|
1
|
Kanemitsu T, Uedo N, Ono T, Nimura S, Hasegawa R, Imamura K, Ohtsu K, Ono Y, Miyaoka M, Ueki T, Tanabe H, Ohta A, Iwashita A, Yao K. Magnifying endoscopy with narrow-band imaging for diagnosis of subtype of gastric intestinal metaplasia. J Gastroenterol Hepatol 2023; 38:94-102. [PMID: 36268636 DOI: 10.1111/jgh.16034] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 10/14/2022] [Accepted: 10/16/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND AND AIM Patients with incomplete gastric intestinal metaplasia (GIM) have a higher risk of gastric cancer (GC) than those with complete GIM. We aimed to clarify whether micromucosal patterns of GIM in magnifying endoscopy with narrow-band imaging (M-NBI) were useful for diagnosis of incomplete GIM. METHODS We enrolled patients with a history of endoscopic resection of GC or detailed inspection for suspicious or definite GC. The antrum greater curvature and corpus lesser curvature were regions of interest. Areas with endoscopic findings of light blue crest and/or white opaque substance (WOS) were defined as endoscopic GIM, and subsequent M-NBI was applied. Micromucosal patterns were classified into Foveola and Groove types, and targeted biopsies were performed on GIM with each pattern. GIM was classified into complete and incomplete types using mucin (MUC)2, MUC5AC, MUC6, and CD10 immunohistochemical staining. The primary endpoint was the association between micromucosal pattern and histological subtype. The secondary endpoint was endoscopic findings associated with incomplete GIM. RESULTS We analyzed 98 patients with 156 GIMs. Univariate analysis (odds ratio [OR] 3.4, P = 0.004), but not multivariate analysis (OR 0.87, P = 0.822), demonstrated a significant association between micromucosal pattern and subtype. The antrum (OR 3.7, P = 0.006) and WOS (OR 43, P = 0.002) were independent predictors for incomplete GIM. The WOS had 69% sensitivity and 93% specificity. CONCLUSIONS The M-NBI micromucosal pattern is not useful for diagnosis of GIM subtype. WOS is a promising endoscopic indicator for diagnosis of incomplete GIM. (UMIN-CTR000041119).
Collapse
Affiliation(s)
- Takao Kanemitsu
- Department of Endoscopy, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Noriya Uedo
- Department of Endoscopy, Fukuoka University Chikushi Hospital, Chikushino, Japan.,Department of Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Takahiro Ono
- Department of Gastroenterology, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Satoshi Nimura
- Department of Pathology, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Rino Hasegawa
- Department of Endoscopy, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Kentaro Imamura
- Department of Gastroenterology, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Kensei Ohtsu
- Department of Gastroenterology, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Yoichiro Ono
- Department of Gastroenterology, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Masaki Miyaoka
- Department of Endoscopy, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Toshiharu Ueki
- Department of Gastroenterology, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Hiroshi Tanabe
- Department of Pathology, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Atsuko Ohta
- Department of Pathology, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Akinori Iwashita
- Department of Pathology, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | - Kenshi Yao
- Department of Endoscopy, Fukuoka University Chikushi Hospital, Chikushino, Japan
| |
Collapse
|
|
2
|
Wang P, Li P, Chen Y, Li L, Lu Y, Zhou W, Bian L, Zhang B, Yin X, Li J, Chen J, Zhang S, Shi Y, Tang X. Chinese integrated guideline on the management of gastric precancerous conditions and lesions. Chin Med 2022; 17:138. [PMID: 36517854 PMCID: PMC9749368 DOI: 10.1186/s13020-022-00677-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 10/17/2022] [Indexed: 12/15/2022] Open
Abstract
The standardized diagnosis and management of gastric precancerous conditions and lesions are important to prevent gastric cancer. This guideline, created by 5 traditional Chinese medicine and Western medicine associations, based on the current morbidity and diagnosis and treatment of gastric precancerous conditions and lesions, provides specific key points and strategies for diagnosis and treatment in the following five aspects: definition and epidemiology, diagnosis and stage, surveillance, treatment and efficacy evaluation. It is hoped that these aspects, assessed by integrating Western medicine and traditional Chinese medicine and involving multidisciplinary participation, will play a guiding role in clinical diagnosis and treatment and achieve effective secondary prevention of gastric cancer.
Collapse
Affiliation(s)
- Ping Wang
- China Academy of Chinese Medical Sciences, Xiyuan Hospital, Beijing, China
| | - Peng Li
- Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, China
| | - Yingxuan Chen
- Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
| | - Li Li
- China Academy of Chinese Medical Sciences, Guanganmen Hospital, Beijing, China
| | - Yuanyuan Lu
- Air Force Medical University Xijing Hospital, Xi'an, China
| | - Weixun Zhou
- Peking Union Medical College Hospital, Beijing, China
| | - Liqun Bian
- China Academy of Chinese Medical Sciences, Xiyuan Hospital, Beijing, China
| | - Beihua Zhang
- China Academy of Chinese Medical Sciences, Xiyuan Hospital, Beijing, China
| | - Xiaolan Yin
- China Academy of Chinese Medical Sciences, Xiyuan Hospital, Beijing, China
| | - Junxiang Li
- Beijing University of Chinese Medicine School of Traditional Chinese Medicine, Beijing, China.
| | - Jie Chen
- Peking Union Medical College Hospital, Beijing, China.
| | - Shutian Zhang
- Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, China.
| | - Yongquan Shi
- Air Force Medical University Xijing Hospital, Xi'an, China.
| | - Xudong Tang
- China Academy of Chinese Medical Sciences, Xiyuan Hospital, Beijing, China.
| |
Collapse
|
|
3
|
Lee JWJ, Zhu F, Srivastava S, Tsao SKK, Khor C, Ho KY, Fock KM, Lim WC, Ang TL, Chow WC, So JBY, Koh CJ, Chua SJ, Wong ASY, Rao J, Lim LG, Ling KL, Chia CK, Ooi CJ, Rajnakova A, Yap WM, Salto-Tellez M, Ho B, Soong R, Chia KS, Teo YY, Teh M, Yeoh KG. Severity of gastric intestinal metaplasia predicts the risk of gastric cancer: a prospective multicentre cohort study (GCEP). Gut 2022; 71:854-863. [PMID: 33975867 PMCID: PMC8995828 DOI: 10.1136/gutjnl-2021-324057] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 04/15/2021] [Accepted: 04/30/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVE To investigate the incidence of gastric cancer (GC) attributed to gastric intestinal metaplasia (IM), and validate the Operative Link on Gastric Intestinal Metaplasia (OLGIM) for targeted endoscopic surveillance in regions with low-intermediate incidence of GC. METHODS A prospective, longitudinal and multicentre study was carried out in Singapore. The study participants comprised 2980 patients undergoing screening gastroscopy with standardised gastric mucosal sampling, from January 2004 and December 2010, with scheduled surveillance endoscopies at year 3 and 5. Participants were also matched against the National Registry of Diseases Office for missed diagnoses of early gastric neoplasia (EGN). RESULTS There were 21 participants diagnosed with EGN. IM was a significant risk factor for EGN (adjusted-HR 5.36; 95% CI 1.51 to 19.0; p<0.01). The age-adjusted EGN incidence rates for patients with and without IM were 133.9 and 12.5 per 100 000 person-years. Participants with OLGIM stages III-IV were at greatest risk (adjusted-HR 20.7; 95% CI 5.04 to 85.6; p<0.01). More than half of the EGNs (n=4/7) attributed to baseline OLGIM III-IV developed within 2 years (range: 12.7-44.8 months). Serum trefoil factor 3 distinguishes (Area Under the Receiver Operating Characteristics 0.749) patients with OLGIM III-IV if they are negative for H. pylori. Participants with OLGIM II were also at significant risk of EGN (adjusted-HR 7.34; 95% CI 1.60 to 33.7; p=0.02). A significant smoking history further increases the risk of EGN among patients with OLGIM stages II-IV. CONCLUSIONS We suggest a risk-stratified approach and recommend that high-risk patients (OLGIM III-IV) have endoscopic surveillance in 2 years, intermediate-risk patients (OLGIM II) in 5 years.
Collapse
Affiliation(s)
- Jonathan W J Lee
- Division of Gastroenterology and Hepatology, National University Hospital, Singapore,Department of Medicine, National University of Singapore, Singapore,Singapore Gastric Cancer Consortium, Singapore
| | - Feng Zhu
- Department of Medicine, National University of Singapore, Singapore,Singapore Gastric Cancer Consortium, Singapore
| | | | - Stephen KK Tsao
- Department of Gastroenterology & Hepatology, Tan Tock Seng Hospital, Singapore
| | - Christopher Khor
- Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore
| | - Khek Yu Ho
- Division of Gastroenterology and Hepatology, National University Hospital, Singapore,Department of Medicine, National University of Singapore, Singapore
| | - Kwong Ming Fock
- Department of Gastroenterology & Hepatology, Changi General Hospital, Singapore
| | - Wee Chian Lim
- Department of Gastroenterology & Hepatology, Tan Tock Seng Hospital, Singapore
| | - Tiing Leong Ang
- Department of Gastroenterology & Hepatology, Changi General Hospital, Singapore
| | - Wan Cheng Chow
- Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore
| | - Jimmy Bok Yan So
- Singapore Gastric Cancer Consortium, Singapore,Department of Surgery, National University of Singapore, Singapore
| | - Calvin J Koh
- Division of Gastroenterology and Hepatology, National University Hospital, Singapore,Department of Medicine, National University of Singapore, Singapore,Singapore Gastric Cancer Consortium, Singapore
| | - Shijia Joy Chua
- Department of Medicine, National University of Singapore, Singapore
| | | | - Jaideepraj Rao
- Department of Surgery, Tan Tock Seng Hospital, Singapore
| | | | | | | | | | - Andrea Rajnakova
- Andrea's Digestive, Colon, Liver and Gallbladder Clinic Pte Ltd, Singapore
| | - Wai Ming Yap
- Department of Pathology, Tan Tock Seng Hospital, Singapore
| | - Manuel Salto-Tellez
- Precision Medicine Centre of Excellence, Queen's University Belfast, Belfast, UK,Integrated Pathology Unit, Institute of Cancer Research, London, UK
| | - Bow Ho
- Department of Microbiology, National University of Singapore, Singapore
| | - Richie Soong
- Cancer Science Institute of Singapore, National University of Singapore, Singapore,Department of Pathology, National University of Singapore, Singapore,Pascific Laboratories, Singapore
| | - Kee Seng Chia
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore
| | - Yik Ying Teo
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore
| | - Ming Teh
- Singapore Gastric Cancer Consortium, Singapore,Department of Pathology, National University of Singapore, Singapore
| | - Khay-Guan Yeoh
- Division of Gastroenterology and Hepatology, National University Hospital, Singapore .,Department of Medicine, National University of Singapore, Singapore.,Singapore Gastric Cancer Consortium, Singapore
| |
Collapse
|
|
4
|
Saberi S, Esmaeili M, Tashakoripour M, Eshagh Hosseini M, Baharvand H, Mohammadi M. Infection with a hypervirulent strain of Helicobacter pylori primes gastric cells toward intestinal transdifferentiation. Microb Pathog 2021; 162:105353. [PMID: 34896202 DOI: 10.1016/j.micpath.2021.105353] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 12/05/2021] [Accepted: 12/05/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Intestinal metaplasia, gastric-to-intestinal transdifferentiation, occurs as a result of the misexpression of certain regulatory factors, leading to genetic reprogramming. Here, we have evaluated the H. pylori-induced expression patterns of these candidate genes. METHODS The expression levels of 1) tissue-specific transcription factors (RUNX3, KLF5, SOX2, SALL4, CDX1 and CDX2), 2) stemness factors (TNFRSF19, LGR5, VIL1) and 3) tissue-specific mucins (MUC5AC, MUC2) were evaluated by quantitative real-time PCR in gastric primary cells (GPCs), in parallel with two gastric cancer (MKN45 and AGS) cell lines, up to 96h following H. pylori infection. RESULTS Following H. pylori infection of GPCs, RUNX3 declined at 24h post infection (-6.2 ± 0.3) and remained downregulated for up to 96h. Subsequently, overexpression of self-renewal and pluripotency transcription factors, KLF5 (3.6 ± 0.2), SOX2 (7.6 ± 0.5) and SALL4 (4.3 ± 0.2) occurred. The expression of TNFRSF19 and LGR5, demonstrated opposing trends, with an early rise of the former (4.5 ± 0.3) at 8h, and a simultaneous fall of the latter (-1.8 ± 0.5). This trend was reversed at 96h, with the decline in TNFRSF19 (-5.5 ± 0.2), and escalation of LGR5 (2.6 ± 0.2) and VIL1 (1.8 ± 0.3). Ultimately, CDX1 and CDX2 were upregulated by 1.9 and 4.7-fold, respectively. The above scenario was, variably observed in MKN45 and AGS cells. CONCLUSION Our data suggests an interdependent gene regulatory network, induced by H. pylori infection. This interaction begins with the downregulation of RUNX3, upregulation of self-renewal and pluripotency transcription factors, KLF5, SOX2 and SALL4, leading to the downregulation of TNFRSF19, upregulation of LGR5 and aberrant expression of intestine-specific transcription factors, potentially facilitating the process of gastric-to-intestinal transdifferentiation.
