mechanisms to respond to injury. Superficial injury heals via surface cells with histopathologic changes like foveolar hyperplasia. Deeper, usually chronic, injury/inflammation, most frequently induced by the carcinogenic bacteria Helicobacter pylori, elicits glandular histopathologic alterations, initially manifesting as pyloric (also known as pseudopyloric) metaplasia. In this pyloric metaplasia, corpus glands become antrum (pylorus)-like with loss of acid-secreting parietal cells (atrophic gastritis), expansion of foveolar cells, and reprogramming of digestive enzyme-secreting chief cells into deep antral gland-like mucous cells. After acute parietal cell loss, chief cells can reprogram through an orderly stepwise progression (paligenosis) initiated by interleukin-13-secreting innate lymphoid cells (ILC2s). First, massive lysosomal activation helps mitigate reactive oxygen species and remove damaged organelles. Second, mucus and wound-healing proteins (eg, TFF2) and other transcriptional alterations are induced, at which point the reprogrammed chief cells are recognized as mucus-secreting spasmolytic polypeptide-expressing metaplasia cells. In chronic severe injury, glands with pyloric metaplasia can harbor both actively proliferating spasmolytic polypeptide-expressing metaplasia cells and eventually intestine-like cells. Gastric glands with such lineage confusion (mixed incomplete intestinal metaplasia and proliferative spasmolytic polypeptide-expressing metaplasia) may be at particular risk for progression to dysplasia and cancer. A pyloric-like pattern of metaplasia after injury also occurs in other gastrointestinal organs including esophagus, pancreas, and intestines, and the paligenosis program itself seems broadly conserved across tissues and species. Here we discuss aspects of metaplasia in stomach, incorporating data derived from animal models and work on human cells and tissues in correlation with diagnostic and clinical implications.
Collapse
Affiliation(s)
- James R Goldenring
- Nashville Veterans Affairs Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
| | - Jason C Mills
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas; Department of Medicine, Baylor College of Medicine, Houston, Texas; Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
| |
Collapse
|
|
33
|
Zhao Y, Wang Q, Zeng Y, Xie Y, Zhou J. Gastrin/CCK-B Receptor Signaling Promotes Cell Invasion and Metastasis by Upregulating MMP-2 and VEGF Expression in Gastric Cancer. J Cancer 2022; 13:134-145. [PMID: 34976177 PMCID: PMC8692687 DOI: 10.7150/jca.51854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 11/09/2021] [Indexed: 11/05/2022] Open
Abstract
Accumulated evidence suggests that a functional loop composed of gastrin and cholecystokinin B receptor (CCK-BR) may exist in gastric carcinogenesis. However, this suggestion is not completely supported due to a lack of direct evidence, and the underlying mechanism is not completely understood. Here, we evaluated the effects of gastrin/CCK-BR signaling on the cell growth, invasion, and expression of MMP-2 and VEGF, as well as xenograft growth in vivo. Furthermore, we detected gastrin mRNA content in human gastric cancer tissues, metastatic lymph nodes, and adjacent nontumor tissues. We found that the forced gastrin could promote the proliferation, migration, and invasion of gastric cancer cells by upregulating the expression of MMP-2 and VEGF. Blocking gastrin/CCK-BR signal using either Proglumide, a CCK-BR antagonist, or shRNA against GASTRIN significantly inhibited the gastrin-promoting effects. In vivo study revealed that the tumor growth in nude mice inoculated with gastrin-overexpressed cells was significantly faster than control cells. The gastrin mRNA content in metastatic lymph nodes was higher in patients with gastric cancer than in primary gastric cancer and adjacent nontumor tissues. In conclusion, we provided direct evidence and possible mechanism of gastrin/CCK-BR signaling in the initiation and progression of gastric cancer.
Collapse
Affiliation(s)
- Yan Zhao
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education and Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang, Guizhou, China
| | - Qinrong Wang
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education and Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang, Guizhou, China
| | - Yi Zeng
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education and Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang, Guizhou, China
| | - Yuan Xie
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education and Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang, Guizhou, China
| | - Jianjiang Zhou
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education and Key Laboratory of Medical Molecular Biology, Guizhou Medical University, Guiyang, Guizhou, China
| |
Collapse
|
|
34
|
Jin D, Huang K, Xu M, Hua H, Ye F, Yan J, Zhang G, Wang Y. Deoxycholic acid induces gastric intestinal metaplasia by activating STAT3 signaling and disturbing gastric bile acids metabolism and microbiota. Gut Microbes 2022; 14:2120744. [PMID: 36067404 PMCID: PMC9467587 DOI: 10.1080/19490976.2022.2120744] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 08/22/2022] [Accepted: 08/31/2022] [Indexed: 02/04/2023] Open
Abstract
Intestinal metaplasia (IM) is the inevitable precancerous stage to develop intestinal-type gastric cancer (GC). Deoxycholic acid (DCA) is the main bile acid (BA) component of duodenogastric reflux and has shown an increased concentration during the transition from chronic gastritis to IM associated with continued STAT3 activation. However, the mechanisms underlying how DCA facilitates IM in the gastric epithelium need exploration. We evaluated IM and bile reflux in corpus tissues from 161 subjects undergoing GC screening. Cell survival and proliferation, proinflammatory cytokine expression and TGR5/STAT3/KLF5 axis activity were measured in normal human gastric cells, cancer cells, and organoid lines derived from C57BL/6, FVB/N and insulin-gastrin (INS-GAS) mice treated with DCA. The effects of DCA on IM development were determined in INS-GAS mice with long-term DCA supplementation, after which the gastric bacterial and BA metabolic profiles were measured by 16S rRNA gene sequencing and LC-MS. We revealed a BA-triggered TGR5/STAT3/KLF5 pathway in human gastric IM tissues. In gastric epithelial cells, DCA promoted proliferation and apoptotic resistance, upregulated proinflammatory cytokines and IM markers, and facilitated STAT3 phosphorylation, nuclear accumulation and DNA binding to the KLF5 promoter. DCA triggered STAT3 signaling and the downstream IM marker KLF5 in mouse gastric organoids in vitro and in vivo. In INS-GAS mice, DCA promoted the accumulation of serum total BAs and accelerated the stepwise development of gastric IM and dysplasia. DCA induced gastric environmental alterations involving abnormal BA metabolism and microbial dysbiosis, in which the Gemmobacter and Lactobacillus genera were specifically enriched. Lactobacillus genus enrichment was positively correlated with increased levels of GCA, CA, T-α-MCA, TCA and β-MCA in DCA-administrated INS-GAS mice. DCA promotes nuclear STAT3 phosphorylation, which mediates KLF5 upregulation associated with gastric inflammation and IM development. DCA disturbs the gastric microbiome and BA metabolism homeostasis during IM induction.
