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1
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Oey O, Sunjaya AF, Khan Y, Redfern A. Stromal inflammation, fibrosis and cancer: An old intuition with promising potential. World J Clin Oncol 2023; 14:230-246. [PMID: 37583950 PMCID: PMC10424089 DOI: 10.5306/wjco.v14.i7.230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/07/2023] [Accepted: 06/21/2023] [Indexed: 07/19/2023] Open
Abstract
It is now well established that the biology of cancer is influenced by not only malignant cells but also other components of the tumour microenvironment. Chronic inflammation and fibrosis have long been postulated to be involved in carcinogenesis. Chronic inflammation can promote tumorigenesis via growth factor/cytokine-mediated cellular proliferation, apoptotic resistance, immunosuppression; and free-radical-induced oxidative deoxyribonucleic acid damage. Fibrosis could cause a perturbation in the dynamics of the tumour microenvironment, potentially damaging the genome surveillance machinery of normal epithelial cells. In this review, we will provide an in-depth discussion of various diseases characterised by inflammation and fibrosis that have been associated with an increased risk of malignancy. In particular, we will present a comprehensive overview of the impact of alterations in stromal composition on tumorigenesis, induced as a consequence of inflammation and/or fibrosis. Strategies including the application of various therapeutic agents with stromal manipulation potential and targeted cancer screening for certain inflammatory diseases which can reduce the risk of cancer will also be discussed.
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Affiliation(s)
- Oliver Oey
- Faculty of Medicine, University of Western Australia, Perth 6009, Crawley NA, Australia
- Department of Medical Oncology, Sir Charles Gardner Hospital, Nedlands 6009, Australia
| | - Angela Felicia Sunjaya
- Institute of Cardiovascular Science, University College London, London WC1E 6DD, United Kingdom
| | - Yasir Khan
- Department of Medical Oncology, St John of God Midland Public and Private Hospital, Midland 6056, WA, Australia
| | - Andrew Redfern
- Department of Medical Oncology, Fiona Stanley Hospital, Murdoch 6150, WA, Australia
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2
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Crispino P, Ciarambino T, Giordano M. Variation in Fatty Acid Synthase, Ki67 and p53 Esophageal Mucosa Expressions in Barrett's Esophagus Patients Treated for One Year with Two Esomeprazole Different Regimens. Curr Issues Mol Biol 2023; 45:4701-4715. [PMID: 37367048 PMCID: PMC10296950 DOI: 10.3390/cimb45060299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 05/23/2023] [Accepted: 05/25/2023] [Indexed: 06/28/2023] Open
Abstract
Barrett's esophagus (BE) is an acquired pre-malignant condition that results from chronic gastroesophageal reflux. The malignant transformation occurred in 0.5% of patients/year and was independent of medical and endoscopic conservative treatments. Fatty acid synthase (FAS) is a multifunctional enzyme that catalyzes the synthesis of long-chain fatty acids from acetyl-coenzyme A, malonyl-coenzyme A, a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), and adenosine triphosphate. Activation of FAS is closely linked to malignant transformation. The aim of the present study was to evaluate the variation of FAS, p53, and Ki67 expressions in two groups of 21 BE patients each, after one year of continuous (group A) or discontinuous (group B) treatment with esomeprazole 40 mg/day in comparison to the initial expression. In both the two groups of BE patients, biopsies were taken from pathologic sites of the mucosa for histological and immuno-histochemical detection of FAS, Ki67, and p53 at entry and after one year of Esomeprazole 40 mg treatment. FAS expression was positive when a strong granular cytoplasmic staining was observed in esophageal cells. Ki67 and p53 were defined as positive when nuclear staining was clearly detected at ×10 magnification. FAS expression was reduced in 43% of patients treated with Esomeprazole continuously in comparison to the 10% of patients treated with Esomeprazole on demand (p = 0.002). Ki67 expression was reduced in 28% of continuously treated patients in comparison to 5% of patients treated on demand (p = 0.001). The p53 expression decreased in 19% of continuously treated patients in comparison to an increase in 2 patients (9%) treated on demand (p = 0.05). Continuously Esomeprazole treatment could help in the diminution of metabolic and proliferative activities in the esophageal columnar epithelium and in part it can help prevent the oxidative damage against cellular DNA, resulting in a diminution in p53 expression.