Collapse
Affiliation(s)
- Samaneh Saberi
- HPGC Research Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Maryam Esmaeili
- HPGC Research Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Mohammad Tashakoripour
- Gastroenterology Department, Amiralam Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmoud Eshagh Hosseini
- Gastroenterology Department, Amiralam Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Baharvand
- Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Developmental Biology, University of Science and Culture, Tehran, Iran
| | - Marjan Mohammadi
- HPGC Research Group, Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
| |
Collapse
|
|
5
|
Smet A, Kupcinskas J, Link A, Hold GL, Bornschein J. The Role of Microbiota in Gastrointestinal Cancer and Cancer Treatment: Chance or Curse? Cell Mol Gastroenterol Hepatol 2021; 13:857-874. [PMID: 34506954 PMCID: PMC8803618 DOI: 10.1016/j.jcmgh.2021.08.013] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 08/18/2021] [Accepted: 08/18/2021] [Indexed: 02/08/2023]
Abstract
The gastrointestinal (GI) tract is home to a complex and dynamic community of microorganisms, comprising bacteria, archaea, viruses, yeast, and fungi. It is widely accepted that human health is shaped by these microbes and their collective microbial genome. This so-called second genome plays an important role in normal functioning of the host, contributing to processes involved in metabolism and immune modulation. Furthermore, the gut microbiota also is capable of generating energy and nutrients (eg, short-chain fatty acids and vitamins) that are otherwise inaccessible to the host and are essential for mucosal barrier homeostasis. In recent years, numerous studies have pointed toward microbial dysbiosis as a key driver in many GI conditions, including cancers. However, comprehensive mechanistic insights on how collectively gut microbes influence carcinogenesis remain limited. In addition to their role in carcinogenesis, the gut microbiota now has been shown to play a key role in influencing clinical outcomes to cancer immunotherapy, making them valuable targets in the treatment of cancer. It also is becoming apparent that, besides the gut microbiota's impact on therapeutic outcomes, cancer treatment may in turn influence GI microbiota composition. This review provides a comprehensive overview of microbial dysbiosis in GI cancers, specifically esophageal, gastric, and colorectal cancers, potential mechanisms of microbiota in carcinogenesis, and their implications in diagnostics and cancer treatment.
Collapse
Affiliation(s)
- Annemieke Smet
- Laboratory of Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences; Infla-Med Research Consortium of Excellence, University of Antwerp, Antwerp, Belgium
| | - Juozas Kupcinskas
- Institute for Digestive Research, Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
| | - Georgina L Hold
- Microbiome Research Centre, St George and Sutherland Clinical School, University of New South Wales, Sydney, Australia
| | - Jan Bornschein
- Translational Gastroenterology Unit, Nuffield Department of Experimental Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
| |
Collapse
|
|
6
|
Battista S, Ambrosio MR, Limarzi F, Gallo G, Saragoni L. Molecular Alterations in Gastric Preneoplastic Lesions and Early Gastric Cancer. Int J Mol Sci 2021; 22:6652. [PMID: 34206291 PMCID: PMC8268370 DOI: 10.3390/ijms22136652] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/11/2021] [Accepted: 06/15/2021] [Indexed: 12/16/2022] Open
Abstract
Prognosis of gastric cancer is dramatically improved by early diagnosis. Correa's cascade correlates the expression of some molecular markers with the progression of preneoplastic lesions toward carcinoma. This article reviews the diagnostic and prognostic values of molecular markers in complete (MUC2) and incomplete (MUC2, MUC5AC, and MUC6) intestinal metaplasia, gastric dysplasia/intra-epithelial neoplasia, and early gastric cancer. In particular, considering preinvasive neoplasia and early gastric cancer, some studies have demonstrated a correlation between molecular alterations and prognosis, for example, mucins phenotype in gastric dysplasia, and GATA6, TP53 mutation/LOH and MUC6 in early gastric cancer. Moreover, this review considers novelties from the literature regarding the (immuno)histochemical characterization of diffuse-type/signet ring cell gastric cancer, with particular attention to clinical outcomes of patients. The aim of this review is the evaluation of the state of the art regarding suitable biomarkers used in the pre-surgical phase, which can distinguish patients with different prognoses and help decide the best therapeutic strategy.
Collapse
Affiliation(s)
- Serena Battista
- Pathology Department, “S. Maria della Misericordia Hospital”, Friuli-Venezia Giulia, 33100 Udine, Italy
| | | | - Francesco Limarzi
- Pathology Department, “G.B. Morgagni-L. Pierantoni Hospital”, Emilia-Romagna, 47121 Forlì, Italy; (F.L.); (L.S.)
| | - Graziana Gallo
- Pathology Department, “M. Bufalini Hospital”, Emilia Romagna, 47521 Cesena, Italy;
| | - Luca Saragoni
- Pathology Department, “G.B. Morgagni-L. Pierantoni Hospital”, Emilia-Romagna, 47121 Forlì, Italy; (F.L.); (L.S.)
| |
Collapse
|
|
7
|
Dong N, Guo R, Gong Y, Yuan Y. Phenotype characteristics of gastric epithelial mucus in patients with different gastric diseases: from superficial gastritis to gastric cancer. PeerJ 2021; 9:e10822. [PMID: 33665018 PMCID: PMC7916529 DOI: 10.7717/peerj.10822] [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: 08/17/2020] [Accepted: 01/02/2021] [Indexed: 11/20/2022] Open
Abstract
Background Gastric gland mucin is important for maintaining the basic function of the gastric mucosa, protecting it from foreign substances and reducing the occurrence of gastric diseases. Exploring the phenotype of gastric gland mucus changes during the progression of gastric disease is of great clinical significance. Methods A total of 483 patients with different gastric diseases were collected in this study, including 82 superficial gastritis (SG), 81 atrophic gastritis (AG), 168 dysplasia (GD), and 152 gastric cancer (GC). Mucin staining was performed using HID-ABpH2.5-PAS method and was further grouped according to the mucin coloration. Results The phenotypic characteristics of mucin during disease progression were divided into neutral, acidic, and mucus-free types. Furthermore, acidic mucus can be divided into type I, type II, and type III. The SG group was dominated by neutral mucus (100%), and the AG was dominated by acid mucus (81.48%), which gradually increased with the severity of atrophy (P < 0.05). The GD and GC groups were dominated by mucus-free (43.45%, 78.29%), and as the degree of GD worsened, neutral and acidic mucus gradually decreased and mucus-free increased (P < 0.001). From the SG, AG, GD, and GC progression, neutral and acidic mucus gradually decreased, and mucus- free gradually increased. Acidic mucin revealed that type III (red-brown black) mucin was predominant in AG, GD, and GC, and increased with the degree of AG, GD, as well as the biological behavior of GC. In the lesion adjacent to high-grade GD or GC, type III acid mucin is predominant. Conclusion There were three mucin phenotypes in the process of gastric diseases. With the disease progression, the trend of phenotypic change was that neutral and acidic mucus gradually decreased and mucus-free increased. The appearance of type III mucin suggested a relatively serious phase of gastric diseases and may be a more suitable candidate for follow-up monitoring of patients with GC risk.
Collapse
Affiliation(s)
- Nannan Dong
- The First Hospital of China Medical University, Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, Shenyang, LiaoNing, China.,The First Hospital of China Medical University, Tumor Etiology and Screening Department of Cancer Institute and General Surgery, Shenyang, LiaoNing, China.,The First Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, Shenyang, LiaoNing, China
| | - Rui Guo
- The First Hospital of China Medical University, Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, Shenyang, LiaoNing, China.,The First Hospital of China Medical University, Tumor Etiology and Screening Department of Cancer Institute and General Surgery, Shenyang, LiaoNing, China.,The First Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, Shenyang, LiaoNing, China
| | - Yuehua Gong
- The First Hospital of China Medical University, Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, Shenyang, LiaoNing, China.,The First Hospital of China Medical University, Tumor Etiology and Screening Department of Cancer Institute and General Surgery, Shenyang, LiaoNing, China.,The First Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, Shenyang, LiaoNing, China
| | - Yuan Yuan
- The First Hospital of China Medical University, Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, Shenyang, LiaoNing, China.,The First Hospital of China Medical University, Tumor Etiology and Screening Department of Cancer Institute and General Surgery, Shenyang, LiaoNing, China.,The First Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, Shenyang, LiaoNing, China
| |
Collapse
|
|
8
|
Rajilic-Stojanovic M, Figueiredo C, Smet A, Hansen R, Kupcinskas J, Rokkas T, Andersen L, Machado JC, Ianiro G, Gasbarrini A, Leja M, Gisbert JP, Hold GL. Systematic review: gastric microbiota in health and disease. Aliment Pharmacol Ther 2020; 51:582-602. [PMID: 32056247 DOI: 10.1111/apt.15650] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 01/09/2020] [Accepted: 01/17/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Helicobacter pylori is the most infamous constituent of the gastric microbiota and its presence is the strongest risk factor for gastric cancer and other gastroduodenal diseases. Although historically the healthy stomach was considered a sterile organ, we now know it is colonised with a complex microbiota. However, its role in health and disease is not well understood. AIM To systematically explore the literature on the gastric microbiota in health and disease as well as the gut microbiota after bariatric surgery. METHODS A systematic search of online bibliographic databases MEDLINE/EMBASE was performed between 1966 and February 2019 with screening in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomised controlled trials, cohort studies and observational studies were included if they reported next-generation sequencing derived microbiota analysis on gastric aspirate/tissue or stool samples (bariatric surgical outcomes). RESULTS Sixty-five papers were eligible for inclusion. With the exception of H pylori-induced conditions, overarching gastric microbiota signatures of health or disease could not be determined. Gastric carcinogenesis induces a progressively altered microbiota with an enrichment of oral and intestinal taxa as well as significant changes in host gastric mucin expression. Proton pump inhibitors usage increases gastric microbiota richness. Bariatric surgery is associated with an increase in potentially pathogenic proteobacterial species in patient stool samples. CONCLUSION While H pylori remains the single most important risk factor for gastric disease, its capacity to shape the collective gastric microbiota remains to be fully elucidated. Further studies are needed to explore the intricate host/microbial and microbial/microbial interplay.