Collapse
Affiliation(s)
- Duochen Jin
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, NanjingChina
- First Clinical Medical College, Nanjing Medical University, Nanjing, China
| | - Keting Huang
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, NanjingChina
- First Clinical Medical College, Nanjing Medical University, Nanjing, China
| | - Miao Xu
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, NanjingChina
- First Clinical Medical College, Nanjing Medical University, Nanjing, China
| | - Hongjin Hua
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Feng Ye
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, NanjingChina
| | - Jin Yan
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, NanjingChina
| | - Guoxin Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, NanjingChina
- First Clinical Medical College, Nanjing Medical University, Nanjing, China
| | - Yun Wang
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, NanjingChina
| |
Collapse
|
|
35
|
Duan S, Rico K, Merchant JL. Gastrin: From Physiology to Gastrointestinal Malignancies. FUNCTION (OXFORD, ENGLAND) 2021; 3:zqab062. [PMID: 35330921 PMCID: PMC8788842 DOI: 10.1093/function/zqab062] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/14/2021] [Accepted: 11/16/2021] [Indexed: 01/07/2023]
Abstract
Abetted by widespread usage of acid-suppressing proton pump inhibitors (PPIs), the mitogenic actions of the peptide hormone gastrin are being revisited as a recurring theme in various gastrointestinal (GI) malignancies. While pathological gastrin levels are intricately linked to hyperplasia of enterochromaffin-like cells leading to carcinoid development, the signaling effects exerted by gastrin on distinct cell types of the gastric mucosa are more nuanced. Indeed, mounting evidence suggests dichotomous roles for gastrin in both promoting and suppressing tumorigenesis. Here, we review the major upstream mediators of gastrin gene regulation, including inflammation secondary to Helicobacter pylori infection and the use of PPIs. We further explore the molecular biology of gastrin in GI malignancies, with particular emphasis on the regulation of gastrin in neuroendocrine neoplasms. Finally, we highlight tissue-specific transcriptional targets as an avenue for targetable therapeutics.
Collapse
Affiliation(s)
- Suzann Duan
- Department of Medicine, Division of Gastroenterology and Hepatology, Arizona Comprehensive Cancer Center, University of Arizona, Tucson, AZ 85724, USA
| | - Karen Rico
- Department of Medicine, Division of Gastroenterology and Hepatology, Arizona Comprehensive Cancer Center, University of Arizona, Tucson, AZ 85724, USA
| | | |
Collapse
|
|
36
|
Zeng Z, Ma C, Chen K, Jiang M, Vasu R, Liu R, Zhao Y, Zhang H. Roles of G Protein-Coupled Receptors (GPCRs) in Gastrointestinal Cancers: Focus on Sphingosine 1-Shosphate Receptors, Angiotensin II Receptors, and Estrogen-Related GPCRs. Cells 2021; 10:2988. [PMID: 34831211 PMCID: PMC8616429 DOI: 10.3390/cells10112988] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 10/19/2021] [Accepted: 10/20/2021] [Indexed: 02/05/2023] Open
Abstract
It is well established that gastrointestinal (GI) cancers are common and devastating diseases around the world. Despite the significant progress that has been made in the treatment of GI cancers, the mortality rates remain high, indicating a real need to explore the complex pathogenesis and develop more effective therapeutics for GI cancers. G protein-coupled receptors (GPCRs) are critical signaling molecules involved in various biological processes including cell growth, proliferation, and death, as well as immune responses and inflammation regulation. Substantial evidence has demonstrated crucial roles of GPCRs in the development of GI cancers, which provided an impetus for further research regarding the pathophysiological mechanisms and drug discovery of GI cancers. In this review, we mainly discuss the roles of sphingosine 1-phosphate receptors (S1PRs), angiotensin II receptors, estrogen-related GPCRs, and some other important GPCRs in the development of colorectal, gastric, and esophageal cancer, and explore the potential of GPCRs as therapeutic targets.
Collapse
Affiliation(s)
- Zhen Zeng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 410061, China; (Z.Z.); (C.M.); (K.C.); (M.J.)
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 410061, China
| | - Chunxiang Ma
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 410061, China; (Z.Z.); (C.M.); (K.C.); (M.J.)
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 410061, China
| | - Kexin Chen
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 410061, China; (Z.Z.); (C.M.); (K.C.); (M.J.)
