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Junhai Z, Suqi Z, Beiying D, Zongbiao T, Chuan L, Yanrui W, Weiguo D. Causal relationships between dietary habits and Barrett's esophagus risk: a univariable and multivariable Mendelian randomization study. Food Funct 2024; 15:2474-2484. [PMID: 38329234 DOI: 10.1039/d3fo05273g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Aims: Dietary habits are reported to be associated with Barrett's esophagus (BE) risk; however, whether there is a causal relationship remains controversial. Here, we systematically examined the causal effects of genetically predicted dietary habits on BE risk through a Mendelian randomization (MR) analysis approach. Methods: Data for exposures were obtained from the UK Biobank (UKB), while the summary-level data for outcomes were obtained from a large sample-size GWAS meta-analysis. Genetic variants associated with 17 ordinary dietary habits at the genome-wide significance level were regarded as instrumental variables (IVs). Univariable and multivariable MR analyses were conducted to explore the causal relationships between dietary habits and BE risk. Sensitivity analyses were implemented to evaluate robustness of the results and determine the potential pleiotropy bias. Results: Univariable MR (UVMR) analysis showed that genetic predisposition to alcohol intake frequency, cooked vegetable intake, beef intake, bread intake, fresh fruit intake, salad/raw vegetable intake, and dried fruit intake were associated with BE risk, with all P values <0.05. After adjusting confounders, the effects of four dietary habits on BE risk persisted; multivariable MR (MVMR) analysis revealed that alcohol intake frequency (adjusted odds ratio (OR) = 1.74 (1.34, 2.27); P = 3.42 × 10-5) was causally associated with higher BE risk, the cooked vegetable intake (adjusted OR = 2.64 (1.16, 5.97); P = 0.02) had suggestively increased BE risk, while higher consumption of bread (adjusted OR = 0.54 (0.32-0.91); P = 0.02) and fresh fruit (adjusted OR = 0.34 (0.15, 0.77); P = 0.01) were suggestively associated with lower BE risk. Conclusions: These MR analyses demonstrate evidence of causal relationships between dietary habits and BE risk. These findings provide new insights into targeted dietary intervention strategies for BE prevention.
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Affiliation(s)
- Zhen Junhai
- Department of General Practice, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Zeng Suqi
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China.
| | - Deng Beiying
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China.
| | - Tan Zongbiao
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China.
| | - Liu Chuan
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China.
| | - Wu Yanrui
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China.
| | - Dong Weiguo
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China.
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Goswami S, Zhang Q, Celik CE, Reich EM, Yilmaz ÖH. Dietary fat and lipid metabolism in the tumor microenvironment. Biochim Biophys Acta Rev Cancer 2023; 1878:188984. [PMID: 37722512 PMCID: PMC10937091 DOI: 10.1016/j.bbcan.2023.188984] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/26/2023] [Accepted: 08/28/2023] [Indexed: 09/20/2023]
Abstract
Metabolic reprogramming has been considered a core hallmark of cancer, in which excessive accumulation of lipids promote cancer initiation, progression and metastasis. Lipid metabolism often includes the digestion and absorption of dietary fat, and the ways in which cancer cells utilize lipids are often influenced by the complex interactions within the tumor microenvironment. Among multiple cancer risk factors, obesity has a positive association with multiple cancer types, while diets like calorie restriction and fasting improve health and delay cancer. Impact of these diets on tumorigenesis or cancer prevention are generally studied on cancer cells, despite heterogeneity of the tumor microenvironment. Cancer cells regularly interact with these heterogeneous microenvironmental components, including immune and stromal cells, to promote cancer progression and metastasis, and there is an intricate metabolic crosstalk between these compartments. Here, we focus on discussing fat metabolism and response to dietary fat in the tumor microenvironment, focusing on both immune and stromal components and shedding light on therapeutic strategies surrounding lipid metabolic and signaling pathways.
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Affiliation(s)
- Swagata Goswami
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
| | - Qiming Zhang
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
| | - Cigdem Elif Celik
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Hacettepe Univ, Canc Inst, Department Basic Oncol, Ankara TR-06100, Turkiye
| | - Ethan M Reich
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Ömer H Yilmaz
- Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Massachusetts General Hospital and Beth Israel Deaconness Medical Center and Harvard Medical School, Boston, MA 02114, USA.
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Kawasaki A, Tsuji K, Uedo N, Kanesaka T, Miyamoto H, Gushima R, Minoda Y, Ihara E, Amano R, Yao K, Naito Y, Aoyagi H, Iwasaki T, Uchita K, Arima H, Doyama H. Non-atrophic gastric mucosa is an independently associated factor for superficial non-ampullary duodenal epithelial tumors: a multicenter, matched, case-control study. Clin Endosc 2023; 56:75-82. [PMID: 36600655 PMCID: PMC9902693 DOI: 10.5946/ce.2022.059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 04/27/2022] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND/AIMS The etiology of superficial non-ampullary duodenal epithelial tumors (SNADETs) remains unclear. Recent studies have reported conflicting associations between duodenal tumor development and Helicobacter pylori infection or endoscopic gastric mucosal atrophy. As such, the present study aimed to clarify the relationship between SNADETs and H. pylori infection and/or endoscopic gastric mucosal atrophy. METHODS This retrospective case-control study reviewed data from 177 consecutive patients with SNADETs who underwent endoscopic or surgical resection at seven institutions in Japan over a three-year period. The prevalence of endoscopic gastric mucosal atrophy and the status of H. pylori infection were compared in 531 sex- and age-matched controls selected from screening endoscopies at two of the seven participating institutions. RESULTS For H. pylori infection, 85 of 177 (48.0%) patients exhibited SNADETs and 112 of 531 (21.1%) control patients were non-infected (p<0.001). Non-atrophic mucosa (C0 to C1) was observed in 96 of 177 (54.2%) patients with SNADETs and 112 of 531 (21.1%) control patients (p<0.001). Conditional logistic regression analysis revealed that non-atrophic gastric mucosa was an independent risk factor for SNADETs (odds ratio, 5.10; 95% confidence interval, 2.44-8.40; p<0.001). CONCLUSION Non-atrophic gastric mucosa, regardless of H. pylori infection status, was a factor independently associated with SNADETs.
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Affiliation(s)
- Azusa Kawasaki
- Department of Gastroenterology, Ishikawa Prefectural Central Hospital, Ishikawa, Japan
| | - Kunihiro Tsuji
- Department of Gastroenterology, Ishikawa Prefectural Central Hospital, Ishikawa, Japan
| | - Noriya Uedo
- Department of Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Takashi Kanesaka
- Department of Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Hideaki Miyamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Ryosuke Gushima
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yosuke Minoda
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eikichi Ihara
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryosuke Amano
- Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Kenshi Yao
- Department of Endoscopy, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Yoshihide Naito
- Department of Gastroenterology, Fukui Prefectural Hospital, Fukui, Japan
| | - Hiroyuki Aoyagi
- Department of Gastroenterology, Fukui Prefectural Hospital, Fukui, Japan
| | - Takehiro Iwasaki
- Department of Gastroenterology, Kochi Red Cross Hospital, Kochi, Japan
| | - Kunihisa Uchita
- Department of Gastroenterology, Kochi Red Cross Hospital, Kochi, Japan
| | - Hisatomi Arima
- Department of Preventive Medicine and Public Health, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Hisashi Doyama
- Department of Gastroenterology, Ishikawa Prefectural Central Hospital, Ishikawa, Japan,Correspondence: Hisashi Doyama Department of Gastroenterology, Ishikawa Prefectural Central Hospital, 2-1 Kuratsukihigashi, Kanazawa, Ishikawa 920-8530, Japan E-mail:
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Wang S, Kuang J, Zhang H, Chen W, Zheng X, Wang J, Huang F, Ge K, Li M, Zhao M, Rajani C, Zhu J, Zhao A, Jia W. Bile Acid-Microbiome Interaction Promotes Gastric Carcinogenesis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2200263. [PMID: 35285172 PMCID: PMC9165488 DOI: 10.1002/advs.202200263] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/21/2022] [Indexed: 05/11/2023]
Abstract
Bile reflux gastritis (BRG) is associated with the development of gastric cancer (GC), but the specific mechanism remains elusive. Here, a comprehensive study is conducted to explore the roles of refluxed bile acids (BAs) and microbiome in gastric carcinogenesis. The results show that conjugated BAs, interleukin 6 (IL-6), lipopolysaccharide (LPS), and the relative abundance of LPS-producing bacteria are increased significantly in the gastric juice of both BRG and GC patients. A secondary BA, taurodeoxycholic acid (TDCA), is significantly and positively correlated with the LPS-producing bacteria in the gastric juice of these patients. TDCA promotes the proliferation of normal gastric epithelial cells (GES-1) through activation of the IL-6/JAK1/STAT3 pathway. These results are further verified in two mouse models, one by gavage of TDCA, LPS, and LPS-producing bacteria (Prevotella melaninogenica), respectively, and the other by bile reflux (BR) surgery, mimicking clinical bile refluxing. Moreover, the bile reflux induced gastric precancerous lesions observed in the post BR surgery mice can be prevented by treatment with cryptotanshinone, a plant-derived STAT3 inhibitor. These results reveal an important underlying mechanism by which bile reflux promotes gastric carcinogenesis and provide an alternative strategy for the prevention of GC associated with BRG.
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Affiliation(s)
- Shouli Wang
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes MellitusShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghai200233China
| | - Junliang Kuang
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes MellitusShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghai200233China
| | - Hongwei Zhang
- Department of Metabolic and Bariatric SurgeryShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghai200233China
| | - Wenlian Chen
- Cancer Institute, Longhua HospitalShanghai University of Traditional Chinese MedicineShanghai200233China
| | - Xiaojiao Zheng
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes MellitusShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghai200233China
| | - Jieyi Wang
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes MellitusShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghai200233China
| | - Fengjie Huang
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes MellitusShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghai200233China
| | - Kun Ge
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes MellitusShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghai200233China
| | - Mengci Li
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes MellitusShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghai200233China
| | - Mingliang Zhao
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes MellitusShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghai200233China
| | - Cynthia Rajani
- Cancer Biology ProgramUniversity of Hawaii Cancer CenterHonoluluHI96813USA
| | - Jinshui Zhu
- Department of GastroenterologyShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghai200233China
| | - Aihua Zhao
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes MellitusShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghai200233China
| | - Wei Jia
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes MellitusShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghai200233China
- Cancer Biology ProgramUniversity of Hawaii Cancer CenterHonoluluHI96813USA
- School of Chinese MedicineHong Kong Baptist UniversityKowloon TongHong Kong999077China
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Role of Obesity, Physical Exercise, Adipose Tissue-Skeletal Muscle Crosstalk and Molecular Advances in Barrett's Esophagus and Esophageal Adenocarcinoma. Int J Mol Sci 2022; 23:ijms23073942. [PMID: 35409299 PMCID: PMC8999972 DOI: 10.3390/ijms23073942] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/28/2022] [Accepted: 03/30/2022] [Indexed: 02/07/2023] Open
Abstract
Both obesity and esophageal adenocarcinoma (EAC) rates have increased sharply in the United States and Western Europe in recent years. EAC is a classic example of obesity-related cancer where the risk of EAC increases with increasing body mass index. Pathologically altered visceral fat in obesity appears to play a key role in this process. Visceral obesity may promote EAC by directly affecting gastroesophageal reflux disease and Barrett’s esophagus (BE), as well as a less reflux-dependent effect, including the release of pro-inflammatory adipokines and insulin resistance. Deregulation of adipokine production, such as the shift to an increased amount of leptin relative to “protective” adiponectin, has been implicated in the pathogenesis of BE and EAC. This review discusses not only the epidemiology and pathophysiology of obesity in BE and EAC, but also molecular alterations at the level of mRNA and proteins associated with these esophageal pathologies and the potential role of adipokines and myokines in these disorders. Particular attention is given to discussing the possible crosstalk of adipokines and myokines during exercise. It is concluded that lifestyle interventions to increase regular physical activity could be helpful as a promising strategy for preventing the development of BE and EAC.