Collapse
|
|
9
|
Danese E, Ruzzenente A, Montagnana M, Lievens PMJ. Current and future roles of mucins in cholangiocarcinoma-recent evidences for a possible interplay with bile acids. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:333. [PMID: 30306072 DOI: 10.21037/atm.2018.07.16] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cholangiocarcinoma (CCA) is rare but highly malignant tumour. The diagnosis is difficult due to its silent clinical character and the inefficiency of currently available diagnostic markers. An enhanced understanding of the molecular pathways involved in CCA carcinogenesis would herald targeted, individualized therapies, as well as new early diagnostic tool with improvement of patient survival. Recently, two mucin proteins, MUC4 and MUC5 have gained interest for their involvement in tumour growth and progression and possible use as diagnostic and prognostic cancer biomarkers. Moreover, a number of studies have demonstrated an association between biliary or serum bile acids (BAs) and some forms of cancers including CCA. More importantly, BAs have been shown to participate in tumour progression by inducing alterations in the expression of oncogenic mucins. This review summarizes the most important findings regarding the possible use of mucin glycoproteins and BAs in the diagnosis and prognostication of CCA and discuss evidences suggesting a role of BAs in regulating the expression of transmembrane and secreted mucins.
Collapse
Affiliation(s)
- Elisa Danese
- Section of Clinical Biochemistry, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Andrea Ruzzenente
- Section of General and Hepatobiliary Surgery, Department of Surgery, Dentistry, Paediatrics and Gynaecology, University of Verona, Verona, Italy
| | - Martina Montagnana
- Section of Clinical Biochemistry, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Patricia Marie-Jeanne Lievens
- Section of Biology and Genetics, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| |
Collapse
|
|
10
|
Asano N, Imatani A, Watanabe T, Fushiya J, Kondo Y, Jin X, Ara N, Uno K, Iijima K, Koike T, Strober W, Shimosegawa T. Cdx2 Expression and Intestinal Metaplasia Induced by H. pylori Infection of Gastric Cells Is Regulated by NOD1-Mediated Innate Immune Responses. Cancer Res 2016; 76:1135-1145. [PMID: 26759244 PMCID: PMC4799656 DOI: 10.1158/0008-5472.can-15-2272] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 12/11/2015] [Indexed: 12/16/2022]
Abstract
Chronic infection with the bacterial Helicobacter pylori is a major cause of gastric and duodenal ulcer disease, gastric mucosal atrophy, and cancer. H. pylori-induced expression of the intestinal epithelial-specific transcription factor caudal-related homeobox 2 (Cdx2) contributes to intestinal metaplasia, a precursor event to gastric cancer. Given a role for the bacterial pattern recognition molecule nucleotide-binding oligomerization domain 1 (NOD1) in the innate immune response to bacterial infection, we investigated mechanisms used by NOD1 to regulate H. pylori infection and its propensity towards the development of intestinal metaplasia. We found that Cdx2 was induced by H. pylori infection in both normal and neoplastic gastric epithelial cells in a manner that was inversely related to NOD1 signaling. Mechanistic investigations revealed that Cdx2 induction relied upon activation of NF-κB but was suppressed by NOD1-mediated activation of TRAF3, a negative regulator of NF-κB. In vivo, prolonged infection of NOD1-deficient mice with H. pylori led to increased Cdx2 expression and intestinal metaplasia. Furthermore, gastric epithelial cells from these mice exhibited increased nuclear expression of the NF-κB p65 subunit and decreased expression of TRAF3. Overall, our findings illuminated a role for NOD1 signaling in attenuating H. pylori-induced Cdx2 expression in gastric epithelial cells, suggesting a rationale to augment NOD1 signaling in H. pylori-infected patients to limit their risks of accumulating precancerous gastric lesions.
Collapse
Affiliation(s)
- Naoki Asano
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
| | - Akira Imatani
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Tomohiro Watanabe
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland. Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan
| | - Jun Fushiya
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Yutaka Kondo
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Xiaoyi Jin
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Nobuyuki Ara
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Kaname Uno
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Katsunori Iijima
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Tomoyuki Koike
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Warren Strober
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| |
Collapse
|
|
11
|
Rossez Y, Burtea C, Laurent S, Gosset P, Léonard R, Gonzalez W, Ballet S, Raynal I, Rousseaux O, Dugué T, Vander Elst L, Michalski JC, Muller RN, Robbe-Masselot C. Early detection of colonic dysplasia by magnetic resonance molecular imaging with a contrast agent raised against the colon cancer marker MUC5AC. CONTRAST MEDIA & MOLECULAR IMAGING 2016; 11:211-21. [PMID: 26762591 DOI: 10.1002/cmmi.1682] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 10/08/2015] [Accepted: 11/27/2015] [Indexed: 11/05/2022]
Abstract
Human gastric mucin MUC5AC is secreted in the colonic mucus of cancer patients and is a specific marker of precancerous lesions called aberrant crypt foci. Using MUC5AC as a specific marker can improve sensitivity in the detection of early colorectal cancer. Here we demonstrated that the accumulation of MUC5AC in xenograft and mouse stomach can be detected by magnetic resonance imaging (MRI). We used ultrasmall particles of iron oxide (USPIOs) conjugated with disulfide constrained heptapeptide that were identified using a screening phage display. To accomplish this, we employed positive selection of the phage display library on MUC5AC purified from fresh human colonic adenomas in combination with negative selection of the phage library on purified human MUC2, which is predominantly found in normal colorectal tissues. This conjugate was tested on human colorectal cancer cell lines that were either able or unable to secrete MUC5AC, both in vitro and in vivo. MUC5AC-USPIO contrast agent and USPIOs alone were not detected in cell lines unable to secrete MUC5AC. A combination of MRI and microscopy studies was performed to detect a specific accumulation of the contrast agent in vivo. Thus, the MUC5AC contrast agent enabled non-invasive detection of precancerous lesions and colorectal cancer, highlighting its potential use in diagnostics, in the early detection of colorectal cancer recurrences after treatment and in mechanistic studies implicating MUC5AC. Copyright © 2016 John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Yannick Rossez
- University of Lille Nord de France, F-59000, Lille, France.,USTL, UGSF, IFR 147, F-59650, Villeneuve d'Ascq, France.,CNRS, UMR 8576, F-59650, Villeneuve d'Ascq, France
| | - Carmen Burtea
- Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons-Hainaut, 19, Avenue Maistriau, Mendeleev Building, B-7000, Mons, Belgium
| | - Sophie Laurent
- Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons-Hainaut, 19, Avenue Maistriau, Mendeleev Building, B-7000, Mons, Belgium
| | - Pierre Gosset
- University of Lille Nord de France, F-59000, Lille, France.,UCLille, Service d'Anatomie Pathologie, F-59000, Lille, France.,Groupe Hospitalier de l'Institut Catholique Lillois/Faculté Libre de Médecine, F-59000, Lille, France
| | - Renaud Léonard
- University of Lille Nord de France, F-59000, Lille, France.,USTL, UGSF, IFR 147, F-59650, Villeneuve d'Ascq, France.,CNRS, UMR 8576, F-59650, Villeneuve d'Ascq, France
| | - Walter Gonzalez
- Guerbet, Research Center, 16-24 rue Jean Chaptal, 93600, Aulnay-sous-Bois, France
| | - Sébastien Ballet
- Guerbet, Research Center, 16-24 rue Jean Chaptal, 93600, Aulnay-sous-Bois, France
| | - Isabelle Raynal
- Guerbet, Research Center, 16-24 rue Jean Chaptal, 93600, Aulnay-sous-Bois, France
| | - Olivier Rousseaux
- Guerbet, Research Center, 16-24 rue Jean Chaptal, 93600, Aulnay-sous-Bois, France
| | - Timothée Dugué
- Groupe Hospitalier de l'Institut Catholique Lillois/Faculté Libre de Médecine, F-59000, Lille, France
| | - Luce Vander Elst
- Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons-Hainaut, 19, Avenue Maistriau, Mendeleev Building, B-7000, Mons, Belgium
| | - Jean-Claude Michalski
- University of Lille Nord de France, F-59000, Lille, France.,USTL, UGSF, IFR 147, F-59650, Villeneuve d'Ascq, France.,CNRS, UMR 8576, F-59650, Villeneuve d'Ascq, France
| | - Robert N Muller
- Department of General, Organic and Biomedical Chemistry, NMR and Molecular Imaging Laboratory, University of Mons-Hainaut, 19, Avenue Maistriau, Mendeleev Building, B-7000, Mons, Belgium
| | - Catherine Robbe-Masselot
- University of Lille Nord de France, F-59000, Lille, France.,USTL, UGSF, IFR 147, F-59650, Villeneuve d'Ascq, France.,CNRS, UMR 8576, F-59650, Villeneuve d'Ascq, France
| |
Collapse
|
|
12
|
Weledji EP, Enow Orock G, Ngowe MN. Intestinal metaplasia and anastomotic recurrence of gastric carcinoma. J Gastrointest Oncol 2014; 5:474-80. [PMID: 25436128 DOI: 10.3978/j.issn.2078-6891.2014.048] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2014] [Accepted: 06/29/2014] [Indexed: 12/16/2022] Open
Abstract
Intestinal metaplasia (IM) of the stomach has been shown to increase the relative risk of gastric cancer. Endoscopic surveillance has been proposed and advocated for populations at risk. Those patients who had undergone surgery for gastric malignancy exhibited precancerous lesions such as atrophic gastritis and IM, and the possibility of anastomotic recurrence is higher than for the patients who had undergone benign gastric surgery. At present, there are no other recognized good markers of gastric dysplasia or cancer. We reviewed the literature on IM of the stomach to ascertain whether residual premalignant (type III) IM may predispose to anastomotic recurrence of gastric cancer.
Collapse
Affiliation(s)
- Elroy Patrick Weledji
- 1 Department of Surgery, 2 Department of Pathology, Faculty of Health Sciences, University of Buea, Buea, S.W. Region, Cameroon
| | - George Enow Orock
- 1 Department of Surgery, 2 Department of Pathology, Faculty of Health Sciences, University of Buea, Buea, S.W. Region, Cameroon
| | - Marcelin Ngowe Ngowe
- 1 Department of Surgery, 2 Department of Pathology, Faculty of Health Sciences, University of Buea, Buea, S.W. Region, Cameroon
| |
Collapse
|
|
13
|
Akhavan-Niaki H, Samadani AA. Molecular insight in gastric cancer induction: an overview of cancer stemness genes. Cell Biochem Biophys 2014; 68:463-73. [PMID: 24078401 DOI: 10.1007/s12013-013-9749-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Gastric cancer is one of the most outgoing human cancers in the world. Two main functional types were described: Intestinal adenocarcinoma and diffuse one. The most important purpose of this review is to analyze and investigate the main genetic factors involved in tumorogenesis of stomach and the molecular mechanism of their expression regulation alongside with the importance of cancer stem cells and their relationship with gastric cancer. It is evident that proper diagnosis of molecular case of cancer may lead to absolute treatment and at least reduction in the disease severity. However, stemness factors such as Sox2, Oct3/4, and Nanog were related with induced pluripotent stem cells, proposing a correlation between these stemness factors and cancer stem cells. Moreover, aberrant induction by Helicobacter pylori of the intestinal-specific homeobox transcription factors, CDX1 and CDX2, also plays an important role in this modification. There are some genes which are directly activated by CDX1 in gastric cancer and distinguished stemness-related reprogramming factors like SALL4 and KLF5. Correspondingly, we also aimed to present the main important epigenetic changes such as DNA methylation, histone modification, and chromatin modeling of stemness genes in disease development. Remarkably, a better understanding of molecular bases of cancer may lead to novel diagnostic, therapeutic, and preventive approaches by some genetic and epigenetic changes such as gene amplifications, gene silencing by DNA methylation, losses of imprinting, LOH, and mutations. Consequently, genome-wide searches of gene expression are widely important for surveying the proper mechanisms of cancer emergence and development. Conspicuously, this review explains an outline of the molecular mechanism and new approaches in gastric cancer.