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 410061, China
| | - Mingshan Jiang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 410061, China; (Z.Z.); (C.M.); (K.C.); (M.J.)
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 410061, China
| | - Reshma Vasu
- West China School of Medicine, Sichuan University, Chengdu 410061, China;
| | - Rui Liu
- Key Laboratory of Green Chemistry & Technology, College of Chemistry, Sichuan University, Chengdu 610064, China;
| | - Yinglan Zhao
- Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China;
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 410061, China; (Z.Z.); (C.M.); (K.C.); (M.J.)
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 410061, China
| |
Collapse
|
|
37
|
Helicobacter pylori-Induced Inflammation: Possible Factors Modulating the Risk of Gastric Cancer. Pathogens 2021; 10:pathogens10091099. [PMID: 34578132 PMCID: PMC8467880 DOI: 10.3390/pathogens10091099] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/21/2021] [Accepted: 08/25/2021] [Indexed: 02/07/2023] Open
Abstract
Chronic inflammation and long-term tissue injury are related to many malignancies, including gastric cancer (GC). Helicobacter pylori (H. pylori), classified as a class I carcinogen, induces chronic superficial gastritis followed by gastric carcinogenesis. Despite a high prevalence of H. pylori infection, only about 1–3% of people infected with this bacterium develop GC worldwide. Furthermore, the development of chronic gastritis in some, but not all, H. pylori-infected subjects remains unexplained. These conflicting findings indicate that clinical outcomes of aggressive inflammation (atrophic gastritis) to gastric carcinogenesis are influenced by several other factors (in addition to H. pylori infection), such as gut microbiota, co-existence of intestinal helminths, dietary habits, and host genetic factors. This review has five goals: (1) to assess our current understanding of the process of H. pylori-triggered inflammation and gastric precursor lesions; (2) to present a hypothesis on risk modulation by the gut microbiota and infestation with intestinal helminths; (3) to identify the dietary behavior of the people at risk of GC; (4) to check the inflammation-related genetic polymorphisms and role of exosomes together with other factors as initiators of precancerous lesions and gastric carcinoma; and (5) finally, to conclude and suggest a new direction for future research.
Collapse
|
|
38
|
Varon C, Azzi-Martin L, Khalid S, Seeneevassen L, Ménard A, Spuul P. Helicobacters and cancer, not only gastric cancer? Semin Cancer Biol 2021; 86:1138-1154. [PMID: 34425210 DOI: 10.1016/j.semcancer.2021.08.007] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 08/11/2021] [Accepted: 08/16/2021] [Indexed: 12/11/2022]
Abstract
The Helicobacter genus actually comprises 46 validly published species divided into two main clades: gastric and enterohepatic Helicobacters. These bacteria colonize alternative sites of the digestive system in animals and humans, and contribute to inflammation and cancers. In humans, Helicobacter infection is mainly related to H. pylori, a gastric pathogen infecting more than half of the world's population, leading to chronic inflammation of the gastric mucosa that can evolve into two types of gastric cancers: gastric adenocarcinomas and gastric MALT lymphoma. In addition, H. pylori but also non-H. pylori Helicobacter infection has been associated with many extra-gastric malignancies. This review focuses on H. pylori and its role in gastric cancers and extra-gastric diseases, as well as malignancies induced by non-H. pylori Helicobacters. Their different virulence factors and their involvement in carcinogenesis is discussed. This review highlights the importance of both gastric and enterohepatic Helicobacters in gastrointestinal and liver cancers.
Collapse
Affiliation(s)
- Christine Varon
- Univ. Bordeaux, INSERM, UMR1053 Bordeaux Research in Translational Oncology, BaRITOn, Bordeaux, France
| | - Lamia Azzi-Martin
- Univ. Bordeaux, INSERM, UMR1053 Bordeaux Research in Translational Oncology, BaRITOn, Bordeaux, France; Univ. Bordeaux, UFR des Sciences Médicales, Bordeaux, France
| | - Sadia Khalid
- Tallinn University of Technology, Department of Chemistry and Biotechnology, Akadeemia RD 15, 12618, Tallinn, Estonia
| | - Lornella Seeneevassen
- Univ. Bordeaux, INSERM, UMR1053 Bordeaux Research in Translational Oncology, BaRITOn, Bordeaux, France
| | - Armelle Ménard
- Univ. Bordeaux, INSERM, UMR1053 Bordeaux Research in Translational Oncology, BaRITOn, Bordeaux, France
| | - Pirjo Spuul
- Tallinn University of Technology, Department of Chemistry and Biotechnology, Akadeemia RD 15, 12618, Tallinn, Estonia.
| |
Collapse
|
|
39
|
Zou X, Ouyang H, Pang D, Han R, Tang X. Pathological alterations in the gastrointestinal tract of a porcine model of DMD. Cell Biosci 2021; 11:131. [PMID: 34266495 PMCID: PMC8281460 DOI: 10.1186/s13578-021-00647-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 07/05/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Patients with Duchenne muscular dystrophy (DMD) develop severe skeletal and cardiac muscle pathologies, which result in premature death. Therefore, the current therapeutic efforts are mainly targeted to correct dystrophin expression in skeletal muscle and heart. However, it was reported that DMD patients may also exhibit gastrointestinal and nutritional problems. How the pathological alterations in gastrointestinal tissues contribute to the disease are not fully explored. RESULTS Here we employed the CRISPR/Cas9 system combined with somatic nuclear transfer technology (SCNT) to establish a porcine model of DMD and explored their pathological alterations. We found that genetic disruption of dystrophin expression led to morphological gastrointestinal tract alterations, weakened the gastrointestinal tract digestion and absorption capacity, and eventually led to malnutrition and gastric dysfunction in the DMD pigs. CONCLUSIONS This work provides important insights into the pathogenesis of DMD and highlights the need to consider the gastrointestinal dysfunction as an additional therapeutic target for DMD patients.