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Affiliation(s)
- Pietro Crispino
- UOC of Internal Medicine, Santa Maria Goretti Hospital, 04100 Latina, Italy
| | - Tiziana Ciarambino
- UOC of Internal Medicine, Hospital of Marcianise, “Caserta Local Health Authority”, 81025 Marcianise, Italy
| | - Mauro Giordano
- Advanced Medical and Surgical Sciences Department, University of Campania, L. Vanvitelli, 81100 Naples, Italy
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3
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Molecular Mechanism of the Effect of Zhizhu Pill on Gastroesophageal Reflux Disease Based on Network Pharmacology and Molecular Docking. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:2996865. [PMID: 35646148 PMCID: PMC9135531 DOI: 10.1155/2022/2996865] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 03/15/2022] [Accepted: 04/19/2022] [Indexed: 11/25/2022]
Abstract
Background To investigate the pharmacological mechanism of Zhizhu pill (ZZP) against gastroesophageal reflux disease (GERD), network pharmacology in combination with molecular docking was applied in this study. Methods Active compounds of ZZP and target genes related to GERD were identified through public databases. Subsequently, the obtained data were used as a basis for further network pharmacological analysis to explore the potential key active compounds, core targets, and biological processes involved in ZZP against GERD. Finally, the results predicted by network pharmacology were validated by molecular docking. Results Twenty active components of ZZP were identified to act on 59 targets related to GERD. Enrichment analysis revealed that multiple biological processes including response to oxygen levels, response to oxidative stress, and response to reactive oxygen species were involved in the GERD ZZP treatment with ZZP. ZZP had an impact on the prognosis of GERD mainly through the HIF-1 signaling pathway, PI3K-Akt signaling pathway, and pathways in cancer. Further analysis identified the key components and core targets of ZZP against GERD, of which nobiletin, didymin, luteolin, and naringenin were key components, and PPARG, MMP9, JUN, TP53, PTGS2, EGFR, MAPK3, CASP3, AKT1, and VEGFA were the core targets. Molecular docking verified the stable bonds formed between the key components and the core targets. Conclusions The results of this study predict that the therapeutic effects of ZZP in GERD are mediated at least in part via PPARG, MMP9, JUN, TP53, PTGS2, EGFR, MAPK3, CASP3, AKT1, and VEGFA. These results may be useful in providing an experimental basis and new ideas for further research on ZZP in GERD.
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Tustumi F, de Sousa JHB, Dornelas NM, Rosa GM, Steinman M, Bianchi ET. The Mechanisms for the Association of Cancer and Esophageal Dysmotility Disorders. Med Sci (Basel) 2021; 9:32. [PMID: 34064058 PMCID: PMC8163009 DOI: 10.3390/medsci9020032] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/12/2021] [Accepted: 05/21/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Achalasia and other esophageal dysmotility disorders mimicking achalasia can be associated with cancer. This study aimed to review the main mechanisms for which cancer may develop in esophageal dysmotility disorder patients. METHODS A narrative review was performed. RESULTS The mechanism for developing squamous cell carcinoma and adenocarcinoma are discussed. Besides, achalasia-like syndromes related to familial KIT-gene mutation and pseudoachalasia are discussed. CONCLUSIONS Knowing the main mechanism for which achalasia can be related to cancer is essential for clinicians to conduct the proper investigation, surveillance, and treatment.
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Affiliation(s)
- Francisco Tustumi
- Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil; (J.H.B.d.S.); (N.M.D.); (G.M.R.); (M.S.); (E.T.B.)
- Department of Gastroenterology, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, Brazil
| | | | - Nicolas Medeiros Dornelas
- Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil; (J.H.B.d.S.); (N.M.D.); (G.M.R.); (M.S.); (E.T.B.)
| | - Guilherme Maganha Rosa
- Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil; (J.H.B.d.S.); (N.M.D.); (G.M.R.); (M.S.); (E.T.B.)
| | - Milton Steinman
- Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil; (J.H.B.d.S.); (N.M.D.); (G.M.R.); (M.S.); (E.T.B.)
| | - Edno Tales Bianchi
- Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil; (J.H.B.d.S.); (N.M.D.); (G.M.R.); (M.S.); (E.T.B.)