Collapse
Affiliation(s)
- Haleh Akhavan-Niaki
- Cellular and Molecular Biology Research Center, Babol University of Medical Sciences, Babol, Iran
| | | |
Collapse
|
|
14
|
Pizzi M, Saraggi D, Fassan M, Megraud F, Di Mario F, Rugge M. Secondary prevention of epidemic gastric cancer in the model of Helicobacter pylori-associated gastritis. Dig Dis 2014; 32:265-274. [PMID: 24732192 DOI: 10.1159/000357857] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Irrespective of its etiology, long-standing, non-self-limiting gastric inflammation (mostly in Helicobacter pylori-associated cases) is the cancerization ground on which epidemic (intestinal-type) gastric carcinoma (GC) can develop. The natural history of invasive gastric adenocarcinoma encompasses gastritis, atrophic mucosal changes, and intraepithelial neoplasia (IEN). The topography, the extent and the severity of the atrophic changes significantly correlate with the risk of developing both IEN and GC. In recent years, both noninvasive (serological) tests and invasive (endoscopy/biopsy) procedures have been proposed to stratify patients according to different classes of GC risk. As a consequence, different patient-tailored GC secondary prevention strategies have been put forward. This review summarizes the histological features of H. pylori-related gastritis and the natural history of the disease. Histological and serological strategies to assess GC risk as well as the clinical management of atrophic gastritis patients are also discussed.
Collapse
Affiliation(s)
- Marco Pizzi
- General Pathology and Cytopathology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy
| | | | | | | | | | | |
Collapse
|
|
15
|
Squire JM, Guerreiro MJ, Sidebotham RL, Reis CA, Wiseman J, Luther PK. Quantitative MUC5AC and MUC6 mucin estimations in gastric mucus by a least-squares minimization method. Anal Biochem 2013; 439:204-11. [DOI: 10.1016/j.ab.2013.04.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Revised: 04/12/2013] [Accepted: 04/13/2013] [Indexed: 10/26/2022]
|
|
16
|
|
|
17
|
Gomes C, Almeida A, Ferreira JA, Silva L, Santos-Sousa H, Pinto-de-Sousa J, Santos LL, Amado F, Schwientek T, Levery SB, Mandel U, Clausen H, David L, Reis CA, Osório H. Glycoproteomic analysis of serum from patients with gastric precancerous lesions. J Proteome Res 2013; 12:1454-66. [PMID: 23312025 DOI: 10.1021/pr301112x] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Gastric cancer is preceded by a carcinogenesis pathway that includes gastritis caused by Helicobacter pylori infection, chronic atrophic gastritis that may progress to intestinal metaplasia (IM), dysplasia, and ultimately gastric carcinoma of the more common intestinal subtype. The identification of glycosylation changes in circulating serum proteins in patients with precursor lesions of gastric cancer is of high interest and represents a source of putative new biomarkers for early diagnosis and intervention. This study applies a glycoproteomic approach to identify altered glycoproteins expressing the simple mucin-type carbohydrate antigens T and STn in the serum of patients with gastritis, IM (complete and incomplete subtypes), and control healthy individuals. The immunohistochemistry analysis of the gastric mucosa of these patients showed expression of T and STn antigens in gastric lesions, with STn being expressed only in IM. The serum glycoproteomic analysis using 2D-gel electrophoresis, Western blot, and MALDI-TOF/TOF mass spectrometry led to the identification of circulating proteins carrying these altered glycans. One of the glycoproteins identified was plasminogen, a protein that has been reported to play a role in H. pylori chronic infection of the gastric mucosa and is involved in extracellular matrix modeling and degradation. Plasminogen was further characterized and showed to carry STn antigens in patients with gastritis and IM. These results provide evidence of serum proteins displaying abnormal O-glycosylation in patients with precursor lesions of gastric carcinoma and include a panel of putative targets for the non-invasive clinical diagnosis of individuals with gastritis and IM.
Collapse
Affiliation(s)
- Catarina Gomes
- Institute of Molecular Pathology and Immunology University of Porto, IPATIMUP, Porto, Portugal
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Gomes J, Magalhães A, Carvalho AS, Hernandez GE, Papp SL, Head SR, Michel V, David L, Gärtner F, Touati E, Reis CA. Glycophenotypic alterations induced by Pteridium aquilinum in mice gastric mucosa: synergistic effect with Helicobacter pylori infection. PLoS One 2012; 7:e38353. [PMID: 22719879 PMCID: PMC3374793 DOI: 10.1371/journal.pone.0038353] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2012] [Accepted: 05/08/2012] [Indexed: 01/13/2023] Open
Abstract
The bracken fern Pteridium aquilinum is a plant known to be carcinogenic to animals. Epidemiological studies have shown an association between bracken fern exposure and gastric cancer development in humans. The biological effects of exposure to this plant within the gastric carcinogenesis process are not fully understood. In the present work, effects in the gastric mucosa of mice treated with Pteridium aquilinum were evaluated, as well as molecular mechanisms underlying the synergistic role with Helicobacter pylori infection. Our results showed that exposure to Pteridium aquilinum induces histomorphological modifications including increased expression of acidic glycoconjugates in the gastric mucosa. The transcriptome analysis of gastric mucosa showed that upon exposure to Pteridium aquilinum several glycosyltransferase genes were differently expressed, including Galntl4, C1galt1 and St3gal2, that are mainly involved in the biosynthesis of simple mucin-type carbohydrate antigens. Concomitant treatment with Pteridium aquilinum and infection with Helicobacter pylori also resulted in differently expressed glycosyltransferase genes underlying the biosynthesis of terminal sialylated Lewis antigens, including Sialyl-Lewisx. These results disclose the molecular basis for the altered pattern of glycan structures observed in the mice gastric mucosa. The gene transcription alterations and the induced glycophenotypic changes observed in the gastric mucosa contribute for the understanding of the molecular mechanisms underlying the role of Pteridium aquilinum in the gastric carcinogenesis process.
Collapse
Affiliation(s)
- Joana Gomes
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Universidade do Porto, Porto, Portugal
- Institut Pasteur, Unité de Pathogenèse de Helicobacter, Paris, France
| | - Ana Magalhães
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Universidade do Porto, Porto, Portugal
| | - Ana S. Carvalho
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Universidade do Porto, Porto, Portugal
| | | | - Suzanne L. Papp
- The Scripps Research Institute, La Jolla, California, United States of America
| | - Steven R. Head
- The Scripps Research Institute, La Jolla, California, United States of America
| | - Valérie Michel
- Institut Pasteur, Unité de Pathogenèse de Helicobacter, Paris, France
| | - Leonor David
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Universidade do Porto, Porto, Portugal
- Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| | - Fátima Gärtner
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Universidade do Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Eliette Touati
- Institut Pasteur, Unité de Pathogenèse de Helicobacter, Paris, France
| | - Celso A. Reis
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Universidade do Porto, Porto, Portugal
- Faculdade de Medicina, Universidade do Porto, Porto, Portugal
- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
- * E-mail:
| |
Collapse
|
|
19
|
Marín F, Bonet C, Muñoz X, García N, Pardo ML, Ruiz-Liso JM, Alonso P, Capellà G, Sanz-Anquela JM, González CA, Sala N. Genetic variation in MUC1, MUC2 and MUC6 genes and evolution of gastric cancer precursor lesions in a long-term follow-up in a high-risk area in Spain. Carcinogenesis 2012; 33:1072-80. [PMID: 22402132 DOI: 10.1093/carcin/bgs119] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
In order to assess whether inherited genetic variability in the mucin genes associates with the evolution of gastric cancer precursor lesions (GCPLs), we genotyped 22 tagSNPs in MUC1, MUC6 and MUC2 genes of 387 patients with GCPLs that had been followed up for 12.8 years. According to the diagnosis at recruitment and at the end of follow-up, the lesions did not change in 43.1% of the patients, regressed in 28.7% and progressed in 28.2%. Three SNPs in the 3'-moiety of MUC2 were significantly associated with a decreased risk of progression of the lesions, whereas another four SNPs, located at the 5'-moiety, were found to be significantly associated either with increased [one single-nucleotide polymorphism (SNP)] or decreased (three SNPs) probability of regression. Stratified analysis indicated that significance was maintained only in those subjects positive for Helicobacter pylori infection and in those not consuming non-steroidal anti-inflammatory drugs, which were found protective against lesion progression. Haplotype analyses indicated the presence of two haplotypes, one in each moiety of the gene, that were significantly associated with decreased risk of progression of the lesions [odds ratio (OR) = 0.49 and 0.46; 95% confidence interval (CI) = 0.28-0.85 and 0.25-0.86, respectively]. The 5'-end haplotype was also associated with increased probability of regression (OR = 1.67; 95% CI = 1.02-2.73), altogether suggesting a protective role against progression of the precancerous lesions. No significant association was found with variants in MUC1 and MUC6 genes. These results indicate, for the first time, that genetic variability in MUC2 is associated with evolution of GCPLs, especially in H.pylori infected patients, suggesting a role of this secreted mucin in gastric carcinogenesis.
Collapse
Affiliation(s)
- Fátima Marín
- Translational Research Laboratory, Institut Català d'Oncologia (IDIBELL-ICO), Gran Via, km 2.7 s/n, 08907 L'Hospitalet de Llobregat, Spain
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Nagata N, Shimbo T, Akiyama J, Nakashima R, Kim HH, Yoshida T, Hoshimoto K, Uemura N. Predictability of Gastric Intestinal Metaplasia by Mottled Patchy Erythema Seen on Endoscopy. Gastroenterology Res 2011; 4:203-209. [PMID: 27957016 PMCID: PMC5139844 DOI: 10.4021/gr357w] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/26/2011] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Intestinal metaplasia (IM) is regarded as a premalignant lesion. However, endoscopic diagnosis of IM has been considered difficult. Using endoscopy, we found a unique pattern of erythema, "Mottled Patchy Erythema (MPE)," which includes severe IM. Helicobacter pylori (Hp) infection itself can cause erythema, which reflects histologic changes in the gastric mucosa. Therefore we enrolled Hp eradication patients to validate the relation between MPE and pathologic findings. METHODS We enrolled patients with chronic gastritis who underwent successful Hp eradication at least 6 months before the study. We defined MPE as multiple flat or depressed erythematous lesions. When encountering MPE on endoscopy, we performed biopsy on both the MPE site and non-MPE site. The non-MPE site was defined as an adjacent mucosa located within 3 cm of the MPE site. All biopsy specimens were evaluated immunohistochemically for IM subtype using MUC2, MUC5AC, MUC6, CD10, and CDX2 stains. The degree of IM was defined according to the Updated Sydney System. The diagnostic accuracy of the MPE findings for pathologic IM was calculated. The relation between MPE and IM subtype was also assessed. RESULTS A total of 102 patients were selected for the study. Of these, 55 (54%) patients had MPE. Biopsy specimens were taken from the MPE sites and non-MPE sites from these 55 patients. The IM percentages and median scores of IM were both significantly higher at the MPE sites (P < 0.001) than at the non-MPE sites. The sensitivity and specificity for MPE in the detection of histologic IM were 72.7% and 84.1%, respectively. No significant associations were observed in the expression of MUC2, MUC5AC, MUC6, CD10, and CDX2 between the MPE sites and non-MPE sites. There were no significant differences in the ratios (complete/incomplete) of IM subtypes between the two groups. CONCLUSIONS MPE is a useful endoscopic finding to detect histologic IM without the use of chromoendoscopy and magnifying endoscopy. However, the IM subtype is difficult to identify. In the era of Hp eradication, MPE has the potential to become a predictive finding for the risk of gastric cancer.