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Filiberti RA, Fontana V, De Ceglie A, Blanchi S, Lacchin T, De Matthaeis M, Ignomirelli O, Cappiello R, Rosa A, D'Onofrio V, Iaquinto G, Conio M. Dietary Habits and Risk of Esophagitis and Barrett's Esophagus: A Multicenter Italian Case-Control Study. Dig Dis Sci 2021; 66:3448-3460. [PMID: 33073332 DOI: 10.1007/s10620-020-06658-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 10/05/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Barrett's esophagus (BE) and esophagitis share potentially modifiable risk factors such as obesity, smoking, and alcohol. The role of diet on BE and esophagitis is still debated. AIMS The objective of this study was to examine the association between some dietary habits and the risk of BE and esophagitis in Italy. METHODS A multicenter case-control study involving 1285 individuals was carried out in 12 areas. Patients with a new diagnosis of BE (320) or esophagitis (359) and a group of endoscopic controls (606) were included. Information on personal history and dietary habits was collected using a structured questionnaire. RESULTS No clear monotonic significant dose-response relationship was found for most of the considered food items. Nevertheless, the most extreme consumption category of red meat, cold cuts, dairy products, and fried foods showed esophagitis risk excesses varying from 19 to 49%. A higher fat rich diet seemed to increase risk by 49% for BE and 94% for esophagitis. A downward tendency in esophagitis (- 27%) and BE risk (- 20%) was found associated with higher frequency of fresh fruit intake. In addition, a statistically significant twofold increased risk for both BE and esophagitis was found for subjects eating late evening snacks more than once every three days in comparison with the lowest intake category (no consumption). CONCLUSIONS BE and esophagitis patients appeared to be more likely than controls to follow a diet rich in fats and poor in fruit and vegetables. Late evening snacks were found to be associated with both disorders.
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Affiliation(s)
- Rosa Angela Filiberti
- Clinical Epidemiology, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi, 16132, Genoa, Italy.
| | - Vincenzo Fontana
- Clinical Epidemiology, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi, 16132, Genoa, Italy
| | - Antonella De Ceglie
- Gastroenterology, General Hospital, Via Giovanni Borea 56, 18038, Sanremo, IM, Italy
| | - Sabrina Blanchi
- Gastroenterology, General Hospital, Via Giovanni Borea 56, 18038, Sanremo, IM, Italy
| | - Teresa Lacchin
- Policlinico San Giorgio, Gastroenterology, Pordenone, Italy
| | - Marina De Matthaeis
- Gastroenterology, General Hospital, Via Giovanni Borea 56, 18038, Sanremo, IM, Italy
| | - Orazio Ignomirelli
- IRCCS CROB, Digestive Endoscopy, Strada Provinciale di Piano del Conte, 85028, Rionero in Vulture, PZ, Italy
| | - Roberta Cappiello
- Gastroenterology, S. Maria degli Angeli Hospital, Via Montereale 24, 33170, Pordenone, Italy
| | - Alessandra Rosa
- Clinical Epidemiology, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi, 16132, Genoa, Italy
| | - Vittorio D'Onofrio
- Gastroenterology and Digestive Endoscopy, S. G. Moscati Hospital, Contrada Amoretta, 83100, Avellino, Italy
| | - Gaetano Iaquinto
- Divisione di Gastroenterologia, Clinica Santa Rita, Via Appia, 83042, Atripalda, AV, Italy
| | - Massimo Conio
- Gastroenterology, General Hospital, Via Giovanni Borea 56, 18038, Sanremo, IM, Italy
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Ebrahimpour-Koujan S, Hassanzadeh Keshteli A, Esmaillzadeh A, Adibi P. Association between Dietary Fat Intake and Odds of Gastro-esophageal Reflux Disorder (GERD) in Iranian Adults. Int J Prev Med 2021; 12:77. [PMID: 34447519 PMCID: PMC8356952 DOI: 10.4103/ijpvm.ijpvm_442_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 04/18/2020] [Indexed: 11/04/2022] Open
Abstract
Background Most information on the association of dietary fat intake and gastro-esophageal reflux disorder (GERD) came from developed countries, where lifestyle and other dietary components might be different from those in developing countries. This cross-sectional study was, therefore, conducted to investigate the association between dietary fat intake and odds of having GERD in a large group of Iranian population. Study Design This cross-sectional study was done among 3362 adult population in Isfahan, Iran. Dietary intakes were collected by the use of a validated semi-quantitative food frequency questionnaire. Methods Assessment of GERD was done using a validated self-administered questionnaire examining the frequency of heartburn in the last 3 months. Individuals with the presence of heartburn symptoms sometimes, often or always during the last 3 months were defined as having GERD. Results Participants in the top category of dietary fat intake had higher daily intakes of energy, macronutrients and micronutrients. Dietary intakes of all food groups were also significantly higher among those in the top quintile as compared with those in the bottom category of dietary fat intake (P < 0.001 for all). There were no significant associations between dietary fat intake and incidence of GERD in general population. Crude and multivariable-adjusted models revealed no significant associations between dietary fat intake and having GERD in either gender. Conclusions We found no significant association between dietary fat intake and odds of having GERD in this population. Further studies, in particular of prospective designs, are warranted to clarify this association.
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Affiliation(s)
- Soraiya Ebrahimpour-Koujan
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Ammar Hassanzadeh Keshteli
- Integrative Functional Gastroenterology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ahmad Esmaillzadeh
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular -Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.,Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Peyman Adibi
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
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8
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Tong Y, Gao H, Qi Q, Liu X, Li J, Gao J, Li P, Wang Y, Du L, Wang C. High fat diet, gut microbiome and gastrointestinal cancer. Theranostics 2021; 11:5889-5910. [PMID: 33897888 PMCID: PMC8058730 DOI: 10.7150/thno.56157] [Citation(s) in RCA: 117] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 03/09/2021] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal cancer is currently one of the main causes of cancer death, with a large number of cases and a wide range of lesioned sites. A high fat diet, as a public health problem, has been shown to be correlated with various digestive system diseases and tumors, and can accelerate the occurrence of cancer due to inflammation and altered metabolism. The gut microbiome has been the focus of research in recent years, and associated with cell damage or tumor immune microenvironment changes via direct or extra-intestinal effects; this may facilitate the occurrence and development of gastrointestinal tumors. Based on research showing that both a high fat diet and gut microbes can promote the occurrence of gastrointestinal tumors, and that a high fat diet imbalances intestinal microbes, we propose that a high fat diet drives gastrointestinal tumors by changing the composition of intestinal microbes.
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Affiliation(s)
- Yao Tong
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Huiru Gao
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Qiuchen Qi
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xiaoyan Liu
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Juan Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Jie Gao
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Peilong Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yunshan Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Lutao Du
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Chuanxin Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan, Shandong, China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan, Shandong, China
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9
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Metataxonomic analysis of microbiota from Pakistani dromedary camelids milk and characterization of a newly isolated Lactobacillus fermentum strain with probiotic and bio-yogurt starter traits. Folia Microbiol (Praha) 2021; 66:411-428. [PMID: 33566278 DOI: 10.1007/s12223-021-00855-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 01/20/2021] [Indexed: 10/22/2022]
Abstract
This study was undertaken to investigate the starter and probiotic potential of lactic acid bacteria isolated from dromedarian camel's milk using both culture-dependent and -independent approaches and metataxonomic analysis. Strains of lactic acid bacteria recovered were examined in vitro for tolerance to gastric acidity, bile, and lysozyme. Bile salt hydrolysis, serum cholesterol-lowering, oxalate degradation, proteolytic activity, exopolysaccharide production, and cell surface characteristics necessary for colonizing intestinal mucosa were also evaluated. A single strain of the species, Lactobacillus fermentum named NPL280, was selected through multivariate analysis as it harbored potential probiotic advantages and fulfilled safety criteria. The strain assimilated cholesterol, degraded oxalate, produced exopolysaccharides, and proved to be a proficient alternate yogurt starter with good viability in stored bio-yogurt. A sensorial analysis of the prepared bio-yogurt was also found to be exemplary. We conclude that the indigenous L. fermentum strain NPL280 has the desired traits of a starter and adjunct probiotic culture for dairy products.
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10
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Ooi GJ, Browning A, Hii MW, Read M. Perioperative screening, management, and surveillance of Barrett's esophagus in bariatric surgical patients. Ann N Y Acad Sci 2020; 1481:224-235. [PMID: 32794237 DOI: 10.1111/nyas.14441] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/06/2020] [Accepted: 06/24/2020] [Indexed: 12/28/2022]
Abstract
Obesity is a strong risk factor for Barrett's esophagus (BE), the only proven precursor lesion to esophageal adenocarcinoma (EAC). Bariatric surgery is currently the only reliable treatment that achieves long-term sustained weight loss; however, it can markedly affect the development of de novo BE, and the progression or regression of existing BE. Bariatric procedures may also have implications on future surgical management of any consequent EAC. In this review, we examine the current evidence and published guidelines for BE in bariatric surgery. Current screening practices before bariatric surgery vary substantially, with conflicting recommendations from bariatric societies. If diagnosed, the presence of BE may alter the type of bariatric procedure. A selective screening approach prevents unnecessary endoscopy; however, there is poor symptom correlation with disease. Studies suggest that sleeve gastrectomy predisposes patients to gastroesophageal reflux and de novo BE. Conversely, Roux-en-Y gastric bypass is associated with decreased reflux and potential improvement or resolution of BE. There are currently no guidelines addressing the surveillance for BE following bariatric surgery. BE is an important consideration in the management of bariatric surgical patients. Evidence-based recommendations are required to guide procedure selection and postoperative surveillance.
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Affiliation(s)
- Geraldine J Ooi
- Department of Surgery, Central Clinical School, Monash University, Prahran, Victoria, Australia
| | - Alison Browning
- Department of Upper Gastrointestinal and Hepatobiliary Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia
| | - Michael W Hii
- Department of Upper Gastrointestinal and Hepatobiliary Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia.,Department of Surgery, the University of Melbourne, St. Vincent's Hospital, Fitzroy, Victoria, Australia
| | - Matthew Read
- Department of Upper Gastrointestinal and Hepatobiliary Surgery, St. Vincent's Hospital, Fitzroy, Victoria, Australia.,Department of Surgery, the University of Melbourne, St. Vincent's Hospital, Fitzroy, Victoria, Australia
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Schlottmann F, Dreifuss NH, Patti MG. Obesity and esophageal cancer: GERD, Barrett´s esophagus, and molecular carcinogenic pathways. Expert Rev Gastroenterol Hepatol 2020; 14:425-433. [PMID: 32441160 DOI: 10.1080/17474124.2020.1764348] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 04/30/2020] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Increases in the rates of esophageal adenocarcinoma (EAC) have paralleled rises in the prevalence of overweight and obesity. Despite not being fully understood, obesity-related EAC seems to have different carcinogenic pathways. AREAS COVERED This comprehensive review will thoroughly evaluate the current literature, describing the underlying mechanisms that help understanding the strong association between obesity and esophageal cancer. EXPERT COMMENTARY The risk of esophageal cancer among obese individuals could be partially explained by several factors: high prevalence of GERD; linear association between central adiposity and Barrett´s esophagus development; low levels of adiponectin and high levels of leptin that alter cell proliferation processes; insulin-resistant state that creates a tumorigenesis environment; and changes in the esophageal microbiota due to unhealthy dietary habits that promote carcinogenesis. In addition, a large proportion of obese patients are undergoing sleeve gastrectomy which can worsen GERD or cause de novo reflux, esophagitis, and Barrett´s metaplasia.