- Department of Gastroenterology, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 05403-000, Brazil
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5
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Baumeister T, Ingermann J, Marcazzan S, Fang HY, Oellinger R, Rad R, Engleitner T, Kleigrewe K, Anand A, Strangmann J, Schmid RM, Wang TC, Quante M. Anti-inflammatory chemoprevention attenuates the phenotype in a mouse model of esophageal adenocarcinoma. Carcinogenesis 2021; 42:1068-1078. [PMID: 33878160 DOI: 10.1093/carcin/bgab032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 01/29/2021] [Accepted: 04/16/2021] [Indexed: 01/20/2023] Open
Abstract
Barrett´s Esophagus (BE) is the main known precursor condition of Esophageal Adenocarcinoma (EAC). BE is defined by the presence of metaplasia above the normal squamous columnar junction and has mainly been attributed to gastroesophageal reflux disease (GERD) and chronic reflux esophagitis. Thus, the rising incidence of EAC in the Western world is likely mediated by chronic esophageal inflammation, secondary to GERD in combination with environmental risk factors such as a Western diet and obesity. However, (at present) risk prediction tools and endoscopic surveillance have shown limited effectiveness. Chemoprevention as an adjunctive approach remains an attractive option to reduce the incidence of neoplastic disease. Here, we investigate the feasibility of chemopreventive approaches in BE and EAC via inhibition of inflammatory signaling in a transgenic mouse model of BE and EAC (L2-IL1B mice), with accelerated tumor formation on a high fat diet (HFD). L2-IL1B mice were treated with the IL-1 receptor antagonist Anakinra and the nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin or Sulindac. Interleukin-1b antagonism reduced tumor progression in L2-IL1B mice with or without a HFD, while both NSAIDs were effective chemoprevention agents in the accelerated HFD fed L2-IL1B mouse model. Sulindac treatment also resulted in a marked change in the immune profile of L2-IL-1B mice. In summary, anti-inflammatory treatment of HFD-treated L2-IL1B mice acted protectively on disease progression. These results from a mouse model of BE support results from clinical trials that suggest that anti-inflammatory medication may be effective in the chemoprevention of EAC.
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Affiliation(s)
- Theresa Baumeister
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Jonas Ingermann
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Sabrina Marcazzan
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Hsin-Yu Fang
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Rupert Oellinger
- Institute of Molecular Oncology and Functional Genomics, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Roland Rad
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany.,Institute of Molecular Oncology and Functional Genomics, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Thomas Engleitner
- Institute of Molecular Oncology and Functional Genomics, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Karin Kleigrewe
- Leibniz-Institute for Food Systems Biology at the Technical University of Munich
| | - Akanksha Anand
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Julia Strangmann
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Roland M Schmid
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany
| | - Timothy C Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Michael Quante
- Department of Medicine II, Klinikum rechts der Isar, Technical University Munich (TUM), Ismaninger Str, München, Germany.,Innere Medizin II, Universitätskliniken Freiburg, Universität Freiburg, Germany
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Kong J, Whelan KA, Laczkó D, Dang B, Caro Monroig A, Soroush A, Falcone J, Amaravadi RK, Rustgi AK, Ginsberg GG, Falk GW, Nakagawa H, Lynch JP. Autophagy levels are elevated in barrett's esophagus and promote cell survival from acid and oxidative stress. Mol Carcinog 2016; 55:1526-1541. [PMID: 26373456 PMCID: PMC4794420 DOI: 10.1002/mc.22406] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Revised: 08/11/2015] [Accepted: 08/17/2015] [Indexed: 12/17/2022]
Abstract
Autophagy is a highly conserved mechanism that is activated during cellular stress. We hypothesized that autophagy may be induced by acid reflux, which causes injury, and inflammation, and therefore, contributes to the pathogenesis of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Currently, the role of autophagy in BE and EAC is poorly studied. We quantitatively define autophagy levels in human BE cell lines, a transgenic mouse model of BE, and human BE, and EAC biopsies. Human non-dysplastic BE had the highest basal number of autophagic vesicles (AVs), while AVs were reduced in normal squamous cells and dysplastic BE cells, and nearly absent in EAC. To demonstrate a functional role for autophagy in BE pathogenesis, normal squamous (STR), non-dysplastic BE (CPA), dysplastic BE (CPD), and EAC (OE19) cell lines were exposed to an acid pulse (pH 3.5) followed by incubation in the presence or absence of chloroquine, an autophagy inhibitor. Acid exposure increased reactive oxygen species (ROS) levels in STR and CPA cells. Chloroquine alone had a small impact on intracellular ROS or cell survival. However, combination of chloroquine with the acid pulse resulted in a significant increase in ROS levels at 6 h in STR and CPA cells, and increased cell death in all cell lines. These findings establish increased numbers of AVs in human BE compared to normal squamous or EAC, and suggest that autophagy functions to improve cell survival after acid reflux injury. Autophagy may thus play a critical role in BE pathogenesis and progression. © 2015 Wiley Periodicals, Inc.