Collapse
Affiliation(s)
- Naoyoshi Nagata
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine (NCGM), Tokyo, Japan
| | - Takuro Shimbo
- Department of Clinical Research and Informatics International Clinical Research Center Research Institute, NCGM, Tokyo, Japan
| | - Junichi Akiyama
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine (NCGM), Tokyo, Japan
| | - Ryo Nakashima
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine (NCGM), Tokyo, Japan
| | - Hyung Hun Kim
- Division of Internal Medicine, Kosin University College of Medicine, Busan, Korea
| | - Takeichi Yoshida
- Department of Gastroenterology and Hepatology, Wakayama Medical University, Wakayama, Japan
| | - Kazufusa Hoshimoto
- Department of Clinical Laboratory Pathological Division, NCGM, Tokyo, Japan
| | - Naomi Uemura
- Department of Gastroenterology and Hepatology, NCGM, Kohnodai Hospital, Chiba, Japan
| |
Collapse
|
|
21
|
Saeki N, Saito A, Choi IJ, Matsuo K, Ohnami S, Totsuka H, Chiku S, Kuchiba A, Lee YS, Yoon KA, Kook MC, Park SR, Kim YW, Tanaka H, Tajima K, Hirose H, Tanioka F, Matsuno Y, Sugimura H, Kato S, Nakamura T, Nishina T, Yasui W, Aoyagi K, Sasaki H, Yanagihara K, Katai H, Shimoda T, Yoshida T, Nakamura Y, Hirohashi S, Sakamoto H. A functional single nucleotide polymorphism in mucin 1, at chromosome 1q22, determines susceptibility to diffuse-type gastric cancer. Gastroenterology 2011; 140:892-902. [PMID: 21070779 DOI: 10.1053/j.gastro.2010.10.058] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2010] [Revised: 10/01/2010] [Accepted: 10/26/2010] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Two major types of gastric cancer, intestinal and diffuse, develop through distinct mechanisms; the diffuse type is considered to be more influenced by genetic factors, although the mechanism is unknown. Our previous genome-wide association study associated 3 single nucleotide polymorphisms (SNPs) with diffuse-type gastric cancer (DGC); 1 was a functional SNP (rs2294008) in prostate stem cell antigen (PSCA), but the loci of the other 2 were not investigated. METHODS We performed high-density mapping to explore a linkage disequilibrium status of the 2 SNPs at chromosome 1q22. A DGC case-control study was conducted using DNA from 606 cases and 1264 controls (all Japanese individuals) and validated using DNA from Japanese (304 cases, 1465 controls) and Korean (452 cases, 372 controls) individuals. The effects of SNPs on function were analyzed by reporter assays and analyses of splice variants. RESULTS A region of a strong linkage disequilibrium with the 2 SNPs contained mucin 1 (MUC1) and other 4 genes and SNPs significantly associated with DGC (rs2070803: P = 4.33 × 10(-13); odds ratio [OR], 1.71 by meta-analysis of the studies on the 3 panels) but not with intestinal-type gastric cancer. Functional studies demonstrated that rs4072037 (P = 1.43 × 10(-11); OR, 1.66 by meta-analysis) in MUC1 affects promoter activity and determines the major splicing variants of MUC1 in the gastric epithelium. Individuals that carry both SNPs rs2294008 in PSCA and rs4072037 in MUC1 have a high risk for developing DGC (OR, 8.38). CONCLUSIONS MUC1 is the second major DGC susceptibility gene identified. The SNPs rs2070803 and rs4072037 in MUC1 might be used to identify individuals at risk for this type of gastric cancer.
Collapse
Affiliation(s)
- Norihisa Saeki
- Genetics Division, National Cancer Center Research Institute, Tokyo, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Structural investigation of porcine stomach mucin by X-ray fiber diffraction and homology modeling. Biochem Biophys Res Commun 2011; 406:570-3. [PMID: 21354107 DOI: 10.1016/j.bbrc.2011.02.092] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2011] [Accepted: 02/18/2011] [Indexed: 11/22/2022]
Abstract
The basic understanding of the three dimensional structure of mucin is essential to understand its physiological function. Technology has been developed to achieve orientated porcine stomach mucin molecules. X-ray fiber diffraction of partially orientated porcine stomach mucin molecules show d-spacing signals at 2.99, 4.06, 4.22, 4.7, 5.37 and 6.5 Å. The high intense d-spacing signal at 4.22 Å is attributed to the antiparallel β-sheet structure identified in the fraction of the homology modeled mucin molecule (amino acid residues 800-980) using Nidogen-Laminin complex structure as a template. The X-ray fiber diffraction signal at 6.5 Å reveals partial organization of oligosaccharides in porcine stomach mucin. This partial structure of mucin will be helpful in establishing a three dimensional structure for the whole mucin molecule.
Collapse
|
|
23
|
Pathophysiology of intestinal metaplasia of the stomach: emphasis on CDX2 regulation. Biochem Soc Trans 2010; 38:358-63. [PMID: 20298183 DOI: 10.1042/bst0380358] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
IM (intestinal metaplasia) of the stomach is a pre-neoplastic lesion that usually follows Helicobacter pylori infection and that confers increased risk for gastric cancer development. After setting the role played by CDX2 (Caudal-type homeobox 2) in the establishment of gastric IM, it became of foremost importance to unravel the regulatory mechanisms behind its de novo expression in the stomach. In the present paper, we review the basic pathology of gastric IM as well as the current knowledge on molecular pathways involved in CDX2 regulation in the gastric context.
Collapse
|
|
24
|
Magalhães A, Reis CA. Helicobacter pylori adhesion to gastric epithelial cells is mediated by glycan receptors. Braz J Med Biol Res 2010; 43:611-8. [PMID: 20521012 DOI: 10.1590/s0100-879x2010007500049] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2010] [Accepted: 05/24/2010] [Indexed: 12/14/2022] Open
Abstract
Helicobacter pylori adhesion to gastric epithelial cells constitutes a key step in the establishment of a successful infection of the gastric mucosa. The high representation of outer membrane proteins in the bacterial genome suggests the relevance of those proteins in the establishment of profitable interactions with the host gastric cells. Gastric epithelial cells are protected by a mucous layer gel, mainly consisting of the MUC5AC and MUC6 mucins. In addition to this protective role, mucins harbor glycan-rich domains that constitute preferential binding sites of many pathogens. In this article we review the main players in the process of H. pylori adhesion to gastric epithelial cells, which contribute decisively to the high prevalence and chronicity of H. pylori infection. The BabA adhesin recognizes both H-type 1 and Lewis b blood-group antigens expressed on normal gastric mucosa of secretor individuals, contributing to the initial steps of infection. Upon colonization, persistent infection induces an inflammatory response with concomitant expression of sialylated antigens. The SabA adhesin mediates H. pylori binding to inflamed gastric mucosa by recognizing sialyl-Lewis a and sialyl-Lewis x antigens. The expression of the BabA and SabA adhesins is tightly regulated, permitting the bacteria to rapidly adapt to the changes of glycosylation of the host gastric mucosa that occur during infection, as well as to escape from the inflammatory response. The growing knowledge of the interactions between the bacterial adhesins and the host receptors will contribute to the design of alternative strategies for eradication of the infection.
Collapse
Affiliation(s)
- A Magalhães
- Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
| | | |
Collapse
|
|
25
|
Affiliation(s)
- Pelayo Correa
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
| | | | | |
Collapse
|
|
26
|
Jonckheere N, Van Seuningen I. The membrane-bound mucins: From cell signalling to transcriptional regulation and expression in epithelial cancers. Biochimie 2009; 92:1-11. [PMID: 19818375 DOI: 10.1016/j.biochi.2009.09.018] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2009] [Accepted: 09/30/2009] [Indexed: 12/26/2022]
Abstract
The membrane-bound mucins belong to an ever-increasing family of O-glycoproteins. Based on their structure and localization at the cell surface they are thought to play important biological roles in cell-cell and cell-matrix interactions, in cell signalling and in modulating biological properties of cancer cells. Among them, MUC1 and MUC4 mucins are best characterized. Their altered expression in cancer (overexpression in the respiratory, gastro-intestinal, urogenital and hepato-biliary tracts) indicates an important role for these membrane-bound mucins in tumour progression, metastasis, cancer cell resistance to chemotherapeutics drugs and as specific markers of epithelial cancer cells. Some mechanisms responsible for MUC1 and MUC4 role in tumour cell properties have been deciphered recently. However, much remains to be done in order to understand the molecular mechanisms and signalling pathways that control the expression of membrane-bound mucins during the different steps of tumour progression toward adenocarcinoma and evaluate their potential as prognostic/diagnostic markers and as therapeutic tools. In this review we focus on the molecular mechanisms and signalling pathways known to control the expression of membrane-bound mucins in cancer. We will discuss the mechanisms of regulation at the promoter level (including genetic and epigenetic modifications) that may be responsible for the mucin altered pattern of expression in epithelial cancers.
Collapse
|
|
27
|
Barros R, Mendes N, Howe JR, Reis CA, de Bolos C, Carneiro F, David L, Almeida R. Juvenile polyps have gastric differentiation with MUC5AC expression and downregulation of CDX2 and SMAD4. Histochem Cell Biol 2009; 131:765-72. [PMID: 19266212 DOI: 10.1007/s00418-009-0579-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2009] [Indexed: 01/20/2023]
Abstract
CDX2 is a homeobox transcription factor that works as a master gene in intestinal differentiation, both in the colon and in aberrant locations such as intestinal metaplasia (IM) of the stomach. Transgenic mice with Cdx2 expression in the stomach develop IM and Cdx2(+/-) mice develop hamartomatous polyps in the colon presenting gastric differentiation. We previously observed regulation of CDX2 by the BMP/SMAD pathway in the gastric context. Here, we hypothesized that juvenile polyps, which are hamartomatous polyps caused by mutations in members of the BMP/SMAD pathway, might recapitulate the gastric differentiation observed in Cdx2(+/-) mice due to SMAD4 and CDX2 downregulation. We characterized SMAD4 and CDX2 expression in a series of 18 solitary juvenile polyps and 2 polyps from juvenile polyposis (JP) patients, one with a germline SMAD4 mutation and one with a germline BMPRIA mutation, as well as the expression of an intestinal differentiation marker, MUC2 (by immunohistochemistry and in situ hybridization), and gastric differentiation markers, MUC5AC and MUC6 (by immunohistochemistry). We observed that juvenile polyps have a heterogeneous expression of CDX2, MUC2 and SMAD4, with negative areas, and 15 of the 18 solitary polyps and the JP case with SMAD4 mutation exhibit de novo expression of MUC5AC but not MUC6. In conclusion, juvenile polyps have gastric transdifferentiation associated with downregulation of CDX2 and SMAD4, lending support to the role of the BMP/SMAD pathway in CDX2 regulation.
Collapse
Affiliation(s)
- Rita Barros
- IPATIMUP, Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Dr. Roberto Frias si/na, 4200 Porto, Portugal
| | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Forné M, Fernández-Bañares F, González-Mínguez C, Casalots J, Poblet-Mas N, Garcia-Gil LJ, Esteve M, Rosinach M, Espinós J, Loras C, Salas A, Viver JM. Lack of clinical usefulness of Das-1 monoclonal antibody and mucin expression as risk markers of gastric carcinoma in patients with gastric intestinal metaplasia. Am J Clin Pathol 2009; 131:99-105. [PMID: 19095572 DOI: 10.1309/ajcpnp7bk3kuuojl] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Our aim was to evaluate the usefulness of the monoclonal antibody Das-1 as a premalignant marker of gastric intestinal metaplasia (GIM) associated with gastric cancer and its association with mucin expression. We evaluated Das-1 and mucin expression in 4 groups: 1 (n = 50), gastric carcinoma, paired samples of the cancer area and GIM away from the tumor; 2 (n = 25), gastric or duodenal ulcer with Helicobacter pylori infection with GIM and chronic gastritis; 3 (n = 25),H pylori- autoimmune chronic atrophic gastritis with GIM; and 4 (n = 25),H pylori- chronic gastritis without GIM. Das-1 immunostaining was observed in 20 (40%) of 50 cases in cancer areas. The expression of Das-1 in GIM from group 1 cases away from the cancer area was different from that in GIM from nontumor cases (groups 2 and 3): 13 (26%) of 50 vs 2 (8%) and 0 (0%) of 25 (P = .004). There was no association between Das-1 and mucin expression. Das-1 expression was associated with GIM from patients with gastric cancer. However, this relation was weaker than previously reported, precluding clinical usefulness as a premalignant marker of GIM.