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Affiliation(s)
| | - Nicolás H Dreifuss
- Department of Surgery, Hospital Alemán of Buenos Aires , Buenos Aires, Argentina
| | - Marco G Patti
- Department of Medicine and Surgery, University of North Carolina , Chapel Hill, NC, USA
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Munemoto M, Mukaisho K, Miyashita T, Oyama K, Haba Y, Okamoto K, Kinoshita J, Ninomiya I, Fushida S, Taniura N, Sugihara H, Fujimura T. Roles of the hexosamine biosynthetic pathway and pentose phosphate pathway in bile acid-induced cancer development. Cancer Sci 2019; 110:2408-2420. [PMID: 31215094 PMCID: PMC6676276 DOI: 10.1111/cas.14105] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 05/17/2019] [Accepted: 05/28/2019] [Indexed: 12/29/2022] Open
Abstract
Esophageal squamous cell carcinomas (ESCCs) as well as adenocarcinomas (EACs) were developed in rat duodenal contents reflux models (reflux model). The present study aimed to shed light on the mechanism by which bile acid stimulation causes cancer onset and progression. Metabolomics analyses were performed on samples of neoplastic and nonneoplastic tissues from reflux models, and K14D, cultivated from a nonmetastatic, primary ESCC, and ESCC-DR, established from a metastatic thoracic lesion. ESCC-DRtca2M was prepared by treating ESCC-DR cells with taurocholic acid (TCA) to accelerate cancer progression. The lines were subjected to comprehensive genomic analyses. In addition, protein expression levels of glucose-6-phosphate dehydrogenase (G6PD), nuclear factor kappa B (NF-κB) (p65) and O-linked N-Acetylglucosamine (O-GlcNAc) were compared among lines. Cancers developed in the reflux models exhibited greater hexosamine biosynthesis pathway (HBP) activation compared with the nonneoplastic tissues. Expression of O-GlcNAc transferase (OGT) increased considerably in both ESCC and EAC compared with nonneoplastic squamous epithelium. Conversely, cell line-based experiments revealed the greater activation of the pentose phosphate pathway (PPP) at higher degrees of malignancy. G6PD overexpression in response to TCA exposure was observed. Both NF-κB (p65) and O-GlcNAc were expressed more highly in ESCC-DRtca2M than in the other cell lines. Moreover, ESCC-DRtca2M cells had additional chromosomal abnormalities in excess of ESCC-DR cells. Overall, glucose metabolism was upregulated in both esophageal cancer tissue and cell lines. While bile acids are not mutagenic, chronic exposure seems to trigger NF-κB(p65) activation, potentially inducing genetic mutations as well as facilitating carcinogenesis and cancer progression. Glucose metabolism was upregulated in both esophageal cancer tissue and cell lines, and the HBP was activated in the former. The cell line-based experiments demonstrated upregulation of the pentose phosphate pathway (PPP) at higher degrees of malignancy. While bile acids are not mutagenic, chronic exposure seems to trigger G6PD overexpression and NF-κB (p65) activation, potentially inducing genetic mutations as well as facilitating carcinogenesis and cancer progression.
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Affiliation(s)
- Masayoshi Munemoto
- Department of Gastroenterological SurgeryKanazawa University HospitalKanazawaJapan
| | - Ken‐ichi Mukaisho
- Division of Molecular and Diagnostic PathologyDepartment of PathologyShiga University of Medical ScienceOtsuJapan
| | - Tomoharu Miyashita
- Department of Gastroenterological SurgeryKanazawa University HospitalKanazawaJapan
| | - Katsunobu Oyama
- Department of SurgeryPublic Central Hospital of Matto IshikawaHakusanJapan
| | - Yusuke Haba
- Department of Gastroenterological SurgeryKanazawa University HospitalKanazawaJapan
| | - Koichi Okamoto
- Department of Gastroenterological SurgeryKanazawa University HospitalKanazawaJapan
| | - Jun Kinoshita
- Department of Gastroenterological SurgeryKanazawa University HospitalKanazawaJapan
| | - Itasu Ninomiya
- Department of Gastroenterological SurgeryKanazawa University HospitalKanazawaJapan
| | - Sachio Fushida
- Department of Gastroenterological SurgeryKanazawa University HospitalKanazawaJapan
| | - Naoko Taniura
- Division of Molecular and Diagnostic PathologyDepartment of PathologyShiga University of Medical ScienceOtsuJapan
| | - Hiroyuki Sugihara
- Division of Molecular and Diagnostic PathologyDepartment of PathologyShiga University of Medical ScienceOtsuJapan
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Mukaisho KI, Kanai S, Kushima R, Nakayama T, Hattori T, Sugihara H. Barretts's carcinogenesis. Pathol Int 2019; 69:319-330. [PMID: 31290583 PMCID: PMC6851828 DOI: 10.1111/pin.12804] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Accepted: 03/22/2019] [Indexed: 12/14/2022]
Abstract
Barrett's esophagus is considered a precancerous lesion of esophageal adenocarcinoma (EAC). Long‐segment Barrett's esophagus, which is generally associated with intestinal metaplasia, has a higher rate of carcinogenesis than short‐segment Barrett's esophagus, which is mainly composed of cardiac‐type mucosa. However, a large number of cases reportedly develop EAC from the cardiac‐type mucosa which has the potential to involve intestinal phenotypes. There is no consensus regarding whether the definition of Barrett's epithelium should include intestinal metaplasia. Basic researches using rodent models have provided information regarding the origins of Barrett's epithelium. Nevertheless, it remains unclear whether differentiated gastric columnar epithelium or stratified esophageal squamous epithelium undergo transdifferentiation into the intestinal‐type columnar epithelium, transcommittment into the columnar epithelium, or whether the other pathways exist. Reflux of duodenal fluid including bile acids into the stomach may occur when an individual lies down after eating, which could cause the digestive juices to collect in the fornix of the stomach. N‐nitroso‐bile acids are produced with nitrites that are secreted from the salivary glands, and bile acids can drive expression of pro‐inflammatory cytokines via EGFR or the NF‐κB pathway. These steps may contribute significantly to carcinogenesis.
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Affiliation(s)
- Ken-Ichi Mukaisho
- Division of Molecular and Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
| | - Shunpei Kanai
- Division of Molecular and Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
| | - Ryoji Kushima
- Division of Diagnostic Pathology, Shiga University of Medical Science Hospital, Otsu, Japan
| | - Takahisa Nakayama
- Division of Molecular and Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
| | - Takanori Hattori
- Division of Molecular and Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
| | - Hiroyuki Sugihara
- Division of Molecular and Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Otsu, Japan
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Kanai S, Mukaisho KI, Yoshida S, Taniura N, Sugihara H. Host factors influence Barrett's carcinogenesis: findings from a mouse gastroduodenal reflux model. Esophagus 2019; 16:264-271. [PMID: 30790117 PMCID: PMC6592968 DOI: 10.1007/s10388-019-00660-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 02/05/2019] [Indexed: 02/03/2023]
Abstract
BACKGROUND Rat gastroduodenal reflux models have been used for analyzing Barrett's carcinogenesis. Mice seem to be more useful than rats for studies targeting genes. METHODS We induced gastroduodenal contents reflux by esophagojejunostomy using C57BL/6J mice. Mice were divided into a standard diet and high-fat diet groups and kept for 60 weeks. Bile was sampled from the gallbladder to analyze bile acid fractions, and the esophagus was removed for a histological investigation. Human esophagogastric junction adenocarcinoma cells (OE19) were exposed to taurocholic acid (TCA), after which cell proliferative activity was measured. Rat esophageal cancer cell lines, ESCC-DR and ESCC-DRtca with higher malignant potential induced by continuous TCA exposure, were used to perform comprehensive genetic analysis (CGH). RESULTS Barrett's epithelium onset occurred in all mice, and no differences in histological changes were noted between the standard diet and high-fat diet groups. However, no development of adenocarcinoma was noted. Most of the mouse bile acid was taurine conjugates. In the experiment using OE-19 cells, TCA promotes cell proliferation in a dose-dependent manner. Array CGH analysis revealed a large number of chromosomal abnormalities in the ESCC-DR, in addition to genetic abnormalities such as in the UGT2B gene, the substrate of which is bile acid. TCA administration resulted in more chromosomal abnormalities being detected. CONCLUSIONS We showed the effects of TCA in cancer progression in vitro. However, Barrett's adenocarcinoma onset rates differ between mice and rats despite undergoing similar reflux stimulation including taurine-conjugated bile acids being detected in mouse bile juice. These results suggest that host factors seem to influence Barrett's carcinogenesis.
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Affiliation(s)
- Shunpei Kanai
- Division of Molecular and Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Seta-tsukinowa-cho, Otsu, Shiga 520-2192 Japan
| | - Ken-ichi Mukaisho
- Division of Molecular and Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Seta-tsukinowa-cho, Otsu, Shiga 520-2192 Japan
| | - Saori Yoshida
- Division of Molecular and Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Seta-tsukinowa-cho, Otsu, Shiga 520-2192 Japan
| | - Naoko Taniura
- Division of Molecular and Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Seta-tsukinowa-cho, Otsu, Shiga 520-2192 Japan
| | - Hiroyuki Sugihara
- Division of Molecular and Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Seta-tsukinowa-cho, Otsu, Shiga 520-2192 Japan
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Liu R, Li X, Hylemon PB, Zhou H. Conjugated Bile Acids Promote Invasive Growth of Esophageal Adenocarcinoma Cells and Cancer Stem Cell Expansion via Sphingosine 1-Phosphate Receptor 2-Mediated Yes-Associated Protein Activation. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:2042-2058. [PMID: 29963993 PMCID: PMC6105923 DOI: 10.1016/j.ajpath.2018.05.015] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 04/05/2018] [Accepted: 05/15/2018] [Indexed: 02/07/2023]
Abstract
Esophageal adenocarcinoma (EAC) is the sixth leading cause of cancer deaths worldwide and has been dramatically increasing in incidence over the past decade. Gastroesophageal reflux and Barrett esophagus are well-established risk factors for disease progression. Conjugated bile acids (CBAs), including taurocholate (TCA), represent the major bile acids in the gastroesophageal refluxate of advanced Barrett esophagus and EAC patients. Our previous studies suggested that CBA-induced activation of sphingosine 1-phosphate receptor 2 (S1PR2) plays a critical role in promoting cholangiocarcinoma cell invasive growth. However, the role of CBAs in EAC development and underlying mechanisms remains elusive. In the current study, we identified that the expression level of S1PR2 is correlated to invasiveness of EAC cells. TCA significantly promoted cell proliferation, migration, invasion, transformation, and cancer stem cell expansion in highly invasive EAC cells (OE-33 cells), but had less effect on the lower invasive EAC cells (OE-19 cells). Pharmacologic inhibition of S1PR2 with specific antagonist JTE-013 or knockdown of S1PR2 expression significantly reduced TCA-induced invasive growth of OE-33 cells, whereas overexpression of S1PR2 sensitized OE-19 cells to TCA-induced invasive growth. Furthermore, TCA-induced activation of S1PR2 was closely associated with YAP and β-catenin signaling pathways. In conclusion, CBA-induced activation of the S1PR2 signaling pathway is critically involved in invasive growth of EAC cells and represents a novel therapeutic target for EAC.
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Affiliation(s)
- Runping Liu
- Department of Microbiology and Immunology, McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia
| | - Xiaojiaoyang Li
- Department of Microbiology and Immunology, McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia
| | - Phillip B Hylemon
- Department of Microbiology and Immunology, McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia
| | - Huiping Zhou
- Department of Microbiology and Immunology, McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia.
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Kennedy L, Alpini G. Therapeutic Role of Sphingosine-1-Phosphate Receptor 2 in the Progression of Esophageal Adenocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:1949-1952. [PMID: 30026028 DOI: 10.1016/j.ajpath.2018.07.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 07/09/2018] [Accepted: 07/10/2018] [Indexed: 02/07/2023]
Abstract
This commentary highlights the article by Liu et al that provides novel mechanistic insights in how conjugated bile acids promote invasive growth of esophageal adenocarcinoma.
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Affiliation(s)
- Lindsey Kennedy
- Research Service, Central Texas Veterans Health Care System, Temple, Texas; Department of Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, Texas
| | - Gianfranco Alpini
- Research Service, Central Texas Veterans Health Care System, Temple, Texas; Department of Medical Physiology, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Baylor Scott & White Health Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas.