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Affiliation(s)
- Jianping Kong
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kelly A Whelan
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Dorottya Laczkó
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Brendan Dang
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Angeliz Caro Monroig
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ali Soroush
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - John Falcone
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ravi K Amaravadi
- Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, Pennsylvania
- Department of Medicine, and the Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Anil K Rustgi
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Gregory G Ginsberg
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Gary W Falk
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Hiroshi Nakagawa
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - John P Lynch
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania.
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7
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Kauppi J, Räsänen J, Sihvo E, Nieminen U, Arkkila P, Ahotupa M, Salo J. Increased Oxidative Stress in the Proximal Stomach of Patients with Barrett's Esophagus and Adenocarcinoma of the Esophagus and Esophagogastric Junction. Transl Oncol 2016; 9:336-9. [PMID: 27567957 PMCID: PMC5006815 DOI: 10.1016/j.tranon.2016.06.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 06/13/2016] [Indexed: 01/24/2023] Open
Abstract
OBJECTIVES: Oxidative stress (OS) is an essential element in the pathogenesis of Barrett’s esophagus (BE) and its transformation to adenocarcinoma (EAC). The state of OS in the proximal stomach of patients with BE and EAC is unknown. Isoprostanes are a specific marker of OS not previously used to determine OS from BE/EAC tissue samples. PATIENTS AND METHODS: OS was measured in 42 patients with BE (n = 9), EAC (n = 9), or both (n = 24) and 15 control patients. A STAT-8-Isoprostane EIA Kit served to identify 8-Isoprostanes (8-IP), and a Glutathione Assay Kit was used to measure glutathione reduced form (GSH) and glutathione oxidized form. An OxiSelect Oxidative DNA Damage ELISA Kit (8-OHdG) served to measure 8-OH-deoxyguanosine. RESULTS: The 8-IP (P = .039) and 8-OHdG (P = .008) levels were higher, and the GSH level lower (P = .031), in the proximal stomach of the study group than in that of the controls. Helicobacter pylori infection was present in 8% of the study patients. CONCLUSIONS: In the proximal stomach of BE and EAC patients, OS was elevated and antioxidative capacity was reduced. This finding suggests that the gastroesophageal reflux causing BE also induces oxidative stress in the proximal stomach and may contribute to the development of cancer in the proximal stomach and gastric cardia.
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Affiliation(s)
- Juha Kauppi
- Helsinki University, Helsinki University Hospital, Heart and Lung Center, Department of General Thoracic and Esophageal Surgery, 00290, Helsinki, Finland
| | - Jari Räsänen
- Helsinki University, Helsinki University Hospital, Heart and Lung Center, Department of General Thoracic and Esophageal Surgery, 00290, Helsinki, Finland
| | - Eero Sihvo
- Helsinki University, Helsinki University Hospital, Heart and Lung Center, Department of General Thoracic and Esophageal Surgery, 00290, Helsinki, Finland
| | - Urpo Nieminen
- Helsinki University, Helsinki University Hospital, Department of Gastroenterology, 00290, Helsinki, Finland
| | - Perttu Arkkila
- Helsinki University, Helsinki University Hospital, Department of Gastroenterology, 00290, Helsinki, Finland
| | - Markku Ahotupa
- Turku University, Department of Biosciences, 20520, Turku, Finland
| | - Jarmo Salo
- Helsinki University, Helsinki University Hospital, Heart and Lung Center, Department of General Thoracic and Esophageal Surgery, 00290, Helsinki, Finland.
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8
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Disintegrin and metalloproteinases (ADAMs) expression in gastroesophageal reflux disease and in esophageal adenocarcinoma. Clin Transl Oncol 2016; 19:58-66. [PMID: 27026568 DOI: 10.1007/s12094-016-1503-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 03/15/2016] [Indexed: 01/26/2023]
Abstract
BACKGROUND Clinically useful marker molecules for the progression of gastroesophageal reflux disease and Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) are lacking. Many adenocarcinomas and inflammatory conditions exhibit increased expression of ADAMs, 'a disintegrin and metalloproteinases'. METHODS We assessed the expression of five ADAMs (9, 10, 12, 17, 19) in three esophageal cell lines (Het-1A, OE19, OE33) by RT-PCR and Western blotting, and in human samples of normal esophagus, esophagitis, BE, Barrett's dysplasia, and EAC by RT-PCR, and in selected samples by immunohistochemistry. RESULTS EAC patients showed increased mRNA expression of ADAMs 9, 12, 17 and 19, as compared to controls. At immunohistochemistry, ADAM9 and ADAM10 proteins were increased in EAC. Patient samples also showed increased mRNA expression of ADAM12 in esophagitis, of ADAM9 in BE, and of ADAMs 9, 12 and 19 in Barrett's dysplasia, as compared to controls. Two EAC cell lines showed increased ADAM9 mRNA. CONCLUSIONS ADAM9 expression is increased in EAC. Its predecessors show increased ADAM9 mRNA expression. The importance of the alterations in ADAM expression for the development of EAC, and their use as marker molecules, warrant further studies.