Collapse
Affiliation(s)
- Montserrat Forné
- Departments of Gastroenterology, Hospital Universitari Mútua Terrassa, Terrassa, Spain
| | | | | | - Jaume Casalots
- Pathology, Hospital Universitari Mútua Terrassa, Terrassa, Spain
| | - Núria Poblet-Mas
- Laboratory of Molecular Microbiology, Department of Biology, University of Girona, Girona, Spain
| | - L. Jesús Garcia-Gil
- Laboratory of Molecular Microbiology, Department of Biology, University of Girona, Girona, Spain
| | - Maria Esteve
- Departments of Gastroenterology, Hospital Universitari Mútua Terrassa, Terrassa, Spain
| | - Mercè Rosinach
- Departments of Gastroenterology, Hospital Universitari Mútua Terrassa, Terrassa, Spain
| | - Jorge Espinós
- Departments of Gastroenterology, Hospital Universitari Mútua Terrassa, Terrassa, Spain
| | - Carme Loras
- Departments of Gastroenterology, Hospital Universitari Mútua Terrassa, Terrassa, Spain
| | - Antonio Salas
- Pathology, Hospital Universitari Mútua Terrassa, Terrassa, Spain
| | - Josep M. Viver
- Departments of Gastroenterology, Hospital Universitari Mútua Terrassa, Terrassa, Spain
| |
Collapse
|
|
29
|
Barrett's esophagus and cardiac intestinal metaplasia: two conditions within the same spectrum. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2008; 22:369-75. [PMID: 18414711 DOI: 10.1155/2008/243254] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Immunostaining for cytokeratin 7 (CK7) and cytokeratin 20 (CK20) has a characteristic pattern in Barrett's esophagus (BE), but reports regarding its sensitivity and specificity are inconsistent. Intestinal metaplasia of the gastric cardia (CIM) is histologically similar to BE, but with no abnormal endoscopic findings. OBJECTIVES To evaluate the sensitivity and specificity of a semi-quantitative CK7/CK20 immunostaining pattern for the diagnosis of BE, and to further elucidate the pathogenesis of CIM. METHODS Tissues were examined by hematoxylin and eosin and periodic acid schiff/alcian blue stains, and then were immunostained with CK7 and CK20 antibodies. Correlations with other clinical parameters were statistically analyzed. RESULTS When values were revised based on follow-up data and auxiliary testing, all BE cases (100%) displayed the characteristic BE CK7/CK20 immunostaining pattern, compared with 66% of CIM cases. In the subgroup of patients who were endoscopically and immunohistochemistry-positive but histologically negative, all patients except for one had documented BE when clinical history, auxiliary testing and follow-up were evaluated. There were no statistically significant differences between BE and CIM regarding Helicobacter pylori infection or the type of metaplasia (complete versus incomplete). The sensitivity of the CK7/CK20 pattern reached 100% in the subgroup of CIM patients with a history of acid reflux. Of 26 cases of CIM where follow-up was available, four cases (15%) progressed to BE, and one developed dysplasia. All four cases showed the BE pattern of CK7/CK20 staining and were negative for H pylori infection. CONCLUSIONS A semiquantitative CK7/CK20 pattern can be used to confirm BE even in the absence of histological evidence. The subgroup of CIM with acid reflux may develop into BE and may need closer follow-up.
Collapse
|
|
30
|
Piazuelo MB, Haque S, Delgado A, Du JX, Rodriguez F, Correa P. Phenotypic differences between esophageal and gastric intestinal metaplasia. Mod Pathol 2008. [PMID: 14631367 DOI: 10.1038/modpathol.3800016] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Intestinal metaplasia is a cancer precursor in the esophagus and the stomach. Marked differences exist between the carcinogenic processes in the two locations in terms of natural history and clinical significance. We investigated biopsies from 52 patients with Barrett's esophagus and from 50 patients with gastric intestinal metaplasia in an attempt to throw light on their pathogenic processes. Morphologic characteristics, presence of Helicobacter pylori (H. pylori), and markers of differentiation, inflammation, and proliferation were evaluated by histochemical and immunohistochemical techniques. The area covered by incomplete type of intestinal metaplasia and the proportion of sulfomucins were significantly higher in the esophagus than in the stomach. Immunoreactivity with MUC1, MUC2, MUC5AC, Das-1, cytokeratins 7 and 20, inducible nitric oxide synthase and cyclooxygenase-2 antibodies was also significantly greater in Barrett's esophagus than in gastric intestinal metaplasia. In gastric intestinal metaplasia, the presence of MUC1, MUC5AC, Das-1 and cytokeratin 7 was restricted to areas with the incomplete type of metaplasia. Cell proliferation (Ki-67) was significantly higher in Barrett's esophagus than in gastric intestinal metaplasia. H. pylori was absent in all of the patients with Barrett's esophagus, while it was present in 70% of the patients with gastric intestinal metaplasia. Our observations made clear that Barrett's esophagus shares some phenotypic characteristics with gastric intestinal metaplasia, leading us to suggest that both could arise in response to injuries with eventual carcinogenic potential. However, the progression to more advanced lesions could be modulated by the nature of the carcinogenic insult.
Collapse
Affiliation(s)
- M Blanca Piazuelo
- Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | | | | | | | | | | |
Collapse
|
|
31
|
Yamamichi N, Inada KI, Ichinose M, Yamamichi-Nishina M, Mizutani T, Watanabe H, Shiogama K, Fujishiro M, Okazaki T, Yahagi N, Haraguchi T, Fujita S, Tsutsumi Y, Omata M, Iba H. Frequent loss of Brm expression in gastric cancer correlates with histologic features and differentiation state. Cancer Res 2007; 67:10727-35. [PMID: 18006815 DOI: 10.1158/0008-5472.can-07-2601] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The mammalian SWI/SNF chromatin remodeling complex, an essential epigenetic regulator, contains either a single Brm or BRG1 molecule as its catalytic subunit. We observed frequent loss of Brm expression but not of BRG1 in human gastric cancer cell lines. Treatment with histone deacetylase inhibitor rescued Brm expression, indicating epigenetic regulation of this gene, and an RNA interference-based colony formation assay revealed antioncogenic properties of Brm. Brm immunostaining of 89 primary gastric cancers showed an obvious reduction in 60 cases (67%) and a severe decrease in 37 cases (42%). Loss of Brm is frequent in the major gastric cancer types (well- or moderately-differentiated tubular adenocarcinoma and poorly-differentiated adenocarcinoma) and positively correlates with the undifferentiated state. Among the minor gastric cancer types, Brm expression persists in signet-ring cell carcinoma and mucinous adenocarcinoma, but a marked decrease is observed in papillary adenocarcinoma. Intestinal metaplasia never shows decreased expression, indicating that Brm is a valid marker of gastric oncogenesis. In contrast, BRG1 is retained in most cases; a concomitant loss of BRG1 and Brm is rare in gastric cancer, contrary to other malignancies. We further show that Brm is required for villin expression, a definitive marker of intestinal metaplasia and differentiation. Via regulating such genes important for gut differentiation, Brm should play significant roles in determining the histologic features of gastric malignancy.
Collapse
Affiliation(s)
- Nobutake Yamamichi
- Division of Host-Parasite Interaction, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Holmes K, Egan B, Swan N, O’Morain C. Genetic Mechanisms and Aberrant Gene Expression during the Development of Gastric Intestinal Metaplasia and Adenocarcinoma. Curr Genomics 2007; 8:379-397. [PMID: 19412438 PMCID: PMC2671722 DOI: 10.2174/138920207783406460] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2007] [Revised: 09/21/2007] [Accepted: 09/28/2007] [Indexed: 02/07/2023] Open
Abstract
Gastric adenocarcinoma occurs via a sequence of molecular events known as the Correa's Cascade which often progresses over many years. Gastritis, typically caused by infection with the bacterium H. pylori, is the first step of the cascade that results in gastric cancer; however, not all cases of gastritis progress along this carcinogenic route. Despite recent antibiotic intervention of H. pylori infections, gastric adenocarcinoma remains the second most common cause of cancer deaths worldwide. Intestinal metaplasia is the next step along the carcinogenic sequence after gastritis and is considered to be a precursor lesion for gastric cancer; however, not all patients with intestinal metaplasia develop adenocarcinoma and little is known about the molecular and genetic events that trigger the progression of intestinal metaplasia into adenocarcinoma. This review aims to highlight the progress to date in the genetic events involved in intestinal-type gastric adenocarcinoma and its precursor lesion, intestinal metaplasia. The use of technologies such as whole genome microarray analysis, immunohistochemical analysis and DNA methylation analysis has allowed an insight into some of the events which occur in intestinal metaplasia and may be involved in carcinogenesis. There is still much that is yet to be discovered surrounding the development of this lesion and how, in many cases, it develops into a state of malignancy.
Collapse
Affiliation(s)
- K Holmes
- Department of Clinical Medicine, Trinity College Dublin, The Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland
| | | | | | | |
Collapse
|
|
33
|
Lee HW, Yang DH, Kim HK, Lee BH, Choi KC, Choi YH, Park YE. Expression of MUC2 in gastric carcinomas and background mucosae. J Gastroenterol Hepatol 2007; 22:1336-43. [PMID: 17559374 DOI: 10.1111/j.1440-1746.2007.04939.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIM Gastric carcinomas contain elements of both intestinal and diffuse types. Such heterogeneous components may distort the evaluation of the role of the mucin MUC2 in gastric carcinoma. The role of MUC2 expression in background mucosa is not yet clarified. METHODS We analyzed the expression of MUC2 in gastric mucosa and intestinal metaplasia adjacent to the tumoral area and carcinomas (n = 98) using immunohistochemistry. The immunoreactivity was quantified using an immunohistochemical scoring system. RESULTS In the intestinal metaplasia adjacent to the tumoral area, MUC2 was detected in 76 (97.4%) of 78 intestinal metaplasia, and MUC2 expression was inversely associated with the depth of wall penetration (P = 0.026) and tumor stage (P = 0.021). Although the expression rate of MUC2 antigens was higher in intestinal-type adenocarcinoma than in diffuse-type adenocarcinoma, a significant correlation with pathologic staging of the TNM system (pTNM staging) and MUC2 expression could not be found in each subtype of gastric carcinomas. CONCLUSION The expression of MUC2 in intestinal metaplasia was higher in tumors of earlier stages. These findings suggest that increased MUC2 expression in intestinal metaplasia in the neighborhood of the carcinomas may play an important role in gastric carcinomas. Further investigations regarding the role of MUC2 expression in gastric carcinoma and background mucosae are necessary.