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Terabe F, Aikou S, Aida J, Yamamichi N, Kaminishi M, Takubo K, Seto Y, Nomura S. Columnar Metaplasia in Three Types of Surgical Mouse Models of Esophageal Reflux. Cell Mol Gastroenterol Hepatol 2017; 4:115-123. [PMID: 28593183 PMCID: PMC5453905 DOI: 10.1016/j.jcmgh.2017.03.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 03/24/2017] [Indexed: 01/11/2023]
Abstract
BACKGROUND AND AIMS Esophageal adenocarcinoma develops in the setting of gastroesophageal reflux and columnar metaplasia in distal esophagus. Columnar metaplasia arising in gastroesophageal reflux models has developed in rat; however, gastroesophageal reflux models in mice have not been well-characterized. METHODS One hundred thirty-five C57Bl/6J mice aged 8 weeks old were divided into the following operations: esophagogastrojejunostomy (side-to-side) (EGJ), esophageal separation and esophagojejunostomy (end-to-side) (EJ), and EJ and gastrectomy (end-to-side) (EJ/TG). The animals were euthanized after 40 weeks and the histology of the junction was examined. Immunohistochemistry for p53, PDX-1, and CDX-2 was performed. RESULTS Metaplasia developed in 15/33 (45.5%) of EGJ, 0/38 (0%) of EJ, and 6/39 (15.4%) of EJ/TG (P < .05) and dysplasia developed 7/33 (21.2%) of EGJ, 0% of EJ, and 1/39 (2.6%) of EJ/TG. p53 was positive in all of the dysplastic regions, 12/15 (80%) metaplasias in the EGJ model, and 1/6 (16.7%) metaplasia in the EJ/TG model. CDX-2 was positive in all cases of metaplasias, but decreased in some cases of dysplasia. PDX-1 was positive in 7/8 (88%) cases of dysplasia and in 15/21 (71%) cases of metaplasia (P < .05). CONCLUSIONS The EGJ model, which causes reflux of gastric acid and duodenal content, developed metaplasia and dysplasia most frequently. No metaplasia developed in the EJ model in which gastric juice and duodenal content mixed before reflux. Thus, duodenal contents alone can induce columnar metaplasia and dysplasia; however, the combination of gastric acid with duodenal content reflux can cause metaplasia and dysplasia more efficiently.
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Affiliation(s)
- Fabio Terabe
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Susumu Aikou
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Junko Aida
- Department of Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Nobutake Yamamichi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | - Kaiyo Takubo
- Department of Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Yasuyuki Seto
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Sachiyo Nomura
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan,Correspondence Address correspondence to: Sachiyo Nomura, MD, PhD, Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyu-ku, Tokyo, Japan 113-8655.fax: +81-3-5800-9734.Department of Gastrointestinal SurgeryGraduate School of MedicineThe University of Tokyo7-3-1, Hongo, Bunkyu-kuTokyoJapan 113-8655
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Kaakoush NO, Lecomte V, Maloney CA, Morris MJ. Cross-talk among metabolic parameters, esophageal microbiota, and host gene expression following chronic exposure to an obesogenic diet. Sci Rep 2017; 7:45753. [PMID: 28362001 PMCID: PMC5374643 DOI: 10.1038/srep45753] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 03/06/2017] [Indexed: 12/29/2022] Open
Abstract
Unhealthy diets, and ensuing weight gain, predispose individuals to the development of esophageal adenocarcinoma. We examined the effect of chronic high fat diet (HFD) on the esophageal microbiota of Sprague Dawley rats using Illumina MiSeq amplicon sequencing (V4, 515 F/806 R) and on esophageal expression of IL18, PTGS2, PPARA, FFAR3, and CRAT. The relationships among metabolic parameters, esophageal microbiota, and host gene expression were determined. We observed a significant difference between the upper and lower esophageal microbiota in control fed rats, emphasized by enrichment of Lactobacillus species in the lower esophagus. Rats on HFD gained significantly more fat and had reduced insulin sensitivity. Diet type significantly affected the esophageal microbiota, with Clostridium sensu stricto being enriched in both upper and lower segments of HFD fed rats. Of interest, bacterial pathways related to carotenoid biosynthesis were significantly decreased in the lower esophagus of HFD fed rats. We observed strong correlations between metabolic parameters, the esophageal microbial profiles, and host esophageal gene expression. In particular, Fusobacterium, Rothia, and Granulicatella showed consistent correlations across a range of metabolic and gene markers. Our data indicates that unhealthy diets can significantly alter the esophageal microbiota, and enrich for bacterial species previously associated with chronic gastrointestinal diseases.
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Affiliation(s)
- Nadeem O Kaakoush
- School of Medical Sciences, UNSW Australia, Sydney 2052, NSW, Australia
| | - Virginie Lecomte
- School of Medical Sciences, UNSW Australia, Sydney 2052, NSW, Australia
| | | | - Margaret J Morris
- School of Medical Sciences, UNSW Australia, Sydney 2052, NSW, Australia
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Feng C, Luo Y, Nian Y, Liu D, Yin X, Wu J, Di J, Zhang R, Zhang J. Diallyl Disulfide Suppresses the Inflammation and Apoptosis Resistance Induced by DCA Through ROS and the NF-κB Signaling Pathway in Human Barrett’s Epithelial Cells. Inflammation 2017; 40:818-831. [DOI: 10.1007/s10753-017-0526-4] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Kaakoush NO, Morris MJ. The oesophageal microbiome: an unexplored link in obesity-associated oesophageal adenocarcinoma. FEMS Microbiol Ecol 2016; 92:fiw161. [PMID: 27465078 DOI: 10.1093/femsec/fiw161] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/22/2016] [Indexed: 12/12/2022] Open
Abstract
The influence of diets rich in saturated fats and simple sugars on the intestinal microbiota plays a central role in obesity. Being overweight or obese predisposes individuals to several diseases including oesophageal adenocarcinoma (OAC), which develops through a cascade of events starting with gastro-oesophageal reflux disease, progressing to Barrett's oesophagus (BO), and then OAC. A range of mechanisms for the increased risk of OAC in obese individuals have been proposed; however, a role for the oesophageal microbiota has been largely ignored. This is despite the fact that it is clear that the composition of the oesophageal microbiota shifts with the development of OAC. Given the well-established impact that unhealthy diets have on the intestinal microbiota, it is plausible that exposure to unhealthy foods, and the ensuing obesity, would result in an imbalance in the oesophageal microbiota. It is also likely that these changes may mimic the changes observed in the intestinal microbiota (i.e. increase in short-chain fatty acid (SCFA) producers and bile acid biosynthesis). The modulation of SCFAs and bile acids in the oesophagus by diet could promote the transdifferentiation from squamous to intestinal-like columnar cells observed in BO, given that intestinal cells proliferate in the presence of SCFAs.
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Affiliation(s)
- Nadeem O Kaakoush
- School of Medical Sciences, UNSW Australia, Sydney, NSW 2052, Australia
| | - Margaret J Morris
- School of Medical Sciences, UNSW Australia, Sydney, NSW 2052, Australia
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Kapoor H, Lohani KR, Lee TH, Agrawal DK, Mittal SK. Animal Models of Barrett's Esophagus and Esophageal Adenocarcinoma-Past, Present, and Future. Clin Transl Sci 2015. [PMID: 26211420 DOI: 10.1111/cts.12304] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Esophageal adenocarcinoma is the fastest rising cancer in the United States. It develops from long-standing gastroesophageal reflux disease which affects >20% of the general population. It carries a very poor prognosis with 5-year survival <20%. The disease is known to sequentially progress from reflux esophagitis to a metaplastic precursor, Barrett's esophagus and then onto dysplasia and esophageal adenocarcinoma. However, only few patients with reflux develop Barrett's esophagus and only a minority of these turn malignant. The reason for this heterogeneity in clinical progression is unknown. To improve patient management, molecular changes which facilitate disease progression must be identified. Animal models can provide a comprehensive functional and anatomic platform for such a study. Rats and mice have been the most widely studied but disease homology with humans has been questioned. No animal model naturally simulates the inflammation to adenocarcinoma progression as in humans, with all models requiring surgical bypass or destruction of existing antireflux mechanisms. Valuable properties of individual models could be utilized to holistically evaluate disease progression. In this review paper, we critically examined the current animal models of Barrett's esophagus, their differences and homologies with human disease and how they have shaped our current understanding of Barrett's carcinogenesis.
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Affiliation(s)
- Harit Kapoor
- Department of Surgery and Center for Clinical & Translational Science, Creighton University School of Medicine, Omaha, Nebraska, USA
| | - Kush Raj Lohani
- Department of Surgery and Center for Clinical & Translational Science, Creighton University School of Medicine, Omaha, Nebraska, USA
| | - Tommy H Lee
- Department of Surgery and Center for Clinical & Translational Science, Creighton University School of Medicine, Omaha, Nebraska, USA
| | - Devendra K Agrawal
- Department of Surgery and Center for Clinical & Translational Science, Creighton University School of Medicine, Omaha, Nebraska, USA
| | - Sumeet K Mittal
- Department of Surgery and Center for Clinical & Translational Science, Creighton University School of Medicine, Omaha, Nebraska, USA
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Pyo JS, Ko YS, Kang G, Kim DH, Kim WH, Lee BL, Sohn JH. Bile acid induces MUC2 expression and inhibits tumor invasion in gastric carcinomas. J Cancer Res Clin Oncol 2015; 141:1181-8. [PMID: 25475007 DOI: 10.1007/s00432-014-1890-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2014] [Accepted: 11/25/2014] [Indexed: 12/14/2022]
Abstract
PURPOSE Bile acids might induce mucin expression and regulate tumor behavior in esophageal and colon cancers. However, little is known about the effect of bile acids on tumor invasiveness of gastric carcinoma (GC). The aim of the current study was to elucidate the mechanisms by which bile acids regulate tumor invasion in GC. METHODS We investigated bile acid-induced MUC2 expression and cell invasion and migration in the cultured GC cell lines, SNU-216, and MKN45. In addition, immunohistochemical analysis of MUC2 and Snail was performed on 389 archival paraffin-embedded tissues of GC to evaluate the correlation of their expression with prognosis. RESULTS Deoxycholic acid (DCA), a secondary bile acid, had no effect on the viability of SNU-216 and MKN45 GC cells at low concentrations (0-100 μM), but decreased viability at a higher concentration (200 μM). MKN45 cells showed higher MUC2 expression than SNU-216 cells under basal conditions. DCA treatment upregulated MUC2 mRNA expression in both SNU-216 and MKN45 cells. Expression of Snail and MMP9 was markedly decreased by DCA treatment, and E-cadherin expression was subsequently increased. DCA significantly inhibited invasion and migration of SNU-216 and MKN45 cells. In human GC, MUC2 expression showed a negative correlation with Snail expression (P = 0.021) and a significantly positive correlation with better prognosis (P = 0.023). CONCLUSIONS Taken together, our data suggest that DCA induced MUC2 expression in GC cells and inhibited tumor invasion and migration. Additionally, MUC2-expressing GCs showed low rates of Snail expression and were associated with a favorable prognosis.
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Affiliation(s)
- Jung-Soo Pyo
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 78 Saemunan-gil, Jongno-gu, Seoul, 110-746, South Korea
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Mukaisho KI, Nakayama T, Hagiwara T, Hattori T, Sugihara H. Two distinct etiologies of gastric cardia adenocarcinoma: interactions among pH, Helicobacter pylori, and bile acids. Front Microbiol 2015; 6:412. [PMID: 26029176 PMCID: PMC4426758 DOI: 10.3389/fmicb.2015.00412] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Accepted: 04/20/2015] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer can be classified as cardia and non-cardia subtypes according to the anatomic site. Although the gastric cancer incidence has decreased steadily in several countries over the past 50 years, the incidence of cardia cancers and esophageal adenocarcinoma (EAC) continue to increase. The etiological factors involved in the development of both cardia cancers and EACs are associated with high animal fat intake, which causes severe obesity. Central obesity plays roles in cardiac-type mucosa lengthening and partial hiatus hernia development. There are two distinct etiologies of cardia cancer subtypes: one associated with gastroesophageal reflux (GER), which predominantly occurs in patients without Helicobacter pylori (H. pylori) infection and resembles EAC, and the other associated with H. pylori atrophic gastritis, which resembles non-cardia cancer. The former can be developed in the environment of high volume duodenal content reflux, including bile acids and a higher acid production in H. pylori-negative patients. N-nitroso compounds, which are generated from the refluxate that includes a large volume of bile acids and are stabilized in the stomach (which has high levels of gastric acid), play a pivotal role in this carcinogenesis. The latter can be associated with the changing colonization of H. pylori from the distal to the proximal stomach with atrophic gastritis because a high concentration of soluble bile acids in an environment of low acid production is likely to act as a bactericide or chemorepellent for H. pylori in the distal stomach. The manuscript introduces new insights in causative factors of adenocarcinoma of the cardia about the role of bile acids in gastro-esophageal refluxate based upon robust evidences supporting interactions among pH, H. pylori, and bile acids.