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9
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Metabolic syndrome in relation to Barrett's esophagus and esophageal adenocarcinoma: Results from a large population-based case-control study in the Clinical Practice Research Datalink. Cancer Epidemiol 2016; 42:9-14. [PMID: 26972225 DOI: 10.1016/j.canep.2016.02.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 02/03/2016] [Accepted: 02/21/2016] [Indexed: 02/06/2023]
Abstract
Gastroesophageal reflux disease (GERD) causes local chronic inflammation that increases risks of Barrett's esophagus (BE) and esophageal adenocarcinoma (EA), yet symptomatic GERD is absent in approximately half of all such patients. Obesity exacerbates GERD and is also a component of metabolic syndrome (MetS). We evaluated the hypothesis that MetS is a GERD-independent mechanism by which obesity is associated with increased risks of BE and EA using data from the UK Clinical Practice Research Datalink. BE cases (n=10,215) and EA cases (n=592) were each individually matched to five population controls based on age, sex, and general practice. MetS was defined as occurrence of at least three of the following: obesity, type 2 diabetes, hypertension, and high cholesterol. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. MetS was marginally associated with BE (OR=1.12, 95%CI 1.00-1.25). Similar effects were found for the individual component factors of obesity, hypertension, and high cholesterol. History of GERD modified the association (P-effect modification <1E-5), with the MetS-BE association confined to patients without a history of GERD (OR=1.33, 95%CI 1.12-1.58). No association between MetS and risk of EA was detected in the main or stratified analyses. In this large population-based case-control study, individuals with MetS had a marginally increased risk of BE in the absence of GERD. The systemic inflammatory state (MetS) may represent a reflux-independent inflammatory pathway that increases the risk of BE. MetS did not increase risk of EA in this study population.
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10
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The tumor microenvironment in esophageal cancer. Oncogene 2016; 35:5337-5349. [PMID: 26923327 PMCID: PMC5003768 DOI: 10.1038/onc.2016.34] [Citation(s) in RCA: 238] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Revised: 01/15/2016] [Accepted: 01/21/2016] [Indexed: 02/08/2023]
Abstract
Esophageal cancer is a deadly disease, ranking sixth among all cancers in mortality. Despite incremental advances in diagnostics and therapeutics, esophageal cancer still carries a poor prognosis, and thus there remains a need to elucidate the molecular mechanisms underlying this disease. There is accumulating evidence that a comprehensive understanding of the molecular composition of esophageal cancer requires attention to not only tumor cells but also the tumor microenvironment, which contains diverse cell populations, signaling factors, and structural molecules that interact with tumor cells and support all stages of tumorigenesis. In esophageal cancer, environmental exposures can trigger chronic inflammation, which leads to constitutive activation of pro-inflammatory signaling pathways that promote survival and proliferation. Anti-tumor immunity is attenuated by cell populations such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), as well as immune checkpoints like programmed death-1 (PD-1). Other immune cells such as tumor-associated macrophages can have other pro-tumorigenic functions, including the induction of angiogenesis and tumor cell invasion. Cancer-associated fibroblasts secrete growth factors and alter the extracellular matrix (ECM) to create a tumor niche and enhance tumor cell migration and metastasis. Further study of how these TME components relate to the different stages of tumor progression in each esophageal cancer subtype will lead to development of novel and specific TME-targeting therapeutic strategies, which offer considerable potential especially in the setting of combination therapy.
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11
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Gockel I, Ahlbrand CJ, Arras M, Schreiber EM, Lang H. Quality Management and Key Performance Indicators in Oncologic Esophageal Surgery. Dig Dis Sci 2015; 60:3536-44. [PMID: 26177703 DOI: 10.1007/s10620-015-3790-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 06/29/2015] [Indexed: 12/16/2022]
Abstract
Ranking systems and comparisons of quality and performance indicators will be of increasing relevance for complex "high-risk" procedures such as esophageal cancer surgery. The identification of evidence-based standards relevant for key performance indicators in esophageal surgery is essential for establishing monitoring systems and furthermore a requirement to enhance treatment quality. In the course of this review, we analyze the key performance indicators case volume, radicality of resection, and postoperative morbidity and mortality, leading to continuous quality improvement. Ranking systems established on this basis will gain increased relevance in highly complex procedures within the national and international comparison and furthermore improve the treatment of patients with esophageal carcinoma.