Collapse
Affiliation(s)
- Xiaodong Zou
- Jilin Provincial Key Laboratory of Animal Embryo Engineering, College of Animal Sciences, Jilin University, Changchun, Jilin, People's Republic of China
| | - Hongsheng Ouyang
- Jilin Provincial Key Laboratory of Animal Embryo Engineering, College of Animal Sciences, Jilin University, Changchun, Jilin, People's Republic of China
| | - Daxin Pang
- Jilin Provincial Key Laboratory of Animal Embryo Engineering, College of Animal Sciences, Jilin University, Changchun, Jilin, People's Republic of China
| | - Renzhi Han
- Department of Surgery, Davis Heart and Lung Research Institute, Biomedical Sciences Graduate Program, Biophysics Graduate Program, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA.
| | - Xiaochun Tang
- Jilin Provincial Key Laboratory of Animal Embryo Engineering, College of Animal Sciences, Jilin University, Changchun, Jilin, People's Republic of China.
| |
Collapse
|
|
40
|
Tumor Classification Should Be Based on Biology and Not Consensus: Re-Defining Tumors Based on Biology May Accelerate Progress, An Experience of Gastric Cancer. Cancers (Basel) 2021; 13:cancers13133159. [PMID: 34202596 PMCID: PMC8269176 DOI: 10.3390/cancers13133159] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/14/2021] [Accepted: 06/21/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Rational treatment of diseases including cancers depends on knowledge of their cause as well as their development. The present review is based upon more than 40 years’ work in clinical gastroenterology, gastric physiology, and pathology. The central role of hormones as well as local endocrine cells in cancer development has become apparent. Moreover, the classification of tumors should focus not only on the organ of origin but also on the cell of origin. All cells with the ability to divide may give rise to tumors. Based upon knowledge of the growth regulation of the cell of origin, prophylaxis and treatment may be tailored. Presently, there is hope for individual treatment of cancer patients based upon genetic analyses of tumors. However, with correct identification of the cell of origin, this may not be necessary. Abstract Malignant tumors are a consequence of genetic changes mainly occurring during cell division, sometimes with a congenital component. Therefore, accelerated cell divisions will necessarily predispose individuals, whether due to conditions of chronic cell destruction or hormonal overstimulation. It has been postulated that two genetic hits are necessary for the development of malignancy (Knudson). The correct view is probably that the number of genetic changes needed depends on the role the mutated genes have in proliferation and growth control. Hormones should accordingly be regarded as complete carcinogens. In this review based upon experience of gastric cancer where gastrin is central in the pathogenesis, it is argued that oxyntic atrophy—and not metaplasia as postulated by Correa—is the central precancer change in gastric mucosa. Moreover, the target cell of gastrin, the enterochromaffin-like (ECL) cell, is central in gastric carcinogenesis and most probably the cell of origin of gastric carcinomas of the diffuse type according to Lauren (a classification probable in accordance with biology). The distinction between adenocarcinomas and neuroendocrine carcinomas based upon a certain percentage of cancer cells with neuroendocrine differentiation is questioned. To make progress in the treatment of cancer, a correct classification system and knowledge of the pathogenesis are necessary.
Collapse
|
|
41
|
Impact of Environmental and Pharmacologic Changes on the Upper Gastrointestinal Microbiome. Biomedicines 2021; 9:biomedicines9060617. [PMID: 34072493 PMCID: PMC8229529 DOI: 10.3390/biomedicines9060617] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/23/2021] [Accepted: 05/26/2021] [Indexed: 02/08/2023] Open
Abstract
Diseases of the upper gastrointestinal tract have become more prevalent over time. Mechanisms of disease formation are still only partially understood. Recent literature has shown that the surrounding microbiome affects the propensity for disease formation in various parts of the upper gastrointestinal tract. A review was performed of any literature to our best knowledge concerning the effects of pharmacologic agents, environmental changes, and surgical intervention on the microbiome of the upper gastrointestinal tract. Searches of the literature were performed using specific keywords related to drugs, surgical procedures, and environmental factors. Many prescription and nonprescription drugs that are commonly used have varying effects on the upper gastrointestinal tract. Proton pump inhibitors may affect the relative prevalence of some organisms in the lower esophagus and have less effect in the proximal esophagus. Changes in the esophageal microbiome correlate with some esophageal diseases. Drugs that induce weight loss have also been shown to affect the microbiomes of the esophagus and stomach. Common surgical procedures are associated with shifts in the microbial community in the gastrointestinal tract. Environmental factors have been shown to affect the microbiome in the upper gastrointestinal tract, as geographic differences correlate with alterations in the microbiome of the gastrointestinal tract. Understanding the association of environmental and pharmacologic changes on the microbiome of the upper gastrointestinal tract will facilitate treatment plans to reduce morbidity from disease.