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Affiliation(s)
- Ken-ichi Mukaisho
- Division of Molecular Diagnostic Pathology, Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan
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Chemoprevention of esophageal adenocarcinoma in a rat model by ursodeoxycholic acid. Clin Exp Med 2014; 15:343-50. [PMID: 25034655 DOI: 10.1007/s10238-014-0301-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Accepted: 06/24/2014] [Indexed: 12/11/2022]
Abstract
Reflux of bile acid into the esophagus induces esophagitis, inflammation-stimulated hyperplasia, metaplasia such as Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC). Caudal-type homeobox 2 (Cdx2) via nuclear factor (NF)-κB induced by bile acid is an important factor in the development of BE and EAC. In colorectal cancer, experimental data suggest a chemopreventive effect of ursodeoxycholic acid (UDCA). We hypothesized that UDCA may protect against the esophageal inflammation-metaplasia-carcinoma sequence by decreasing the overall proportion of the toxic bile acids. Wistar male rats that underwent a duodenoesophageal reflux procedure were divided into two groups. One group was given commercial chow (control group), and the other was given experimental chow containing UDCA (UDCA group). The animals were killed at 40 weeks after surgery, and their bile and esophagus were examined. In the UDCA group, the esophagitis was milder and the incidence of BE was significantly lower (p < 0.05) than in the control group, and EAC was not observed (p < 0.05). In analysis of the compartment of bile acid, UDCA was markedly increased in the UDCA group compared with the control group (32.7 ± 11.4 vs. 0.82 ± 0.33 mmol/L, p < 0.05) and cholic acid was decreased (32.7 ± 4.05 vs. 60.9 ± 8.26 mmol/L, p < 0.05). Expression intensity of Cdx2 and NF-κB was greater in the control group than in the UDCA group (p < 0.05). UDCA may be a chemopreventive agent against EAC by varying the bile acid composition.
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McAdam E, Haboubi HN, Griffiths AP, Baxter JN, Spencer-Harty S, Davies C, Jenkins GJ. Reflux composition influences the level of NF-κB activation and upstream kinase preference in oesophageal adenocarcinoma cells. Int J Cancer 2014; 136:527-35. [PMID: 24931696 DOI: 10.1002/ijc.29029] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Revised: 06/03/2014] [Accepted: 06/06/2014] [Indexed: 01/17/2023]
Abstract
Oesophageal adenocarcinoma (OA) incidence is rising and prognosis is poor. Understanding the molecular basis of this malignancy is key to finding new prevention and treatment strategies. Gastroesophageal reflux disease is the primary cause of OA, usually managed with acid suppression therapy. However, this often does little to control carcinogenic bile acid reflux. The transcription factor nuclear factor kappa B (NF-κB) plays a key role in the pathogenesis of OA and its activity is associated with a poor response to chemotherapy, making it an attractive therapeutic target. We sought to decipher the role of different bile acids in NF-κB activation in oesophageal cell lines using short, physiologically relevant exposure times. The effect of an acidic or neutral extracellular pH was investigated concurrently, to mimic in vivo conditions associated with or without acid suppression. We found that some bile acids activated NF-κB to a greater extent when combined with acid, whereas others did so in its absence, at neutral pH. The precise composition of an individual's reflux, coupled with whether they are taking acid suppressants may therefore dictate the extent of NF-κB activation in the oesophagus, and hence the likelihood of histological progression and chemotherapy success. Regardless of pH, the kinase inhibitor of κB kinase was pivotal in mediating reflux induced NF-κB activation. Its importance was confirmed further as its increased activation was associated with histological progression in patient samples. We identified further kinases important in acid or bile induced NF-κB signalling in oesophageal cells, which may provide suitable targets for therapeutic intervention.
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Affiliation(s)
- E McAdam
- Institute of Life Science, School of Medicine, Swansea University, Singleton Park, Swansea, SA2 8PP, United Kingdom
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Green NH, Nicholls Z, Heath PR, Cooper-Knock J, Corfe BM, MacNeil S, Bury JP. Pulsatile exposure to simulated reflux leads to changes in gene expression in a 3D model of oesophageal mucosa. Int J Exp Pathol 2014; 95:216-28. [PMID: 24713057 DOI: 10.1111/iep.12083] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2013] [Accepted: 03/07/2014] [Indexed: 01/11/2023] Open
Abstract
Oesophageal exposure to duodenogastroesophageal refluxate is implicated in the development of Barrett's metaplasia (BM), with increased risk of progression to oesophageal adenocarcinoma. The literature proposes that reflux exposure activates NF-κB, driving the aberrant expression of intestine-specific caudal-related homeobox (CDX) genes. However, early events in the pathogenesis of BM from normal epithelium are poorly understood. To investigate this, our study subjected a 3D model of the normal human oesophageal mucosa to repeated, pulsatile exposure to specific bile components and examined changes in gene expression. Initial 2D experiments with a range of bile salts observed that taurochenodeoxycholate (TCDC) impacted upon NF-κB activation without causing cell death. Informed by this, the 3D oesophageal model was repeatedly exposed to TCDC in the presence and absence of acid, and the epithelial cells underwent gene expression profiling. We identified ~300 differentially expressed genes following each treatment, with a large and significant overlap between treatments. Enrichment analysis (Broad GSEA, DAVID and Metacore™; GeneGo Inc) identified multiple gene sets related to cell signalling, inflammation, proliferation, differentiation and cell adhesion. Specifically NF-κB activation, Wnt signalling, cell adhesion and targets for the transcription factors PTF1A and HNF4α were highlighted. Our data suggest that HNF4α isoform switching may be an early event in Barrett's pathogenesis. CDX1/2 targets were, however, not enriched, suggesting that although CDX1/2 activation reportedly plays a role in BM development, it may not be an initial event. Our findings highlight new areas for investigation in the earliest stages of BM pathogenesis of oesophageal diseases and new potential therapeutic targets.
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Affiliation(s)
- Nicola H Green
- Kroto Research Institute, North Campus, University of Sheffield, Sheffield, UK
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Sato S, Yamamoto H, Mukaisho KI, Saito S, Hattori T, Yamamoto G, Sugihara H. Continuous taurocholic acid exposure promotes esophageal squamous cell carcinoma progression due to reduced cell loss resulting from enhanced vascular development. PLoS One 2014; 9:e88831. [PMID: 24551170 PMCID: PMC3925151 DOI: 10.1371/journal.pone.0088831] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Accepted: 01/16/2014] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Refluxogenic effects of smoking and alcohol abuse may be related to the risk of esophageal squamous cell carcinoma (ESCC). The present study attempts to clarify the effects of continuous taurocholic acid (TCA) exposure, which is neither mutagenic nor genotoxic, on ESCC progression. METHODS A squamous carcinoma cell line (ESCC-DR) was established from a tumor induced in a rat model of gastroduodenal reflux. ESCC-DR cells were incubated with 2 mM TCA for ≥2 months. The effects of continuous TCA exposure were evaluated in vitro on cell morphology, growth, and invasion and in vivo on xenograft tumor growth in nude mice. Moreover, the mean level of secreted transforming growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF) proteins in cell culture supernatants and mRNA synthesis of TGF-β1 and VEGF-A of ESCC cells were measured. The angiogenic potential was further examined by a migration assay using human umbilical vein endothelial cells (HUVECs). RESULTS Continuous TCA exposure induced marked formation of filopodia in vitro. Expression levels of angiogenic factors were significantly higher in the cells treated with TCA than in control cells. Tumor xenografts derived from cells pre-exposed to TCA were larger and more vascularized than those derived from control cells. In addition, TCA exposure increased HUVEC migration. CONCLUSION Continuous TCA exposure enhanced ESCC progression due to reduced cell loss in vivo. Cell loss was inhibited by TCA-induced vascular endothelial cell migration, which was mediated by TGF-β1 and VEGF-A released from ESCC cells.
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MESH Headings
- Animals
- Carcinoma, Squamous Cell/blood supply
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/pathology
- Carcinoma, Squamous Cell/ultrastructure
- Cell Cycle/drug effects
- Cell Cycle/genetics
- Cell Line, Tumor
- Cell Movement/drug effects
- Cell Movement/genetics
- Cell Proliferation/drug effects
- Cell Shape/drug effects
- Cell Shape/genetics
- Disease Progression
- Esophageal Neoplasms/blood supply
- Esophageal Neoplasms/genetics
- Esophageal Neoplasms/pathology
- Esophageal Neoplasms/ultrastructure
- Esophageal Squamous Cell Carcinoma
- Flow Cytometry
- Gene Expression Regulation, Neoplastic/drug effects
- Human Umbilical Vein Endothelial Cells
- Humans
- Mice
- Mice, Nude
- Neoplasm Invasiveness
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/pathology
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Rats
- Taurocholic Acid/adverse effects
- Transforming Growth Factor beta1/genetics
- Transforming Growth Factor beta1/metabolism
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Sho Sato
- Department of Pathology, Division of Molecular and Diagnostic Pathology, Shiga University of Medical Science, Shiga, Japan
- Department of Oral and Maxillofacial Surgery, Shiga University of Medical Science, Shiga, Japan
| | - Hiroto Yamamoto
- Department of Pathology, Division of Molecular and Diagnostic Pathology, Shiga University of Medical Science, Shiga, Japan
| | - Ken-ichi Mukaisho
- Department of Pathology, Division of Molecular and Diagnostic Pathology, Shiga University of Medical Science, Shiga, Japan
- * E-mail:
| | - Shota Saito
- Department of Pathology, Division of Molecular and Diagnostic Pathology, Shiga University of Medical Science, Shiga, Japan
- Department of Oral and Maxillofacial Surgery, Shiga University of Medical Science, Shiga, Japan
| | - Takanori Hattori
- Department of Pathology, Division of Molecular and Diagnostic Pathology, Shiga University of Medical Science, Shiga, Japan
| | - Gaku Yamamoto
- Department of Oral and Maxillofacial Surgery, Shiga University of Medical Science, Shiga, Japan
| | - Hiroyuki Sugihara
- Department of Pathology, Division of Molecular and Diagnostic Pathology, Shiga University of Medical Science, Shiga, Japan
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Zhang R, Yin X, Shi H, Wu J, Shakya P, Liu D, Zhang J. Adiponectin modulates DCA-induced inflammation via the ROS/NF-κ B signaling pathway in esophageal adenocarcinoma cells. Dig Dis Sci 2014; 59:89-97. [PMID: 24096876 DOI: 10.1007/s10620-013-2877-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2013] [Accepted: 09/04/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND Deoxycholic acid (DCA) promotes the development and progression of esophageal adenocarcinoma (EAC) by inducing inflammation. Adiponectin is reported to have anti-inflammatory and anti-tumor effects. PURPOSE This study investigated the effects of two types of adiponectin, full-length adiponectin (f-Ad) and globular adiponectin (g-Ad), on DCA-induced inflammation, and investigated the involvement of the reactive oxygen species (ROS)/NF-κB signaling pathway in inflammation in EAC. METHODS OE19 cells were treated with DCA (50-300 μM) and/or f-Ad/g-Ad (10.0 μg/ml) or N-acetylcysteine (NAC). The viability of cells exposed to DCA was measured by use of the MTT assay. mRNA and protein levels of the inflammatory factors were examined by real-time PCR and ELISA. Intra-cellular ROS levels were determined by use of flow cytometry. Protein levels of total and p-NF-κB p65 were measured by western blot. RESULTS DCA induced dose and time-dependent cytotoxicity. mRNA and protein expression of TNF-α, IL-8, and IL-6 in cells treated with DCA alone were up-regulated, and intra-cellular ROS and p-NF-κB p65 protein levels were also increased. g-Ad promoted inflammatory factor production, ROS levels, and p-NF-κB p65 protein expression whereas f-Ad had a suppressive effect. When combined with DCA, g-Ad enhanced the pro-inflammatory effect of DCA whereas f-Ad, similar to NAC, suppressed the effect. CONCLUSION DCA has a pro-inflammatory effect in EAC. f-Ad has an anti-inflammatory effect whereas g-Ad seems to have a pro-inflammatory effect in an ROS/NF-κB p65-dependent manner. This indicates that f-Ad could be a potential anti-inflammatory reagent for cancer therapy.