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Affiliation(s)
- Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Medical Center of Leipzig, Leipzig, Germany. .,Department of General, Visceral, and Transplant Surgery, University Medical Center of Mainz, Mainz, Germany.
| | - Constantin Johannes Ahlbrand
- Department of General, Visceral, and Transplant Surgery, University Medical Center of Mainz, Mainz, Germany. .,1st Department of Medicine, Medical Center of Worms, Worms, Germany.
| | - Michael Arras
- Department of General, Visceral, and Transplant Surgery, University Medical Center of Mainz, Mainz, Germany.
| | - Elke Maria Schreiber
- Institute of Quality Management, University Medical Center of Mainz, Mainz, Germany.
| | - Hauke Lang
- Department of General, Visceral, and Transplant Surgery, University Medical Center of Mainz, Mainz, Germany.
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12
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Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway. J Transl Med 2014; 94:1068-82. [PMID: 25068653 DOI: 10.1038/labinvest.2014.100] [Citation(s) in RCA: 115] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 06/04/2014] [Accepted: 06/05/2014] [Indexed: 12/31/2022] Open
Abstract
During the pathogenesis of systemic inflammation, reactive oxygen species (ROS) circulate in the bloodstream and interact with endothelial cells (ECs), increasing intracellular oxidative stress. Although endothelial dysfunction is crucial in the pathogenesis of systemic inflammation, little is known about the effects of oxidative stress on endothelial dysfunction. Oxidative stress induces several functions, including cellular transformation. A singular process of cell conversion is tendothelial-to-mesenchymal transition, in which ECs become myofibroblasts, thus losing their endothelial properties and gaining fibrotic behavior. However, the participation of oxidative stress as an inductor of conversion of ECs into myofibroblasts is not known. Thus, we studied the role played by oxidative stress in this conversion and investigated the underlying mechanism. Our results show that oxidative stress induces conversion of ECs into myofibroblasts through decreasing the levels of endothelial markers and increasing those of fibrotic and ECM proteins. The underlying mechanism depends on the ALK5/Smad3/NF-κB pathway. Oxidative stress induces the expression and secretion of TGF-β1 and TGF-β2 and p38 MAPK phosphorylation. Downregulation of TGF-β1 and TGF-β2 by siRNA technology abolished the H2O2-induced conversion. To our knowledge, this is the first report showing that oxidative stress is able to induce conversion of ECs into myofibroblasts via TGF-β secretion, emerging as a source for oxidative stress-based vascular dysfunction. Thus, oxidative stress emerges as a decisive factor in inducing conversion of ECs into myofibroblasts through a TGF-β-dependent mechanism, changing the ECs protein expression profile, and converting normal ECs into pathological ones. This information will be useful in designing new and improved therapeutic strategies against oxidative stress-mediated systemic inflammatory diseases.
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O'Sullivan KE, Phelan JJ, O'Hanlon C, Lysaght J, O'Sullivan JN, Reynolds JV. The role of inflammation in cancer of the esophagus. Expert Rev Gastroenterol Hepatol 2014; 8:749-60. [PMID: 24857183 DOI: 10.1586/17474124.2014.913478] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Esophageal adenocarcinoma is the eighth most common malignancy worldwide. The overall prognosis is poor, with 5-year survival ranges of approximately 15-25%, and 30-50% for patients who can be treated with curative intent. There has been a marked increase in incidence of esophageal adenocarcinoma over the last 30 years, with chronic and severe reflux, diet and obesity identified as principal factors fuelling this rise in the West. Esophageal adenocarcinoma is an exemplar model of an inflammation-associated cancer. The key molecular pathways driving tumor development and influencing tumor biology are the subject of considerable research efforts, and is the principal focus of this review. In addition, the diverse range of changes occurring in the local immune response, tissue microenvironment, metabolic profile, intracellular signaling mechanisms and microRNA signatures are discussed, as well as novel targeted therapies.