Collapse
|
|
42
|
Link A, Bornschein J, Thon C. Helicobacter pylori induced gastric carcinogenesis - The best molecular model we have? Best Pract Res Clin Gastroenterol 2021; 50-51:101743. [PMID: 33975683 DOI: 10.1016/j.bpg.2021.101743] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/19/2021] [Accepted: 03/25/2021] [Indexed: 01/31/2023]
Abstract
Gastric carcinogenesis can be described as a consequence of multilevel molecular alterations that is triggered by a cascade of events. Historically, diet and environmental factors have been identified to substantially contribute to carcinogenesis before the discovery of Helicobacter pylori (H. pylori). But H. pylori infection has revolutionized the understanding of gastric carcinogenesis. Although the model of H. pylori-driven carcinogenesis remains valid, there is a continuous effort to precisely delineate the molecular pathways involved and to understand the interplay with additional risk factors including recent relevant knowledge on the stomach microbiota. In this review, we provide an updated view on the models of gastric carcinogenesis. This includes historically appreciated H. pylori-induced models and expands these taking recent molecular data into consideration. Based on the data provided, we conclude that indeed H. pylori-carcinogenesis remains one of the best-established models at least for a subset of gastric cancers. Implementation of the recently identified molecular subtypes in novel genetic animal models is required to expand our knowledge on H. pylori-independent carcinogenesis.
Collapse
Affiliation(s)
- Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Section of Molecular Gastroenterology and Microbiota-associated Diseases, Otto-von-Guericke University, Magdeburg, Germany.
| | - Jan Bornschein
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford University Hospitals, Headington, Oxford, UK
| | - Cosima Thon
- Department of Gastroenterology, Hepatology and Infectious Diseases, Section of Molecular Gastroenterology and Microbiota-associated Diseases, Otto-von-Guericke University, Magdeburg, Germany
| |
Collapse
|
|
43
|
Jain T, Sharma P, Are AC, Vickers SM, Dudeja V. New Insights Into the Cancer-Microbiome-Immune Axis: Decrypting a Decade of Discoveries. Front Immunol 2021; 12:622064. [PMID: 33708214 PMCID: PMC7940198 DOI: 10.3389/fimmu.2021.622064] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 01/11/2021] [Indexed: 12/13/2022] Open
Abstract
The past decade has witnessed groundbreaking advances in the field of microbiome research. An area where immense implications of the microbiome have been demonstrated is tumor biology. The microbiome affects tumor initiation and progression through direct effects on the tumor cells and indirectly through manipulation of the immune system. It can also determine response to cancer therapies and predict disease progression and survival. Modulation of the microbiome can be harnessed to potentiate the efficacy of immunotherapies and decrease their toxicity. In this review, we comprehensively dissect recent evidence regarding the interaction of the microbiome and anti-tumor immune machinery and outline the critical questions which need to be addressed as we further explore this dynamic colloquy.
Collapse
Affiliation(s)
| | | | | | - Selwyn M. Vickers
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Vikas Dudeja
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| |
Collapse
|
|
44
|
Pereira-Marques J, Ferreira RM, Machado JC, Figueiredo C. The influence of the gastric microbiota in gastric cancer development. Best Pract Res Clin Gastroenterol 2021; 50-51:101734. [PMID: 33975676 DOI: 10.1016/j.bpg.2021.101734] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/12/2021] [Accepted: 02/15/2021] [Indexed: 01/31/2023]
Abstract
Colonization of the stomach by Helicobacter pylori is the trigger for a series of gastric mucosal changes that culminate in gastric cancer. Infection with this bacterium is considered the major risk factor for this malignancy. The introduction of high-throughput sequencing technologies coupled to advanced computational pipelines offered an improved understanding of the microbiome, and it is now currently accepted that, besides H. pylori, the stomach harbours a complex microbial community. While it is well established that H. pylori plays a central role in gastric carcinogenesis, the significance of the non-H. pylori microbiota is yet to be clarified. This review will address the state of the art on the relationship between the gastric microbiota and gastric cancer development, and identify areas where additional research is needed before translating microbiome research into preventive and therapeutic strategies to reduce gastric cancer burden.
Collapse
Affiliation(s)
- Joana Pereira-Marques
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal; Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal.
| | - Rui M Ferreira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal; Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal.
| | - Jose C Machado
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal; Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal; Department of Pathology, Faculty of Medicine of the University of Porto, Alameda Prof. Hernâni Monteiro, 4200 - 319, Porto, Portugal.
| | - Ceu Figueiredo
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal; Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal; Department of Pathology, Faculty of Medicine of the University of Porto, Alameda Prof. Hernâni Monteiro, 4200 - 319, Porto, Portugal.
| |
Collapse
|
|
45
|
Watanabe T, Nadatani Y, Suda W, Higashimori A, Otani K, Fukunaga S, Hosomi S, Tanaka F, Nagami Y, Taira K, Tanigawa T, Nakatsu G, Hattori M, Fujiwara Y. Long-term persistence of gastric dysbiosis after eradication of Helicobacter pylori in patients who underwent endoscopic submucosal dissection for early gastric cancer. Gastric Cancer 2021; 24:710-720. [PMID: 33201352 PMCID: PMC8065006 DOI: 10.1007/s10120-020-01141-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 10/31/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric microbiome, other than Helicobacter pylori, plays a role in the tumorigenesis of gastric cancer (GC). Patients who undergo endoscopic submucosal dissection for early GC have a high risk of developing metachronous GC even after successful eradication of H. pylori. Thus, we investigated the microbial profiles and associated changes in such patients after the eradication of H. pylori. METHODS A total of 19 H. pylori-infected patients with early GC who were or to be treated by endoscopic resection, with paired biopsy samples at pre- and post-eradication therapy, were retrospectively enrolled. Ten H. pylori-negative patients were enrolled as controls. Biopsy samples were analyzed using 16S rRNA sequencing. RESULTS H. pylori-positive patients exhibited low richness and evenness of bacteria with the deletion of several genera, including Blautia, Ralstonia, Faecalibacterium, Methylobacterium, and Megamonas. H. pylori eradication partially restored microbial diversity, as assessed during a median follow-up at 13 months after eradication therapy. However, post-eradication patients had less diversity than that in the controls and possessed a lower abundance of the five genera mentioned above. The eradication of H. pylori also altered the bacterial composition, but not to the same extent as that in controls. The microbial communities could be clustered into three separate groups: H. pylori-negative, pre-eradication, and post-eradication. CONCLUSION Changes in dysbiosis may persist long after the eradication of H. pylori in patients with a history of GC. Dysbiosis may be involved in the development of both primary and metachronous GC after the eradication of H. pylori in such patients.