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Affiliation(s)
- Rong Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of School of Medicine, Xi'an Jiaotong University, No. 157, Xi Wu Road, Xi'an, 710004, Shaanxi Province, China
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Yates M, Cheong E, Luben R, Igali L, Fitzgerald R, Khaw KT, Hart A. Body mass index, smoking, and alcohol and risks of Barrett's esophagus and esophageal adenocarcinoma: a UK prospective cohort study. Dig Dis Sci 2014; 59:1552-9. [PMID: 24500448 PMCID: PMC4067535 DOI: 10.1007/s10620-013-3024-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Accepted: 12/30/2013] [Indexed: 12/22/2022]
Abstract
BACKGROUND The timing of the risk factors cigarette smoking, alcohol and obesity in the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) is unclear. AIMS To investigate these exposures in the aetiology of BE and EAC in the same population. METHODS The cohort included 24,068 men and women, aged 39-79 years, recruited between 1993 and 1997 into the prospective EPIC-Norfolk Study who provided information on anthropometry, smoking and alcohol intake. The cohort was monitored until December 2008 and incident cases identified. RESULTS One hundred and four participants were diagnosed with BE and 66 with EAC. A body mass index (BMI) above 23 kg/m(2) was associated with a greater risk of BE [BMI ≥23 vs. 18.5 to <23, hazard ratio (HR) 3.73, 95 % CI 1.37-10.16], and within a normal BMI, the risk was greater in the higher category (HR 3.76, 95 % CI 1.30-10.85, BMI 23-25 vs. 18.5 to >23 kg/m(2)). Neither smoking nor alcohol intake were associated with risk for BE. For EAC, all BMI categories were associated with risk, although statistically significant for only the highest (BMI >35 vs. BMI 18.5 to <23, HR 4.95, 95 % CI 1.11-22.17). The risk was greater in the higher category of a normal BMI (HR 2.73, 95 % CI 0.93-8.00, p = 0.07, BMI 23-25 vs. 18.5 to >23 kg/m(2)). There was an inverse association with ≥7 units alcohol/week (HR 0.51, 95 % CI 0.29-0.88) and with wine (HR 0.49, 95 % CI 0.23-1.04, p = 0.06, drinkers vs. non-drinkers). CONCLUSIONS Obesity may be involved early in carcinogenesis and the association with EAC and wine should be explored. The data have implications for aetiological investigations and prevention strategies.
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Affiliation(s)
- Max Yates
- Norfolk and Norwich University Hospital NHS Trust, Colney Lane, Norwich, NR4 7UY UK
| | - Edward Cheong
- Norfolk and Norwich University Hospital NHS Trust, Colney Lane, Norwich, NR4 7UY UK
| | - Robert Luben
- Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN UK
| | - Laszlo Igali
- Norfolk and Norwich University Hospital NHS Trust, Colney Lane, Norwich, NR4 7UY UK
| | - Rebecca Fitzgerald
- Medical Research Council Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge, CB2 0XZ UK
| | - Kay-Tee Khaw
- Department of Public Health and Primary Care, Cambridge University, Cambridge, CB2 0SP UK
| | - Andrew Hart
- Norfolk and Norwich University Hospital NHS Trust, Colney Lane, Norwich, NR4 7UY UK ,Norwich Medical School, University of East Anglia, Norwich, NR4 7TJ UK
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Matsuzaki J, Suzuki H, Tsugawa H, Watanabe M, Hossain S, Arai E, Saito Y, Sekine S, Akaike T, Kanai Y, Mukaisho KI, Auwerx J, Hibi T. Bile acids increase levels of microRNAs 221 and 222, leading to degradation of CDX2 during esophageal carcinogenesis. Gastroenterology 2013; 145:1300-11. [PMID: 23933602 DOI: 10.1053/j.gastro.2013.08.008] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 08/03/2013] [Accepted: 08/05/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Bile reflux contributes to development of Barrett's esophagus (BE) and could be involved in its progression to esophageal adenocarcinoma (EAC). We investigated whether bile acids affect levels or functions of microRNAs (MIRs) 221 and 222, which bind to the 3'-UTR of p27Kip1 messenger RNA to inhibit its translation. Reduced p27Kip1 increases degradation of the transcription factor CDX2; levels of CDX2 have been reported to decrease during progression of BE to EAC. METHODS We used quantitative reverse transcriptase polymerase chain reaction to compare levels of MIRs 221 and 222 and immunohistochemistry to compare levels of p27Kip1 and CDX2 proteins in areas of BE and EAC from each of 11 patients. We examined the effects of bile acid exposure on levels of MIRs 221 and 222 and CDX2 in EAC cells. We investigated the effects of inhibitors of MIRs 221 and 222 on growth of human EAC xenograft tumors in NOD/SCID/IL-2Rγ(null) mice. RESULTS Levels of MIRs 221 and 222 increased and levels of p27Kip1 and CDX2 decreased in areas of EAC vs BE. Levels of MIRs 221 and 222 increased, along with activity of nuclear bile acid receptor/farnesoid X receptor (FXR), when cultured cells were exposed to bile acids. Incubation of cells with bile acids increased degradation of CDX2; this process was reduced when cells were also incubated with proteasome inhibitors. Overexpression of MIRs 221 and 222 reduced levels of p27Kip1 and CDX2, and knockdown of these MIRs increased levels of these proteins in cultured cells. Inhibitors of MIRs 221 and 222 increased levels of p27Kip1 and CDX2 in EAC cells and reduced growth of xenograft tumors in NOD/SCID/IL-2Rγ(null) mice. CONCLUSIONS We observed increased levels of MIRs 221 and 222 in human EAC tissues, compared with areas of BE from the same patient. We found that exposure of esophageal cells to bile acids activates FXR and increases levels of MIRs 221 and 222, reducing levels of p27Kip1 and promoting degradation of CDX2 by the proteasome. Our work opened the perspective of therapeutically targeting this pathway either via FXR antagonists or inhibitors of MIRs as a treatment option for BE and EAC.
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Affiliation(s)
- Juntaro Matsuzaki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan
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Jiao L, Kramer JR, Chen L, Rugge M, Parente P, Verstovsek G, Alsarraj A, El-Serag HB. Dietary consumption of meat, fat, animal products and advanced glycation end-products and the risk of Barrett's oesophagus. Aliment Pharmacol Ther 2013; 38:817-24. [PMID: 23957669 PMCID: PMC3811083 DOI: 10.1111/apt.12459] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Revised: 05/17/2013] [Accepted: 07/30/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND Advanced glycation end-products (AGEs) are found in high quantity in high-fat foods and meat cooked at high temperature. AGEs have been shown to contribute to chronic inflammation and oxidative stress in humans. AIM To investigate the associations between consumption of meat, fat and AGEs, and the risk of Barrett's oesophagus (BO). METHODS We conducted a case-control study using data from the patients who were scheduled for elective esophagogastroduodenoscopy (EGD) and from a random sample of patients who were identified at primary care clinics. Daily consumption of meat, fat and Nε-(carboxymethyl) lysine (CML), a major type of AGEs, was derived from the food frequency questionnaire (FFQ). Multivariate logistic regression models were used to estimate the odds ratio (OR) and its 95% confidence interval (CI) for BO. RESULTS A total of 151 cases with BO and 777 controls without BO completed the FFQ. The multivariate OR (95% CI) for BO was 1.91 (1.07-3.38) for total meat, 1.80 (1.02-3.16) for saturated fat and 1.63 (0.96-2.76) for CML-AGE, when the highest tertile of intake was compared with the lowest. The association for total meat was attenuated to 1.61 (0.82-3.16), and that for saturated fat to 1.54 (0.81-2.94) after adjusting for CML-AGE. CONCLUSIONS Higher consumption of total meat, saturated fat or possibly CML-AGE was associated with an increased risk of Barrett's oesophagus. CML-AGE may partly explain the association between total meat and saturated fat consumption and the risk of Barrett's oesophagus.
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Affiliation(s)
- Li Jiao
- Houston VA Health Services Research and Development Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA,Department of Medicine, Baylor College of Medicine, Houston, Texas, USA,Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Jennifer R. Kramer
- Houston VA Health Services Research and Development Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA,Department of Medicine, Baylor College of Medicine, Houston, Texas, USA,Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
| | - Liang Chen
- Houston VA Health Services Research and Development Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA,Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Massimo Rugge
- Surgical Pathology & Cytopathology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy
| | - Paola Parente
- Casa Sollievo della Sofferenza, Department of Pathology, San Giovanni Rotondo, Italy
| | | | - Abeer Alsarraj
- Houston VA Health Services Research and Development Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Hashem B. El-Serag
- Houston VA Health Services Research and Development Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA,Department of Medicine, Baylor College of Medicine, Houston, Texas, USA,Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA
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[Barrett's esophagus: analyses from human and experimental animal studies]. DER PATHOLOGE 2013; 34:138-47. [PMID: 23430135 DOI: 10.1007/s00292-012-1731-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Whereas attention in the past has been focused on goblet cells as the primary marker for Barrett's esophagus (BE), the recent change in the definition now includes the non-goblet cell columnar cell-lined esophagus. In the present study the histological features of neoplasia of the lower esophagus and esophago-gastric junction in a German cohort were examined using immunohistochemical staining for MUC, CD10, intestinal and gastric type major tight junction proteins (claudins). Experimental studies using rat duodenogastric content reflux models have also been performed and data show that most neoplastic lesions of the esophageal glands in humans express gastric mucin phenotypes. Cardiac type mucosa was the main histological type in the surrounding mucosa of neoplastic lesions; however, most cardiac type mucosa has intestinal type tight junction proteins. BE with goblet cells has been reported to originate from stem cells located in the basal layer of esophageal squamous cell epithelium in previous models. However, the cardiac type mucosa seems to develop from the site of the stomach and not from the basal layer of esophageal squamous cell epithelium according to our model.
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Cheng P, Li JS, Zhang LF, Chen YZ, Gong J. Exposure to gastric juice may not cause adenocarcinogenesis of the esophagus. World J Gastroenterol 2013; 19:2419-2424. [PMID: 23613638 PMCID: PMC3631996 DOI: 10.3748/wjg.v19.i15.2419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2012] [Revised: 01/20/2013] [Accepted: 03/23/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the effects of gastric juice on the development of esophageal adenocarcinoma (EAC).
METHODS: A animal model of duodenogastroesophageal reflux was established in Sprague-Dawley rats undergoing esophagoduodenostomy. The development of EAC and forestomach adenocarcinoma was investigated 40 wk after the treatment. Intraluminal pH and bile of the forestomach were measured.
RESULTS: There were no significant differences in pH (t = 0.117, P = 0.925) or bile (χ2 = 0.036, P = 0.85) in the forestomach before and 40 wk after esophagoduodenostomy. There were also no significant differences between the model and controls during esophagoduodenostomy or 40 wk after esophagoduodenostomy. The incidence of intestinal metaplasia (88%) and intestinal metaplasia with dysplasia and adenocarcinoma (28%) in the esophagus in the model was higher than in the controls 40 wk after surgery (χ2 = 43.06, P < 0.001 and χ2 = 9.33, P = 0.002, respectively) and in the forestomach in the model (χ2 = 32.05, P < 0.001 and χ2 = 8.14, P = 0.004, respectively). The incidence rates of inflammation in the esophagus and forestomach were 100% and 96%, respectively (χ2 = 1.02, P = 0.31) in the model, which was higher than in the esophageal control (6.8%) (χ2 = 42.70, P < 0.001).