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Affiliation(s)
- Katie E O'Sullivan
- Department of Surgery, Institute of Molecular Medicine, St. James Hospital, Dublin 8, Ireland
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14
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di Pietro M, Alzoubaidi D, Fitzgerald RC. Barrett's esophagus and cancer risk: how research advances can impact clinical practice. Gut Liver 2014; 8:356-70. [PMID: 25071900 PMCID: PMC4113043 DOI: 10.5009/gnl.2014.8.4.356] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Accepted: 04/15/2014] [Indexed: 12/18/2022] Open
Abstract
Barrett’s esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC), whose incidence has increased sharply in the last 4 decades. The annual conversion rate of BE to cancer is significant, but small. The identification of patients at a higher risk of cancer therefore poses a clinical conundrum. Currently, endoscopic surveillance is recommended in BE patients, with the aim of diagnosing either dysplasia or cancer at early stages, both of which are curable with minimally invasive endoscopic techniques. There is a large variation in clinical practice for endoscopic surveillance, and dysplasia as a marker of increased risk is affected by sampling error and high interobserver variability. Screening programs have not yet been formally accepted, mainly due to the economic burden that would be generated by upper gastrointestinal endoscopy. Screening programs have not yet been formally accepted, mainly due to the economic burden that would be generated by widespread indication to upper gastrointestinal endoscopy. In fact, it is currently difficult to formulate an accurate algorithm to confidently target the population at risk, based on the known clinical risk factors for BE and EAC. This review will focus on the clinical and molecular factors that are involved in the development of BE and its conversion to cancer and on how increased knowledge in these areas can improve the clinical management of the disease.
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Affiliation(s)
| | - Durayd Alzoubaidi
- Department of Gastroenterology, Basildon and Thurrock University Hospital, Basildon, UK
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15
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The esophagitis to adenocarcinoma sequence; the role of inflammation. Cancer Lett 2013; 345:182-9. [PMID: 23994342 DOI: 10.1016/j.canlet.2013.08.017] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Revised: 08/08/2013] [Accepted: 08/13/2013] [Indexed: 12/19/2022]
Abstract
Esophageal adenocarcinoma (EAC) is the eighth most common cancer worldwide, and approximately 15% of patients survive 5years. Reflux disease (GERD) and Barrett's esophagus (BE) are major risk factors for the development of EAC, and epidemiologic studies highlight a strong association with obesity. The immune, inflammatory and intracellular signaling changes resulting from chronic inflammation of the esophageal squamous epithelium are increasingly well characterized. In GERD and Barrett's, an essential role for T-cells in the initiation of inflammation in the esophagus has been identified, and a balance between T-cell responses and phenotype may play an important role in disease progression. Obesity is a chronic low-grade inflammatory state, fueled by adipose tissue derived- inflammatory mediators such as IL-6, TNF-α and leptin, representing a novel area for targeted research. Additionally, reactive oxygen species (ROS) and receptor tyrosine kinase (RTK) activation may drive progression from esophagitis to EAC, and downstream signaling pathways employed by these molecules may be important. This review will explain the diverse range of mechanisms potentially driving and maintaining inflammation within the esophagus and explore both existing and future therapeutic strategies targeting the process.
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16
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Droeser RA, Hirt C, Eppenberger-Castori S, Zlobec I, Viehl CT, Frey DM, Nebiker CA, Rosso R, Zuber M, Amicarella F, Iezzi G, Sconocchia G, Heberer M, Lugli A, Tornillo L, Oertli D, Terracciano L, Spagnoli GC. High myeloperoxidase positive cell infiltration in colorectal cancer is an independent favorable prognostic factor. PLoS One 2013; 8:e64814. [PMID: 23734221 PMCID: PMC3667167 DOI: 10.1371/journal.pone.0064814] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Accepted: 04/17/2013] [Indexed: 01/11/2023] Open
Abstract
Background Colorectal cancer (CRC) infiltration by adaptive immune system cells correlates with favorable prognosis. The role of the innate immune system is still debated. Here we addressed the prognostic impact of CRC infiltration by neutrophil granulocytes (NG). Methods A TMA including healthy mucosa and clinically annotated CRC specimens (n = 1491) was stained with MPO and CD15 specific antibodies. MPO+ and CD15+ positive immune cells were counted by three independent observers. Phenotypic profiles of CRC infiltrating MPO+ and CD15+ cells were validated by flow cytometry on cell suspensions derived from enzymatically digested surgical specimens. Survival analysis was performed by splitting randomized data in training and validation subsets. Results MPO+ and CD15+ cell infiltration were significantly correlated (p<0.0001; r = 0.76). However, only high density of MPO+ cell infiltration was associated with significantly improved survival in training (P = 0.038) and validation (P = 0.002) sets. In multivariate analysis including T and N stage, vascular invasion, tumor border configuration and microsatellite instability status, MPO+ cell infiltration proved an independent prognostic marker overall (P = 0.004; HR = 0.65; CI:±0.15) and in both training (P = 0.048) and validation (P = 0.036) sets. Flow-cytometry analysis of CRC cell suspensions derived from clinical specimens showed that while MPO+ cells were largely CD15+/CD66b+, sizeable percentages of CD15+ and CD66b+ cells were MPO−. Conclusions High density MPO+ cell infiltration is a novel independent favorable prognostic factor in CRC.