Collapse
Affiliation(s)
- Hae-Wan Lee
- Department of Surgery, College of Medicine, Hallym University, Chunchon, Korea
| | | | | | | | | | | | | |
Collapse
|
|
34
|
Aihara R, Mochiki E, Ohotake S, Kamiyama Y, Ohono T, Kuwano H, Kurokawa K, Suzuki K. Peritoneal recurrence of gastric cancer with mucin phenotype 12 years after curative resection: report of a case. Surg Today 2007; 37:325-9. [PMID: 17387567 DOI: 10.1007/s00595-006-3392-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2006] [Accepted: 09/21/2006] [Indexed: 01/29/2023]
Abstract
We report a case of peritoneal recurrence of gastric cancer in a 58-year-old man, 12 years after curative surgery. Urinary wall thickness was seen on follow-up computed tomography and magnetic resonance imaging scans. We performed total nephroureterectomy and cystectomy for urinary tract cancers, but histological examination of the resected specimen revealed poorly differentiated adenocarcinoma with severe fibrosis, resembling the gastric cancer resected 12 years earlier. Immunohistological examination revealed human gastric mucin (45M1) and intestinal mucin (MUC2) phenotype in both the original gastric cancers and the urinary tract cancers. Thus, we concluded that the second cancer was a peritoneal recurrence of gastric cancer with gastric and intestinal mucin phenotypes. Although peritoneal recurrence so many years after curative gastrectomy is rare, careful long-term follow-up should be done for all patients undergoing surgery for gastric cancer with mucin phenotype.
Collapse
Affiliation(s)
- Ryuusuke Aihara
- Department of General Surgical Science (Surgery I), Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Shiotani A, Haruma K, Uedo N, Iishi H, Ishihara R, Tatsuta M, Kumamoto M, Nakae Y, Ishiguro S, Graham DY. Histological risk markers for non-cardia early gastric cancer. Pattern of mucin expression and gastric cancer. Virchows Arch 2006; 449:652-659. [PMID: 17058096 DOI: 10.1007/s00428-006-0300-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2006] [Accepted: 08/23/2006] [Indexed: 12/11/2022]
Abstract
There are limited data regarding the prognostic value of the pattern of mucin expression in IM. To examine the role of the type of IM and pattern of mucin expression in IM as histological risk markers of gastric cancer, 80 patients with a history of endoscopic mucosal resection (EMR) for early gastric cancer and 80 sex and age-matched controls were studied. Serum levels of pepsinogen (PG) were measured by RIA, and MUC2, MUC5AC and MUC6 were evaluated immunohistochemically. There is a significant association between types of IM and atrophic scores or PG levels. The most incomplete IM (type II and III) preserving gastric mucin is the gastric and intestinal mixed (GI) type, whereas the complete type is the intestinal (I) type especially in the corpus lesser curve. Gastric cancer was most significantly associated with incomplete IM in the corpus lesser curve (OR=6.4; 95% CI, 2.0-21, p=0.002). Asynchronous multiple lesions were associated with incomplete IM in the corpus greater curve (OR=4.8; 95% CI, 1.4-16, p=0.01). Classification of IM obtained using fixed-point biopsy samples may enhance the ability of surveillance programs to detect patients at increased risk of gastric cancer.
Collapse
Affiliation(s)
- Akiko Shiotani
- Department of Internal Medicine, Kawasaki Medical School, Okayama, Japan.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Rapoport EM, Pazynina GV, Sablina MA, Crocker PR, Bovin NV. Probing sialic acid binding Ig-like lectins (siglecs) with sulfated oligosaccharides. BIOCHEMISTRY (MOSCOW) 2006; 71:496-504. [PMID: 16732727 DOI: 10.1134/s0006297906050051] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Soluble siglecs-1, -4, -5, -6, -7, -8, -9, and -10 were probed with polyacrylamide glycoconjugates in which: 1) the Neu5Ac residue was substituted by a sulfate group (Su); 2) glycoconjugates contained both Su and Neu5Ac; 3) sialoglycoconjugates contained a tyrosine-O-sulfate residue. It was shown that sulfate derivatives of LacNAc did not bind siglecs-1, -4, -5, -6, -7, -8, -9, and -10; binding of 6'-O-Su-LacNAc to siglec-8 was stronger than binding of 3'SiaLacNAc. The relative affinity of 3'-O-Su-TF binding to siglecs-1, -4, and -8 was similar to that of 3'SiaTF. 3'-O-Su-Le(c) displayed two-fold weaker binding to siglec-1 and siglec-4 than 3'SiaLe(c). The interaction of soluble siglecs with sulfated oligosaccharides containing sialic acid was also studied. It was shown that siglecs-1, -4, -5, -6, -7, -9, and -10 did not interact with these compounds; binding of 6-O-Su-3'SiaLacNAc and 6-O-Su-3'SiaTF to siglec-8 was weaker than that of the corresponding sulfate-free sialoside probes. Siglec-8 displayed affinity to 6'-O-Su-LacNAc and 6'-O-Su-SiaLe(x), and defucosylation of the latter compound led to an increase in the binding. Sialoside probes containing tyrosine-O-sulfate residue did not display increased affinity to siglecs-1 and -5 compared with glycoconjugates containing only sialoside. Cell-bound siglecs-1, -5, -7, and -9 did not interact with 6-O-Su-3'SiaLacNAc, whereas the sulfate-free probe 3'SiaLacNAc demonstrated binding. In contrast, the presence of sulfate in 6-O-Su-6'SiaLacNAc did not affect binding of the sialoside probe to siglecs. 6'-O-Su-SiaLe(x) displayed affinity to cell-bound siglecs-1 and -5; its isomer 6-O-Su-SiaLe(x) bound more strongly to siglecs-1, -5, and -9 than SiaLe(x).
Collapse
Affiliation(s)
- E M Rapoport
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | | | | | | | | |
Collapse
|
|
37
|
Kim JH, Huang Z, Mo R. Gli3 null mice display glandular overgrowth of the developing stomach. Dev Dyn 2006; 234:984-91. [PMID: 16247775 DOI: 10.1002/dvdy.20542] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The role of the Hedgehog signaling pathway in various aspects of gut development is still poorly understood. In the developing stomach, Sonic (Shh) and Indian (Ihh) hedgehog are expressed in both distinct and overlapping regions. Loss of Sonic hedgehog function in the stomach results in a glandular phenotype of intestinal transformation and overgrowth. These changes are reminiscent of the pre-malignant lesion, intestinal metaplasia. To determine the role of Hedgehog-related transcription factors, Gli2 and Gli3, in Shh signaling during stomach development, we conducted a mutant analysis of glandular stomach from Shh, Gli2, and Gli3 mutant mice. Although Gli2 principally mediates the activator function of Shh, surprisingly we observed minimal changes in glandular development in the Gli2 mutant stomach. Furthermore, Gli3, which typically functions as a repressor of Hedgehog signal, showed a striking phenocopy of the glandular expansion and intestinal transformation found in Shh mutant stomach. A reduction in apoptotic events was seen in all mutant stomachs with no appreciable changes in proliferation. Both Shh and Gli3 mutant stomachs displayed early changes of intestinal transformation but these did not impact on the overall differentiation of the gastric epithelium. Interestingly, the observation that Gli3 shares a similar glandular phenotype to Shh mutant stomach reveals a possible novel role of Gli3 activator in the developing stomach. The embryonic stomach is a unique model of the Hedgehog pathway function and one that may help to uncover some of the mechanisms underlying the development of intestinal metaplasia.
Collapse
Affiliation(s)
- Jae H Kim
- Program in Integrative Biology, The Research Institute, The Hospital for Sick Children, Toronto, Canada.
| | | | | |
Collapse
|
|
38
|
Ferreira B, Marcos NT, David L, Nakayama J, Reis CA. Terminal α1,4-linked N-acetylglucosamine in Helicobacter pylori-associated Intestinal Metaplasia of the Human Stomach and Gastric Carcinoma Cell Lines. J Histochem Cytochem 2006; 54:585-91. [PMID: 16618943 DOI: 10.1369/jhc.5a6836.2006] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Helicobacter pylori (Hp) infection is associated with the development of gastric lesions including gastritis, intestinal metaplasia (IM), and gastric carcinoma. In humans, Hp is found almost exclusively in the foveolar epithelium of the gastric mucosa and rarely colonizes the deeper portions where mucous cells of the glands produce mucins with terminal α1, 4-GlcNAc O-glycans. This structure exerts antimicrobial activity against Hp. The development of IM in the stomach is characterized by Hp clearance from the metaplastic glands and by major alterations in the expression of mucins and mucin-carbohydrates. The present work evaluated whether terminal α1,4-GlcNAc and sialyl-Tn antigen are implicated in the process of Hp clearance from metaplastic glands by analyzing the expression of these antigens in different types of IM—complete ( n=12) and incomplete ( n=8)—and in gastric cell lines. Terminal α1,4-GlcNAc was not detected in IM except in a single foci of one case, indicating that this structure is not implicated in the clearance of Hp from IM, in contrast to what is observed in normal gastric mucosa. None of the gastric carcinoma cell lines studied showed terminal α1,4-GlcNAc, suggesting that they do not display a gastric gland mucous cell phenotype and therefore are useful models for in vitro Hp studies. Finally, sialyl-Tn antigen colocalizes with MUC2 mucin and is present in all cases of complete and incomplete IM, suggesting that either or both can be implicated in Hp clearance from IM. (J Histochem Cytochem 54:585-591, 2006)
Collapse
Affiliation(s)
- Bibiana Ferreira
- Institute of Molecular Pathology and Immunology, University of Porto, Portugal
| | | | | | | | | |
Collapse
|
|
39
|
Tanaka H, Tsukamoto T, Mizoshita T, Inada KI, Ogasawara N, Cao X, Kato S, Joh T, Tatematsu M. Expression of small intestinal and colonic phenotypes in complete intestinal metaplasia of the human stomach. Virchows Arch 2005; 447:806-15. [PMID: 16088401 DOI: 10.1007/s00428-005-0040-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2005] [Accepted: 06/26/2005] [Indexed: 12/15/2022]
Abstract
The incomplete intestinal metaplasia (IM) that is reported to be a risk factor for gastric carcinogenesis in man usually features sulfomucin production and thus is considered of colonic type. To cast light on the underlying mechanisms, we here examined the proportions of colonic and small intestinal phenotypes in IM by immunohistochemistry and real-time reverse transcription-polymerase chain reaction at the single isolated gland level. Carbonic anhydrase 1 (CA1) is a specific marker of colonic epithelial cells, whereas sucrase is specific to absorptive cells of the small intestine. Totals of 139 (23.5%) and 452 (76.5%) IM glands were judged to be CA1 positive and CA1 negative, respectively, in resected pyloric mucosa from cancer patients. The average score for MUC5AC in CA1-positive IMs was significantly lower than in CA1-negative counterpart tissue (P<0.0001), whereas the opposite was the case for sucrase (P<0.0001). High iron diamine-Alcian blue staining revealed CA1 expression to coincide with type I complete IM. The expression of CA1 mRNA strongly correlated with that of sucrase-isomaltase, and inversely with that of MUC5AC in isolated IM glands. In conclusion, CA1 could be colocalized with small intestinal proteins such as sucrase, but only rarely with the gastric mucin, MUC5AC. Its expression warrants further study, with the focus on stimulation and/or suppression mechanisms by gastric and intestinal transcription factors.
Collapse
Affiliation(s)
- Harunari Tanaka
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Nagoya, 464-8681, Japan
| | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Aihara R, Ajioka Y, Watanabe H, Shiroshita H, Akazawa K, Kuwano H. Incidence and distribution of hybrid goblet cells in complete type intestinal metaplasia of the stomach. Pathol Res Pract 2005; 201:11-9. [PMID: 15807306 DOI: 10.1016/j.prp.2004.09.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Previous reports suggest that hybrid goblet cells (HGCs) sharing both gastric and intestinal mucin phenotypes are rarely observed in complete intestinal metaplasia (cIM) of the stomach. However, we have made a different observation. Thus, we compared the incidence and distribution of HGCs within the tubules of gastric cIM and the duodenum in order to define the significance of HGCs. Fifteen antral sections and 16 fundic sections from tissue with cIM and gastric cancer, as well as 19 sections from duodenal tissue with cancer of the Papilla of Vater, were stained for human gastric mucin (HGM), Con A, MUC2, CD10, and Ki-67. Multivariate analysis showed that antral location, a distance of 5mm or less from the tumor margin, and the presence of underlying pyloric glands were significant predictive factors for tubules containing >50% HGCs as part of their goblet cell population. The incidence of tubules with HGCs differed significantly in tissue samples from the antrum, body and duodenum. HGCs did not stain for Ki-67 and were not surrounded by gastric foveolar-type epithelium within the tubules of cIM foci. These findings indicate that alterations in the proportion of HGCs may occur under some circumstances, and that HGCs are not precursors to gastric foveolar-type cells in the stomach and duodenum.