Collapse
Affiliation(s)
- Toshio Watanabe
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi Abeno-ku, Osaka, Japan
| | - Yuji Nadatani
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi Abeno-ku, Osaka, Japan
| | - Wataru Suda
- RIKEN Center for Integrative Medical Sciences Laboratory for Microbiome Sciences, Yokohama, Kanagawa Japan
| | - Akira Higashimori
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi Abeno-ku, Osaka, Japan
| | - Koji Otani
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi Abeno-ku, Osaka, Japan
| | - Shusei Fukunaga
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi Abeno-ku, Osaka, Japan
| | - Shuhei Hosomi
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi Abeno-ku, Osaka, Japan
| | - Fumio Tanaka
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi Abeno-ku, Osaka, Japan
| | - Yasuaki Nagami
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi Abeno-ku, Osaka, Japan
| | - Koichi Taira
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi Abeno-ku, Osaka, Japan
| | - Tetsuya Tanigawa
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi Abeno-ku, Osaka, Japan ,Department of Gastroenterology, Osaka City Juso Hospital, Osaka, Japan
| | - Geicho Nakatsu
- Department of Immunology and Infectious Diseases/Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA USA
| | - Masahira Hattori
- RIKEN Center for Integrative Medical Sciences Laboratory for Microbiome Sciences, Yokohama, Kanagawa Japan ,Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Yasuhiro Fujiwara
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi Abeno-ku, Osaka, Japan
| |
Collapse
|
|
46
|
Veysey-Smith R, Moore AR, Murugesan SV, Tiszlavicz L, Dockray GJ, Varro A, Pritchard DM. Effects of Proton Pump Inhibitor Therapy, H. pylori Infection and Gastric Preneoplastic Pathology on Fasting Serum Gastrin Concentrations. Front Endocrinol (Lausanne) 2021; 12:741887. [PMID: 34867785 PMCID: PMC8637328 DOI: 10.3389/fendo.2021.741887] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 10/22/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Hypergastrinaemia occasionally indicates the presence of a gastrinoma. However it is much more commonly associated with various benign causes including proton pump inhibitor (PPI) use, Helicobacter pylori infection and/or atrophic gastritis. The extent to which these factors interact to influence fasting serum gastrin concentrations remains incompletely understood. MATERIALS AND METHODS Fasting serum gastrin concentrations were measured by radioimmunoassay in 1,400 patients attending for diagnostic oesophagogastro-duodenoscopy. After exclusions, 982 patients were divided into four groups and their results analysed. We compared gastrin concentrations in normal patients (no H. pylori infection, no PPI use and no histological evidence of gastric preneoplasia (n=233)), with those in patients who were taking regular PPIs (H. pylori negative with no gastric preneoplasia (n=301)), patients who had active H. pylori infection but no gastric preneoplasia (n=164) and patients with histologically confirmed gastric preneoplasia (n=284). RESULTS Median fasting gastrin concentration in the normal group was 20pM and was significantly increased in PPI users (46pM, p<0.0001), patients with active H. pylori infection (27pM, p<0.0001), and patients with antral (25pM, p<0.01) or corpus (48pM, p<0.0001) gastric preneoplasia. PPI use resulted in further significant increases in fasting serum gastrin concentrations in patients who were infected with H. pylori (50pM, n=56) or who had antral gastric preneoplasia (53pM, n=87), but did not significantly alter serum gastrin concentrations in patients with corpus preneoplasia (90pM, n=66). CONCLUSIONS PPI use, H. pylori infection and atrophic gastritis all caused significant elevations of median fasting gastrin concentrations. However, several patients who had potential risk factors for hypergastrinaemia still demonstrated fasting serum gastrin concentrations within the normal range.