CONCLUSION: Gastric juice exposure may not cause intestinal metaplasia with dysplasia or adenocarcinoma of the forestomach and may not be related to EAC.
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Oryu M, Mori H, Kobara H, Nishiyama N, Fujihara S, Kobayashi M, Yasuda M, Masaki T. Differences in the Characteristics of Barrett's Esophagus and Barrett's Adenocarcinoma between the United States and Japan. ISRN GASTROENTEROLOGY 2013; 2013:840690. [PMID: 23606979 PMCID: PMC3625601 DOI: 10.1155/2013/840690] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Accepted: 03/10/2013] [Indexed: 12/12/2022]
Abstract
In Europe and the United States, the incidence of esophageal adenocarcinoma has increased 6-fold in the last 25 years and currently accounts for more than 50% of all esophageal cancers. Barrett's esophagus is the source of Barrett's adenocarcinoma and is characterized by the replacement of squamous epithelium with columnar epithelium in the lower esophagus due to chronic gastroesophageal reflux disease (GERD). Even though the prevalence of GERD has recently been increasing in Japan as well as in Europe and the United States, the clinical situation of Barrett's esophagus and Barrett's adenocarcinoma differs from that in Western countries. In this paper, we focus on specific differences in the background factors and pathophysiology of these lesions.
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Affiliation(s)
- Makoto Oryu
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Takamatsu, Kagawa 761-0793, Japan
| | - Hirohito Mori
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Takamatsu, Kagawa 761-0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Takamatsu, Kagawa 761-0793, Japan
| | - Noriko Nishiyama
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Takamatsu, Kagawa 761-0793, Japan
| | - Shintaro Fujihara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Takamatsu, Kagawa 761-0793, Japan
| | - Mitsuyoshi Kobayashi
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Takamatsu, Kagawa 761-0793, Japan
| | - Mitsugu Yasuda
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Takamatsu, Kagawa 761-0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Takamatsu, Kagawa 761-0793, Japan
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Macke RA, Nason KS, Mukaisho KI, Hattori T, Fujimura T, Sasaki S, Oyama K, Miyashita T, Ohta T, Miwa K, Gibson MK, Zaidi A, Malhotra U, Atasoy A, Foxwell T, Jobe B. Barrett's esophagus and animal models. Ann N Y Acad Sci 2011; 1232:392-400. [PMID: 21950831 DOI: 10.1111/j.1749-6632.2011.06061.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
The following on Barrett's esophagus (BE) and animal models contains commentaries on the factors of BE carcinogenesis; a duodenoesophageal reflux model; translation of targeted therapies for esophageal adenocarcinoma; and novel target regimens selected through a proteomics screen.
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Affiliation(s)
- Ryan A Macke
- Esophageal Cancer Program, University of Pittsburgh and University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, Pennsylvania, USA
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O'Doherty MG, Cantwell MM, Murray LJ, Anderson LA, Abnet CC, FINBAR Study Group. Dietary fat and meat intakes and risk of reflux esophagitis, Barrett's esophagus and esophageal adenocarcinoma. Int J Cancer 2011; 129:1493-502. [PMID: 21455992 PMCID: PMC3144995 DOI: 10.1002/ijc.26108] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
The aim of our study was to investigate whether dietary fat and meat intakes are associated with reflux esophagitis (RE), Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). In this all-Ireland case-control study, dietary intake data were collected using a food frequency questionnaire in 219 RE patients, 220 BE patients, 224 EAC patients and 256 frequency-matched controls between 2002 and 2005. Unconditional multiple logistic regression analysis was used to examine the association between dietary variables and disease risk using quartiles of intake, to attain odds ratios (ORs) and 95% confidence intervals (95% CIs), while adjusting for potential confounders. Patients in the highest quartile of total fat intake had a higher risk of RE (OR = 3.54; 95% CI = 1.32-9.46) and EAC (OR = 5.44; 95% CI = 2.08-14.27). A higher risk of RE and EAC was also reported for patients in the highest quartile of saturated fat intake (OR = 2.79; 95% CI = 1.11-7.04; OR = 2.41; 95% CI = 1.14-5.08, respectively) and monounsaturated fat intake (OR = 2.63; 95% CI = 1.01-6.86; OR = 5.35; 95% CI = 2.14-13.34, respectively). Patients in the highest quartile of fresh red meat intake had a higher risk of EAC (OR = 3.15; 95% CI = 1.38-7.20). Patients in the highest category of processed meat intake had a higher risk of RE (OR = 4.67; 95% CI = 1.71-12.74). No consistent associations were seen for BE with either fat or meat intakes. Further studies investigating the association between dietary fat and food sources of fat are needed to confirm these results.
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Affiliation(s)
- Mark G O'Doherty
- Cancer Epidemiology Health Services Research Group, Centre for Public Health, Queens University Belfast, Belfast, Northern Ireland, United Kingdom.
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Takahashi Y, Amano Y, Yuki T, Mishima Y, Tamagawa Y, Uno G, Ishimura N, Sato S, Ishihara S, Kinoshita Y. Impact of the composition of gastric reflux bile acids on Barrett's oesophagus. Dig Liver Dis 2011; 43:692-7. [PMID: 21466977 DOI: 10.1016/j.dld.2011.02.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2010] [Revised: 01/28/2011] [Accepted: 02/23/2011] [Indexed: 12/11/2022]
Abstract
BACKGROUND The effect of the composition of reflux bile acids, especially the ratio of hydrophobic to hydrophilic ones, on the development of Barrett's oesophagus has not been fully investigated in human studies. AIMS To evaluate the influence of the bile acid composition of gastric juice on Barrett's oesophagus, a prospective study was designed. METHODS Fifty patients with and 100 patients without Barrett's oesophagus were enrolled. For all enrolled patients, gastric juice was collected by the endoscopic procedure for bile acid analysis. The ratio of hydrophobic to hydrophilic bile acids (bile hydrophobicity ratio, BHR) was calculated from 6 kinds of bile acids analysed in gastric juice. The relationship between the ratio and clinico-pathological factors of Barrett's oesophagus was investigated. RESULTS The mean of BHR of patients with Barrett's oesophagus was significantly higher than that of patients without Barrett's oesophagus (0.26 ± 0.05 vs. 0.08 ± 0.02, p<0.05). In multivariate analysis, a high BHR value was a predictor for the presence of Barrett's oesophagus (OR 5.74, p<0.001). In patients with Barrett's oesophagus, the BHR correlated with COX-2 protein expression and with accelerated cellular proliferation. CONCLUSIONS Patients with Barrett's oesophagus had a higher BHR in the gastric juice than those without.
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Affiliation(s)
- Yoshiko Takahashi
- Second Department of Internal Medicine, Shimane University, Faculty of Medicine, Izumo, Japan
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Oue K, Mukaisho KI, Higo T, Araki Y, Nishikawa M, Hattori T, Yamamoto G, Sugihara H. Histological examination of the relationship between respiratory disorders and repetitive microaspiration using a rat gastro-duodenal contents reflux model. Exp Anim 2011; 60:141-50. [PMID: 21512269 DOI: 10.1538/expanim.60.141] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Microaspiration due to gastroesophageal reflux (GER) has been suggested as a factor contributing to the development and exacerbation of several respiratory disorders. To explore the relationship between GER and respiratory disorders, we histologically examined the bilateral lungs of a rat gastroduodenal contents reflux model, which was previously used to investigate the histogenesis of Barrett's esophagus and esophageal carcinoma. GER was surgically induced in male Wistar rats. The bilateral lungs of the reflux rats were examined with hematoxylin and eosin (HE), PAS-Alcian blue, and Azan staining at 10 and 20 weeks after surgery. Immunohistochemical staining of CD68 and α-SMA was also performed. Aspiration pneumonia with severe peribronchiolar neutrophilic and lymphocytic infiltrates, goblet cell hyperplasia, prominence of blood vessels, and increased thickness of the smooth muscle layer were detected. Bronchiolitis obliterans (BO)-like lesions comprising granulation tissue with macrophages, spindle cells, and multinucleated giant cells in the lumen of respiratory bronchioles were observed in the bilateral lungs of the reflux animals. These findings suggest that the severe inflammation and the BO-like lesions may play a role in exacerbation of the forced expiratory volume in 1 second (FEV 1) in human cases. In conclusion, we speculate that repetitive microaspiration due to GER may contribute to the exacerbation of various respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD), and the development of BO syndrome following lung transplantation. The reflux model is a good tool for examining the causal relationships between GER and respiratory disorders.
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Affiliation(s)
- Keisuke Oue
- Department of Pathology, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan
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Cheng P, Li JS, Gong J, Zhang LF, Chen RZ. Effects of refluxate pH values on duodenogastroesophageal reflux-induced esophageal adenocarcinoma. World J Gastroenterol 2011; 17:3060-5. [PMID: 21799654 PMCID: PMC3132259 DOI: 10.3748/wjg.v17.i25.3060] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2010] [Revised: 03/23/2011] [Accepted: 03/30/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the effects of duodenogastric juice pH on the development of esophageal adenocarcinoma (EAC).
METHODS: An animal model of duodenogastroesophageal reflux was established using Sprague-Dawley (SD) rats undergoing esophagoduodenostomy (ED). The development of EAC was investigated in rats exposed to duodenogastric juice of different pH. The rats were divided into three groups: low-pH group (group A), high-pH group (group B) and a sham-operated group as a control (group C) (n = 30 rats in each group). The incidence of esophagitis, Barrett’s esophagus (BE), intestinal metaplasia with dysplasia and EAC was observed 40 wk after the treatment.
RESULTS: The incidence rate of esophagitis, BE, intestinal metaplasia with dysplasia and EAC was higher in groups A and B compared with the control group after 40 wk (P < 0.01), being 96% and 100% (P > 0.05), 88% and 82.4% (P > 0.05), 20% and 52.1% (P < 0.05), and 8% and 39% (P < 0.05), respectively.
CONCLUSION: Non-acidic refluxate increases the occurrence of intestinal metaplasia with dysplasia and EAC while the low-pH gastric juice exerts a protective effect in the presence of duodenal juice. The non-acid reflux is particularly important in the progression from BE to cancer. Therefore, control of duodenal reflux may be an important prophylaxis for EAC.
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41
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Chavalitdhamrong D, Chen GC, Roth BE, Goltzer O, Sul J, Jutabha R. Esophageal capsule endoscopy for evaluation of patients with chronic gastroesophageal reflux symptoms: findings and its image quality. Dis Esophagus 2011; 24:295-8. [PMID: 21668569 DOI: 10.1111/j.1442-2050.2010.01136.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Esophageal capsule endoscopy (ECE) may offer an alternative approach to visualize esophageal lesions associated with gastroesophageal reflux (GER) disease. The objective of this study was to report the ECE findings in patients with GER symptoms and validate a new scoring system to assess ECE video quality. Five hundred two ECE were performed in patients with GER symptoms. We devised a new grading scale called ECE Utility score to assess the quality of images using five different parameters: anatomic landmarks visualized, esophageal transit time, image quality, illumination, and artifacts. The ECE cases were independently scored by two interpreters in a randomized, blinded fashion. Reflux esophagitis was diagnosed via ECE in 254 patients (50.5%). We identified 12 cases (2.4%) with suspected Barrett's esophagus and all of them had endoscopic evidence of Barrett's esophagus on esophagogastroduodenoscopy. Histologic confirmation Barrett's esophagus was found in six patients and dysplasia was found in one patient. From the 502 cases, mean ± standard deviation total ECE Utility score was 8.89 ± 0.96 for interpreter 1 and 8.96 ± 0.93 for interpreter 2. The concordance rate between the two interpreters for the ECE Utility score ranged from 75.9-96.8% across the parameters and the Pearson correlation rate of the total score was 0.81. ECE is shown to be a simple noninvasive valuable technique for evaluating esophageal mucosa and producing high quality images in patients with GER symptoms. ECE can help as an alternative screening tool for diagnosing Barrett's esophagus.