Collapse
Affiliation(s)
- Ryuusuke Aihara
- Division of Molecular and Diagnostic Pathology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori Ichibancho, Niigata-city 951-8510, Japan.
| | | | | | | | | | | |
Collapse
|
|
41
|
Zhang XY, Yi YF, Xiao CW. MUC2 antisense oligodeoxynucleotide inhibits proliferation of human gastric carcinoma cells in vitro. Shijie Huaren Xiaohua Zazhi 2005; 13:1278-1282. [DOI: 10.11569/wcjd.v13.i11.1278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the inhibitory effect of mucin gene (MUC2) antisense oligodeoxynucleotides (ASODNs) on proliferation of gastric cancer cells SGC7901.
METHODS: Phosphorothioate MUC2 ASODNs were synthesized and then transfected into gastric carcinoma SGC7901 cells mediated by lipofectin. The inhibitory effects on cell proliferation were determined by MTT method, light and electronic microscopy, flow cytometry (FCM) and immunohistochemistry.
RESULTS: MUC2 ASODN at varied concentration significantly inhibited the growth of SGC7901 cells in a dose- and time-dependent manner. The inhibitory peak appeared at 48th hour after transfection, and the inhibition rate reached 55% when the concentration of MUC2 ASODN was 0.5 mol/L. After transfected with MUC2 ASODN, SGC7901 cells decreased in number, volume and karyokinesis, increased in necrosis under light microscopy. And most of the cells arrested in S phase. Swollen mitochondrion, increased liposomes, myelin figures, chromatin margination were found under electronic microscopy. Immunohistochemistry indicated that after transfected with MUC2 ASODN, the expression of MUC2 and nm23 protein were down-regulated, but the expression of p16 protein was up-regulated.
CONCLUSION: MUC2 ASODN transfection can significantly inhibit the proliferation of gastric carcinoma SGC7901 cells.
Collapse
|
|
42
|
Aihara R, Mochiki E, Nakabayashi T, Akazawa K, Asao T, Kuwano H. Clinical significance of mucin phenotype, beta-catenin and matrix metalloproteinase 7 in early undifferentiated gastric carcinoma. Br J Surg 2005; 92:454-62. [PMID: 15609380 DOI: 10.1002/bjs.4868] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND The aim of this study was to examine the clinical significance of mucin phenotypes of early undifferentiated gastric carcinoma, and to identify variables that might be used to select patients suitable for minimally invasive surgery. METHODS A total of 129 patients with early undifferentiated gastric carcinoma were studied. The mucin phenotype was determined immunohistochemically using markers for M1, apomucin (MUC) 6 and MUC2. Tumours were classified into gastric (G), intestinal, gastrointestinal (GI) or unclassified type. Undifferentiated carcinomas were classified into signet-ring cell carcinoma (SIG) and non-SIG. The immunoreactivity of matrix metalloproteinase (MMP) 7 and beta-catenin was also investigated. RESULTS GI-type tumours more commonly expressed non-SIG than SIG histology. The GI phenotype was associated with a higher incidence of submucosal invasion, lymphatic invasion, MMP-7 expression and nuclear accumulation of beta-catenin than the G type. Non-SIG histology, and the combination of GI type and nuclear accumulation of beta-catenin were independent predictors of submucosal invasion. The combination of GI type and MMP-7 expression independently predicted lymphatic invasion. MMP-7 expression correlated with lymph node metastasis. CONCLUSION GI-type early undifferentiated carcinomas and those with non-SIG histology had increased potential for invasion and metastasis. GI type, MMP-7 expression and nuclear accumulation of beta-catenin might prove useful markers in the selection of patients for less invasive surgery.
Collapse
Affiliation(s)
- R Aihara
- Department of General Surgical Science (Surgery I), Graduate School of Medicine, Gunma 371-8511, Japan.
| | | | | | | | | | | |
Collapse
|
|
43
|
Niwa T, Ikehara Y, Nakanishi H, Tanaka H, Inada KI, Tsukamoto T, Ichinose M, Tatematsu M. Mixed gastric- and intestinal-type metaplasia is formed by cells with dual intestinal and gastric differentiation. J Histochem Cytochem 2005; 53:75-85. [PMID: 15637340 DOI: 10.1177/002215540505300109] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
We have proposed to divide intestinal metaplasia (IM) into two categories, i.e., a mixed gastric and intestinal (GI) type, and a solely intestinal (I) type, based on the residual gastric phenotype cells. The GI-mixed-type IM can be identified by the presence of both cells with either gastric or intestinal phenotypes in a single gland. This study is conducted to elucidate whether cells in the GI-mixed-type IM glands can simultaneously present both gastric and intestinal phenotypes. MUC5AC, MUC2, CD10 and villin expressions were investigated in 20 samples from five gastric cancer cases, directly using either AlexaFluor 488- or 568-labeled specific monoclonal antibodies and observed by fluorescent microscopy and confocal laser-scanning microscopy. GI-mixed IM glands comprise a population expressing MUC5AC and MUC2, MUC5AC and villin, and MUC5AC and CD10. MUC2 and villin expressions were reciprocally increased with decreasing MUC5AC expression, while CD10 expression was limited to cells with only a residual MUC5AC expression or no expression. These results suggest that a heterogeneous cell population with both gastric and intestinal phenotypes would develop into a single intestinal phenotype, as reflected in the progression of intestinal metaplasia from GI-mixed-type- to I-type IM-type glands.
Collapse
Affiliation(s)
- Toru Niwa
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
| | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Oshima T, Joh T, Sasaki M, Tanida S, Itoh K, Mizoshita T, Kawade M, Ohara H, Nomura T, Itoh M. Gastric gland heterotopic in muscularis mucosa treated by endoscopic polypectomy: a case report. Gastrointest Endosc 2004; 60:664-7. [PMID: 15472707 DOI: 10.1016/s0016-5107(04)01888-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Affiliation(s)
- Tadayuki Oshima
- Department of Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Bodger K, Campbell F, Rhodes JM. Detection of sulfated glycoproteins in intestinal metaplasia: a comparison of traditional mucin staining with immunohistochemistry for the sulfo-Lewis(a) carbohydrate epitope. J Clin Pathol 2003; 56:703-8. [PMID: 12944557 PMCID: PMC1770063 DOI: 10.1136/jcp.56.9.703] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/25/2003] [Indexed: 11/04/2022]
Abstract
BACKGROUND Premalignant Barrett's oesophagus (BO) and gastric intestinal metaplasia (IM) show phenotypic variability. Incompletely differentiated sulfomucin rich gastric IM (type III) may have increased malignant potential. The types of sulfated oligosaccharide structures present in IM, BO, and colon have not been fully characterised. AIMS To compare sulfo-Lewis(a) epitope tissue distribution with high iron diamine (HID) positive sulfomucin in metaplastic, dysplastic, and neoplastic tissues from oesophagus and stomach. METHODS Sections containing gastric IM or BO (some associated with dysplasia or adenocarcinoma) were stained by the HID/alcian blue (AB) method and immunohistochemically (antibody 91.9H) to detect sulfo-Lewis(a). Based on HID/AB staining, IM was subtyped into type I (complete) or types II and III (incomplete). RESULTS In total, 125 sections from 38 subjects were studied. Normal squamous oesophagus, normal gastric epithelium, and type I IM were negative for sulfomucin and sulfo-Lewis(a). In type II IM, occasional goblet cells were HID and sulfo-Lewis(a) positive, but sialomucin secreting (AB positive) columnar cells were sulfo-Lewis(a) negative. Type III IM was always sulfo-Lewis(a) positive. Sulfomucin staining in dysplasia and cancer was variable, but HID positive areas were always sulfo-Lewis(a) positive. CONCLUSIONS Sulfo-Le(a), which is expressed on colonic mucin, is invariably present on sulfomucins in gastric IM and BO. Its presence in incomplete variants of IM and its absence from type I IM emphasises the phenotypic differences between complete and incomplete forms of metaplasia. 91.9H immunostaining is useful in IM subtyping. Characterising the molecular basis of sulfo-Lewis(a) expression may help understand the process of aberrant differentiation.
Collapse
Affiliation(s)
- K Bodger
- Department of Medicine, University of Liverpool, Liverpool L9 7AL, UK.
| | | | | |
Collapse
|
|
46
|
Liu YQ, Zhao H, Ning T, Ke Y, Li JY. Expression of 1A6 gene and its correlation with intestinal gastric carcinoma. World J Gastroenterol 2003; 9:238-41. [PMID: 12532438 PMCID: PMC4611318 DOI: 10.3748/wjg.v9.i2.238] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of 1A6 gene in the lesions during the development of intestinal gastric carcinoma.
METHODS: One hundred and thirty-six cases of intestinal metaplasia (IM) from surgical resections and biopsy were classified by mucous staining. Expression of 1A6 in all cases was detected using immunohistochemical S-P method.
RESULTS: The positive rates of 1A6 in normal and superficial gastritis (SG), severe atrophic gastritis (SAG), type I, II, III IM, dysplasia (Dys) and intestinal gastric carcinoma (IGC) were 12.2%, 16.7%, 7.1%, 22.6%, 47.8%, 46.9% and 60.8%, respectively. A significant difference among type III IM and SG, SAG, type I and II IM was found (P < 0.01), the difference between type III and Dys, IGC being not significant.
CONCLUSION: As a new tumor-related gene, expression of 1A6 may be an effective parameter to predict the malignant transformation of precancerous lesion to gastric carcinoma.
Collapse
Affiliation(s)
- Yi-Qiang Liu
- Department of Pathology, Peking University School of Oncology, Beijing 100036, China
| | | | | | | | | |
Collapse
|
|
47
|
Almeida R, Silva E, Santos-Silva F, Silberg DG, Wang J, De Bolós C, David L. Expression of intestine-specific transcription factors, CDX1 and CDX2, in intestinal metaplasia and gastric carcinomas. J Pathol 2003; 199:36-40. [PMID: 12474224 DOI: 10.1002/path.1246] [Citation(s) in RCA: 212] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Intestinal metaplasia (IM) is part of a stepwise sequence of alterations of the gastric mucosa, leading ultimately to gastric cancer, and is strongly associated with chronic Helicobacter pylori infection. The molecular mechanisms underlying the onset of IM remain elusive. The aim of this study was to assess the putative involvement of two intestine-specific transcription factors, CDX1 and CDX2, in the pathogenesis of gastric IM and gastric carcinoma. Eighteen foci of IM and 46 cases of gastric carcinoma were evaluated by immunohistochemistry for CDX1 and CDX2 expression. CDX1 was expressed in all foci of IM and in 41% of gastric carcinomas; CDX2 was expressed in 17/18 foci of IM and in 54% of gastric carcinomas. In gastric carcinomas, a strong association was observed between the expression of CDX1 and CDX2, as well as between the intestinal mucin MUC2 and CDX1 and CDX2. No association was observed between the expression of CDX1 and CDX2 and the histological type of gastric carcinoma. In conclusion, these results show that aberrant expression of CDX1 and CDX2 is consistently observed in IM and in a subset of gastric carcinomas. The association of CDX1 and CDX2 with expression of the intestinal mucin MUC2, both in IM and in gastric carcinoma, indirectly implies that CDX1 and CDX2 may be involved in intestinal differentiation along the gastric carcinogenesis pathway.
Collapse
Affiliation(s)
- Raquel Almeida
- Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), 4200 Porto, Portugal.
| | | | | | | | | | | | | |
Collapse
|