Collapse
Affiliation(s)
- Reuben Veysey-Smith
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Andrew R. Moore
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
- Gastroenterology Department, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Senthil V. Murugesan
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
- Gastroenterology Department, Blackpool Teaching Hospitals NHS Foundation Trust, Blackpool, United Kingdom
| | | | - Graham J. Dockray
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - Andrea Varro
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
| | - D. Mark Pritchard
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
- Gastroenterology Department, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
- *Correspondence: D. Mark Pritchard,
| |
Collapse
|
|
47
|
Ness-Jensen E, Bringeland EA, Mattsson F, Mjønes P, Lagergren J, Grønbech JE, Waldum HL, Fossmark R. Hypergastrinemia is associated with an increased risk of gastric adenocarcinoma with proximal location: A prospective population-based nested case-control study. Int J Cancer 2020; 148:1879-1886. [PMID: 33091962 PMCID: PMC7984285 DOI: 10.1002/ijc.33354] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 10/12/2020] [Accepted: 10/14/2020] [Indexed: 12/15/2022]
Abstract
The incidence of proximal gastric adenocarcinoma is increasing among younger adults. Rodent models have shown that hypergastrinemia causes carcinogenesis in the proximal stomach. The aim of our study was therefore to assess if hypergastrinemia was associated with an increased risk of developing gastric adenocarcinoma also in humans. A prospective population‐based nested case‐control study within the Nord‐Trøndelag Health Study (HUNT) cohort, Norway, was used to assess this association. Serum was collected from 78 962 participants in 1995 to 1997 and 2006 to 2008. In the cohort, 181 incident gastric adenocarcinoma cases were identified from the Norwegian Cancer and Patient Registries through 2015 and matched with 359 controls. The risk of gastric adenocarcinoma was compared between participants with prediagnostic hypergastrinemia (>60 pmol/L) and normal serum gastrin (≤60 pmol/L). Logistic regression provided odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for body mass index, tobacco smoking and comorbidity. Hypergastrinemia was associated with increased risk of gastric adenocarcinoma overall (OR 2.2, 95% CI 1.4‐3.4) and in particular for gastric adenocarcinoma with proximal location (OR 6.1, 95% CI 2.7‐13.8), but not with gastric adenocarcinoma with distal location (OR 1.7, 95% CI 0.9‐3.4). Moreover, hypergastrinemia was associated with an increased risk of gastric adenocarcinoma of intestinal histological type (OR 3.8, 95% CI 1.8‐7.9), but not for diffuse histological type (OR 1.6, 95% CI 0.7‐3.7). In conclusion, hypergastrinemia was associated with an increased risk of proximal and intestinal type gastric adenocarcinoma. What's new? The incidence of proximal gastric adenocarcinoma has been reported to increase among younger adults in Western countries. Rodent models have shown that serum gastrin levels above the normal range cause carcinogenesis in the proximal stomach. In this first prospective population‐based study on the association between hypergastrinemia and gastric adenocarcinoma, the risk of gastric adenocarcinoma in the proximal stomach, but not in the distal stomach, was markedly increased in hypergastrinemic individuals. The finding supports the hypothesis that hypergastrinemia mediates the development of gastric adenocarcinoma in the proximal stomach, where mucosal proliferation is stimulated by gastrin.
Collapse
Affiliation(s)
- Eivind Ness-Jensen
- HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway.,Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.,Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Erling Audun Bringeland
- Department of Gastrointestinal Surgery, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.,Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
| | - Fredrik Mattsson
- Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Patricia Mjønes
- Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Pathology, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Jesper Lagergren
- Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.,School of Cancer and Pharmaceutical Sciences, King's College London, London, UK
| | - Jon Erik Grønbech
- Department of Gastrointestinal Surgery, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.,Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
| | - Helge Lyder Waldum
- Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
| | - Reidar Fossmark
- Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Gastroenterology and Hepatology, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway
| |
Collapse
|
|
48
|
The ALPK1/TIFA/NF-κB axis links a bacterial carcinogen to R-loop-induced replication stress. Nat Commun 2020; 11:5117. [PMID: 33037203 PMCID: PMC7547021 DOI: 10.1038/s41467-020-18857-z] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 09/16/2020] [Indexed: 02/07/2023] Open
Abstract
Exposure of gastric epithelial cells to the bacterial carcinogen Helicobacter pylori causes DNA double strand breaks. Here, we show that H. pylori-induced DNA damage occurs co-transcriptionally in S-phase cells that activate NF-κB signaling upon innate immune recognition of the lipopolysaccharide biosynthetic intermediate β-ADP-heptose by the ALPK1/TIFA signaling pathway. DNA damage depends on the bi-functional RfaE enzyme and the Cag pathogenicity island of H. pylori, is accompanied by replication fork stalling and can be observed also in primary cells derived from gastric organoids. Importantly, H. pylori-induced replication stress and DNA damage depend on the presence of co-transcriptional RNA/DNA hybrids (R-loops) that form in infected cells during S-phase as a consequence of β-ADP-heptose/ ALPK1/TIFA/NF-κB signaling. H. pylori resides in close proximity to S-phase cells in the gastric mucosa of gastritis patients. Taken together, our results link bacterial infection and NF-κB-driven innate immune responses to R-loop-dependent replication stress and DNA damage. The bacterial pathogen Helicobacter pylori is known for its ability to induce DNA double-strand breaks in the genome of its target cells. Here, we show that H. pylori-induced DNA damage and replication stress occurs in S-phase cells as a result of R-loop-mediated transcription/replication conflicts that are triggered by activation of the ALPK1/TIFA/NF-κB signaling axis.