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Affiliation(s)
- D Chavalitdhamrong
- David Geffen School of Medicine at University of California, Los Angeles, California, USA
| | - G C Chen
- David Geffen School of Medicine at University of California, Los Angeles, California, USA
| | - B E Roth
- David Geffen School of Medicine at University of California, Los Angeles, California, USA
| | - O Goltzer
- David Geffen School of Medicine at University of California, Los Angeles, California, USA
| | - J Sul
- David Geffen School of Medicine at University of California, Los Angeles, California, USA
| | - R Jutabha
- David Geffen School of Medicine at University of California, Los Angeles, California, USA
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42
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Kubo A, Corley DA, Jensen CD, Kaur R. Dietary factors and the risks of oesophageal adenocarcinoma and Barrett's oesophagus. Nutr Res Rev 2010; 23:230-46. [PMID: 20624335 PMCID: PMC3062915 DOI: 10.1017/s0954422410000132] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Incidence rates for oesophageal adenocarcinoma have increased by over 500% during the past few decades without clear reasons. Gastro-oesophageal reflux disease, obesity and smoking have been identified as risk factors, although the demographic distribution of these risk factors is not consistent with the demographic distribution of oesophageal adenocarcinoma, which is substantially more common among whites and males than any other demographic groups. Numerous epidemiological studies have suggested associations between dietary factors and the risks of oesophageal adenocarcinoma and its precursor, Barrett's oesophagus, though a comprehensive review is lacking. The main aim of the present review is to consider the evidence linking dietary factors with the risks of oesophageal adenocarcinoma, Barrett's oesophagus, and the progression from Barrett's oesophagus to oesophageal adenocarcinoma. The existing epidemiological evidence is strongest for an inverse relationship between intake of vitamin C, β-carotene, fruits and vegetables, particularly raw fruits and vegetables and dark green, leafy and cruciferous vegetables, carbohydrates, fibre and Fe and the risk of oesophageal adenocarcinoma and Barrett's oesophagus. Patients at higher risk for Barrett's oesophagus and oesophageal adenocarcinoma may benefit from increasing their consumption of fruits and vegetables and reducing their intake of red meat and other processed food items. Further research is needed to evaluate the relationship between diet and the progression of Barrett's oesophagus to oesophageal adenocarcinoma. Evidence from cohort studies will help determine whether randomised chemoprevention trials are warranted for the primary prevention of Barrett's oesophagus or its progression to cancer.
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Affiliation(s)
- Ai Kubo
- Northern California Kaiser Permanente, Division of Research, Oakland, CA, USA.
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43
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Stamp D. Bile acids and esophageal cancer the elusive "pulsatile acid or bile acid-induced" proliferation. Med Hypotheses 2010; 75:338-40. [PMID: 20427131 DOI: 10.1016/j.mehy.2010.03.034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2009] [Revised: 03/23/2010] [Accepted: 03/24/2010] [Indexed: 12/12/2022]
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Slack JMW, Colleypriest BJ, Quinlan JM, Yu WY, Farrant MJ, Tosh D. Barrett's metaplasia: molecular mechanisms and nutritional influences. Biochem Soc Trans 2010; 38:313-9. [PMID: 20298175 DOI: 10.1042/bst0380313] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Barrett's metaplasia is discussed in the context of a general theory for the formation of metaplasias based on developmental biology. The phenotype of a particular tissue type becomes established during embryonic development by the expression of a specific set of transcription factors. If this combination becomes altered, then the tissue type can be altered. Such events may occur by mutation or by environmental effects on gene expression, normally within the stem cell population of the tissue. A macroscopic patch of metaplastic tissue will arise only if the new gene activity state is self-sustaining in the absence of its original causes, and if the new tissue type can outgrow the parent tissue type. An important candidate gene for the causation of Barrett's metaplasia is Cdx2 (Caudal-type homeobox 2). In normal development, this is expressed in the future intestine, but not the future foregut. Mouse knockout studies have shown that it is needed for intestinal development, and that its loss from adult intestine can lead to squamous transformations. It is also expressed in Barrett's metaplasia and can be activated in oesophageal cell cultures by treatment with bile acids. We have investigated the ability of Cdx2 to bring about intestinal transformations in oesophageal epithelium. Our results show that Cdx2 can activate a programme of intestinal gene expression when overexpressed in HET-1A cells, or in fetal epithelium, but not in the adult epithelium. This suggests that Cdx2, although necessary for formation of intestinal tissue, is not sufficient to provoke Barrett's metaplasia in adult life and that overexpression of additional transcription factors is necessary. In terms of diet and nutrition, there is a known association of Barrett's metaplasia with obesity. This may work through an increased risk of gastro-oesophageal reflux. Acid and bile are known to activate Cdx2 expression in oesophageal cells. It may also increase circulating levels of TNFalpha (tumour necrosis factor alpha), which activates Cdx2. In addition, there may be effects of diet on the composition of the bile.
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Affiliation(s)
- Jonathan M W Slack
- Centre for Regenerative Medicine, Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K
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45
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Ling ZQ, Mukaisho KI, Yamamoto H, Chen KH, Asano S, Araki Y, Sugihara H, Mao WM, Hattori T. Initiation of malignancy by duodenal contents reflux and the role of ezrin in developing esophageal squamous cell carcinoma. Cancer Sci 2010; 101:624-30. [PMID: 20128822 PMCID: PMC11159458 DOI: 10.1111/j.1349-7006.2009.01470.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Gastroesophageal reflux has recently been implicated as a causative factor in upper aerodigestive tract carcinogenesis. Esophageal squamous cell carcinomas (ESCCs) have developed in duodenal-content reflux animals without any known carcinogen present. We established a cell line, designated ESCC-DR, from a thoracic metastatic tumor in a reflux animal. To gain insight into the genomic alterations associated with duodenal content reflux-induced carcinogenesis, we first performed comparative genomic hybridization using an Agilent rat 244K array in ESCC-DR and identified many chromosomal gains and losses. Of the many genes identified, we detected an interesting ezrin amplicon that has been recently reported in human ESCC. Ezrin, which cross-links the cytoskeleton and plasma membrane, is involved in the growth and metastatic potential of cancer cells. Overexpression of ezrin protein in ESCC-DR was confirmed by Western blotting. We also compared ezrin protein expression levels and patterns in hyperplastic, dysplastic, ESCC, and metastatic sites developed in two distinct reflux models using immunohistochemistry. Immunohistochemical staining of ezrin revealed overexpression in the nucleus, and the cytoplasm as well as plasma membrane of ESCC cells. Phosphorylated ERM (ezrin, radixin, moesin) was expressed at the leading edge, or invasive front, of larger metastatic sites. Taken together, duodenal reflux has a great potential for initiating malignancy, and thus likely plays a role in development of ESCC. Ezrin probably influences the growth and invasiveness of ESCC cells, and phosphorylation is only required in metastatic behavior of tumor cells at the leading edge and invasive front.
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Affiliation(s)
- Zhi-Qiang Ling
- Department of Pathology, Shiga University of Medical Science, Shiga, Japan
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46
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Kubo A, Block G, Quesenberry CP, Buffler P, Corley DA. Effects of dietary fiber, fats, and meat intakes on the risk of Barrett's esophagus. Nutr Cancer 2010; 61:607-16. [PMID: 19838934 DOI: 10.1080/01635580902846585] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Animal and human models suggest associations between fat intake, fiber intake, and the risk of esophageal adenocarcinoma. We evaluated whether these factors may act early in the carcinogenic pathway as a risk factor for Barrett's esophagus, a potentially premalignant precursor to esophageal adenocarcinoma using a case-control design within the Kaiser Permanente, Northern California population. Incident Barrett's esophagus cases (n = 296) were matched to persons with gastroesophageal reflux disease (GERD) (n = 308) and to population controls (n = 309). Higher intakes of omega-3-fatty-acids [cases vs. population controls; OR = 0.46, 95% CI = 0.22-0.97, 4th vs. 1st quartiles of intake], polyunsaturated fat, total fiber (OR = 0.34, 95% CI = 0.15-0.76), and fiber from fruits and vegetables (OR = 0.47 95% CI = 0.25-0.88) were associated with a lower risk of Barrett's esophagus. Higher meat intakes were associated with a lower risk of long-segment Barrett's esophagus (OR = 0.25, 95% CI = 0.09-0.72). In contrast, higher trans-fat intakes were associated with increased risk (OR = 1.11; 95% CI = 1.03-1.21 per g/day). Total fat intake, barbecued foods, and fiber intake from sources other than fruits and vegetables were not associated with Barrett's esophagus. Future studies to evaluate whether dietary interventions might influence the risk of Barrett's esophagus or esophageal adenocarcinoma in high risk persons are needed.
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Affiliation(s)
- Ai Kubo
- Northern California Kaiser Permanente, Oakland, California 94612, USA.
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47
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Costarelli V. Bile acids as possible human carcinogens: new tricks from an old dog. Int J Food Sci Nutr 2009; 60 Suppl 6:116-25. [DOI: 10.1080/09637480902970967] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Bernstein H, Bernstein C, Payne CM, Dvorak K. Bile acids as endogenous etiologic agents in gastrointestinal cancer. World J Gastroenterol 2009; 15:3329-40. [PMID: 19610133 PMCID: PMC2712893 DOI: 10.3748/wjg.15.3329] [Citation(s) in RCA: 227] [Impact Index Per Article: 14.2] [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
Bile acids are implicated as etiologic agents in cancer of the gastrointestinal (GI) tract, including cancer of the esophagus, stomach, small intestine, liver, biliary tract, pancreas and colon/rectum. Deleterious effects of bile acid exposure, likely related to carcinogenesis, include: induction of reactive oxygen and reactive nitrogen species; induction of DNA damage; stimulation of mutation; induction of apoptosis in the short term, and selection for apoptosis resistance in the long term. These deleterious effects have, so far, been reported most consistently in relation to esophageal and colorectal cancer, but also to some extent in relation to cancer of other organs. In addition, evidence is reviewed for an association of increased bile acid exposure with cancer risk in human populations, in specific human genetic conditions, and in animal experiments. A model for the role of bile acids in GI carcinogenesis is presented from a Darwinian perspective that offers an explanation for how the observed effects of bile acids on cells contribute to cancer development.
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Higo T, Mukaisho K, Ling ZQ, Oue K, Chen KH, Araki Y, Sugihara H, Yamamoto G, Hattori T. An animal model of intrinsic dental erosion caused by gastro-oesophageal reflux disease. Oral Dis 2009; 15:360-5. [PMID: 19371399 DOI: 10.1111/j.1601-0825.2009.01561.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVES To explore the association between dental erosion and gastro-oesophageal reflux disease (GORD), we used an animal model of GORD. MATERIALS AND METHODS We performed an operation to force gastro-duodenal contents reflux in male Wistar rats, and examined the teeth in the reflux rats at 15 or 30 weeks postoperatively. Dental erosion was evaluated based on a slightly modified index from a previous report. Estimation of pH was employed in the oesophageal and gastric contents. RESULTS Macroscopically, dental erosion was only detected in the reflux rats. Histopathologically, dentin exposure was detected in three of the seven cases after 30 weeks. Alveolar bone destruction and osteomyelitis were also noted in severe cases. The pH of the oesophageal and stomach contents was 6.93 +/- 0.15 and 3.7 +/- 0.39, respectively. CONCLUSIONS We confirmed the relationship between dental erosion and GORD. First step of dental erosion caused by GORD is the loss of surface enamel induced by regurgitation of an acidic liquid and acidic gas. Subsequently, further destruction of dental hard tissues and tooth supporting structure is accelerated by mixed juice with gastric and duodenal contents. The reflux animal model is a useful tool to examine the mechanism of dental erosion in GORD.
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Affiliation(s)
- T Higo
- Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan
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Abstract
Barrett's esophagus is an important step in the pathway to esophageal adenocarcinoma. Since most patients with Barrett's esophagus are undiagnosed and patients present with advanced adenocarcinoma de novo, prognosis for this disease remains poor. To identify those people with Barrett's esophagus who are at particular risk many new technologies are being developed. In association with these advances in risk stratification, progress is being made in the endoscopic treatment of Barrett's. Chemoprevention is also an area of interest and trials are underway.
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