Collapse
|
|
49
|
Yuan P, Lin L, Zheng K, Wang W, Wu S, Huang L, Wu B, Chen T, Li X, Cai L. Risk factors for gastric cancer and related serological levels in Fujian, China: hospital-based case-control study. BMJ Open 2020; 10:e042341. [PMID: 32963075 PMCID: PMC7509973 DOI: 10.1136/bmjopen-2020-042341] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 08/11/2020] [Accepted: 08/12/2020] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE To explore the relationships between gastric cancer and serum pepsinogen I (PG I), PG II, PG I/II ratio, gastrin 17 (G-17) and Helicobacter pylori infection, and to investigate dietary and lifestyle risk factors for gastric cancer in Fujian Province, China. DESIGN A hospital-based, 1:1 matched case-control study. SETTING Patients with newly diagnosed gastric cancer were recruited from the Fujian Provincial Hospital and the No. 900 Hospital of the Joint Support Force of the Chinese People's Liberation Army between July 2014 and December 2016. PARTICIPANTS A total of 180 pairs of patients with gastric cancer and control subjects were recruited in the study, including 134 (74.4%) male pairs and 46 (25.6%) female pairs. INVESTIGATION AND ANALYSIS MEASURES Serological indicators were tested with ELISA kits. Dietary, lifestyle and psychological factors were investigated through face-to-face questionnaire. Relationships between gastric cancer and these influencing factors were examined by Χ2 test and conditional logistic regression. RESULTS Serum PG II and G-17 levels and H. pylori infection rate were higher in patients with gastric cancer than in control subjects (p<0.05), while PG I/II ratio was lower in patients with gastric cancer (p<0.05). Serum G-17 levels were higher in patients with corpus gastric cancer than in patients with antral gastric cancer (p<0.05). Serum PG II levels were higher in patients with advanced gastric cancer than in patients with early-stage cancer (p<0.05), however, PG I/II ratio was lower in patients with advanced-stage gastric cancer than in patients with early-stage cancer (p<0.05). Eating hot food (OR=2.32), eating pickled vegetables (OR=4.05) and often feel troubled (OR=2.21) were found to significantly increase the risk of gastric cancer (all p<0.05), while consuming onion or garlic (OR=0.35), drinking tea (OR=0.26), eating fresh fruits (OR=0.55), and high serum PG I (OR=0.99) or PG I/II ratio (OR=0.73) were found to be protective against gastric cancer. CONCLUSION Study results showed that serum PG, G-17 and H. pylori antibodies could be useful indicators for early diagnosis of gastric cancer. Increase in serum G-17 level might indicate the location of gastric cancer. Increase in serum PG II level and decrease in PG I/II ratio might imply the clinical stage. Eating hot food, eating pickled vegetables and often feel troubled may be risk factors for gastric cancer, while eating fresh fruits, eating onion or garlic, and drinking tea may be protective factors against the disease.
Collapse
Affiliation(s)
- Ping Yuan
- Fujian Key Laboratory of Zoonoses Research, Fujian Center for Disease Control and Prevention, Fuzhou, Fujian, China
- School of Public Health, Fujian Medical University, Fuzhou, Fujian, China
| | - Lan Lin
- Chronic Disease Prevention, Fujian Center for Disease Control and Prevention, Fuzhou, Fujian, China
- Gastrointestinal Surgery, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Kuicheng Zheng
- Fujian Key Laboratory of Zoonoses Research, Fujian Center for Disease Control and Prevention, Fuzhou, Fujian, China
- School of Public Health, Fujian Medical University, Fuzhou, Fujian, China
| | - Wen Wang
- Gastroenterology, Fuzhou General Hospital of Nanjing Military Command Area, Fuzhou, Fujian, China
| | - Sihan Wu
- Chronic Disease Prevention, Fujian Center for Disease Control and Prevention, Fuzhou, Fujian, China
| | - Liangxiang Huang
- Gastrointestinal Surgery, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Bingshan Wu
- Fujian Key Laboratory of Zoonoses Research, Fujian Center for Disease Control and Prevention, Fuzhou, Fujian, China
| | - Tiehui Chen
- Chronic Disease Prevention, Fujian Center for Disease Control and Prevention, Fuzhou, Fujian, China
| | - Xiaoqing Li
- Chronic Disease Prevention, Fujian Center for Disease Control and Prevention, Fuzhou, Fujian, China
| | - Lin Cai
- School of Public Health, Fujian Medical University, Fuzhou, Fujian, China
| |
Collapse
|
|
50
|
Han S, Zhuang J, Wu Y, Wu W, Yang X. Progress in Research on Colorectal Cancer-Related Microorganisms and Metabolites. Cancer Manag Res 2020; 12:8703-8720. [PMID: 33061569 PMCID: PMC7518784 DOI: 10.2147/cmar.s268943] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 08/25/2020] [Indexed: 12/24/2022] Open
Abstract
Intestinal flora is an important component in the human body, which have been reported to be involved in the occurrence and development of colorectal cancer (CRC). Indeed, changes in the intestinal flora in CRC patients compared to those in control subjects have been reported. Several bacterial species have been shown to exhibit the pro-inflammatory and pro-carcinogenic properties, which could consequently have an impact on colorectal carcinogenesis. In this review, we summarize the current knowledge on the potential links between the intestinal microbiota and CRC. We illustrated the mechanisms by which intestinal flora imbalance affects CRC, mainly focusing on inflammation, microbial metabolites, and specific bacteria species. In addition, we discuss how a diet exhibits a strong impact on microbial composition and provides risks for developing CRC. Finally, we describe the potential future directions that are based on intestinal microbiota manipulation for CRC diagnosis and treatment.
Collapse
Affiliation(s)
- Shuwen Han
- Department of Oncology, Huzhou Cent Hospital, Affiliated Cent Hospital HuZhou University, Huzhou 313000, People's Republic of China
| | - Jing Zhuang
- Graduate School of Nursing, Huzhou University, Huzhou 313000, People's Republic of China
| | - Yinhang Wu
- Graduate School of Second Clinical Medicine Faculty, Zhejiang Chinese Medical University, Hangzhou 310053, People's Republic of China
| | - Wei Wu
- Department of Gastroenterology, Huzhou Cent Hospital, Affiliated Cent Hospital HuZhou University, Huzhou 313000, People's Republic of China
| | - Xi Yang
- Department of Oncology, Huzhou Cent Hospital, Affiliated Cent Hospital HuZhou University, Huzhou 313000, People's Republic of China
| |
Collapse
|