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Affiliation(s)
- Raoul A Droeser
- Department of Surgery, University Hospital Basel, Switzerland.
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17
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Jiao L, Kramer JR, Rugge M, Parente P, Verstovsek G, Alsarraj A, El-Serag HB. Dietary intake of vegetables, folate, and antioxidants and the risk of Barrett's esophagus. Cancer Causes Control 2013; 24:1005-14. [PMID: 23420329 DOI: 10.1007/s10552-013-0175-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Accepted: 02/11/2013] [Indexed: 02/08/2023]
Abstract
PURPOSE Diet is a potentially modifiable risk factor for Barrett's esophagus (BE). We investigated the associations between intakes of fruits and vegetables and risk of BE. METHODS We identified study subjects from 1,859 participants who underwent the endoscopy in a single VA Medical Center in the US between 2008 and 2011. Dietary intake in the previous year was elicited using a self-administered Block food frequency questionnaire (FFQ). Logistic regression model was used to estimate odds ratio (OR) and its 95 % confidence interval (CI) for BE. RESULTS A total of 151 cases with definite BE and 777 controls completed the FFQ. When highest tertile of intake was compared with the lowest, the OR (95 % CI) was 0.46 (0.26-0.81) for dark green vegetables, 0.52 (0.30-0.90) for legumes, 0.50 (0.28-0.90) for total fiber, 0.45 (0.25-0.81) for isoflavones, 0.52 (0.30-0.67) for total folate, and 0.45 (0.26-0.79) for lutein, adjusting for multiple confounding factors including use of aspirin or proton pump inhibitor, gastro-esophageal reflux symptoms, and physical activity. The association for dark green vegetables was attenuated after adjustment for lutein, total fiber, and total folate (OR = 0.82; 95 % CI 0.30-2.22). CONCLUSION Higher intake of dark green vegetables was associated with a decreased risk of BE in a veteran population. Such an inverse association may be partially mediated by lutein, fiber, and folate. The novel findings on the association between intake of lutein, total folate, or isoflavones and risk of BE need further confirmation.
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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, TX, USA.
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18
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Abstract
This review summarizes clinical studies in which glutathione was measured in tumor tissue from patients with brain, breast, gastrointestinal, gynecological, head and neck and lung cancer. Glutathione tends to be elevated in breast, ovarian, head and neck, and lung cancer and lower in brain and liver tumors compared to disease-free tissue. Cervical, colorectal, gastric, and esophageal cancers show both higher and lower levels of tumor glutathione. Some studies show an inverse relationship between patient survival and tumor glutathione. Based on this survey, we recommend approaches that may improve the clinical value of glutathione as a biomarker.
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Affiliation(s)
- Michael P Gamcsik
- UNC/NCSU Joint Department of Biomedical Engineering, Raleigh, NC 27695-7115, USA.
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19
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Zhou SK, Zhang RL, Xu YF, Bi TN. Antioxidant and immunity activities of Fufang Kushen Injection Liquid. Molecules 2012; 17:6481-90. [PMID: 22728348 PMCID: PMC6268272 DOI: 10.3390/molecules17066481] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2012] [Revised: 05/22/2012] [Accepted: 05/23/2012] [Indexed: 01/20/2023] Open
Abstract
We investigated the effects of Fufang Kushen Injection Liquid (FFKSIL) on gastric immunity and oxidant-antioxidant status during N-methyl-N′-nitro-N-nitroso-guanidine (MNNG)-induced gastric carcinogenesis. The extent of lipid peroxidation and the levels of reduced glutathione (GSH) and activities of the GSH-dependent enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were used to monitor the peroxidative balance. Enhanced lipid peroxidation in the gastric cancer animals was accompanied by significant decreases in the activities of GSH, GPx, GST and GR. Administration of FFKSIL significantly enhanced serum IgA, IgG, IgM, IL-2, IL-4 and IL-10 levels, decreased serum IL-6 and TNF-α levels, lowered the levels of lipid peroxides and enhanced GSH levels and activities of GSH-dependent enzymes. Our results suggest that FFKSIL blocks experimental gastric carcinogenesis by protecting against carcinogen-induced oxidative damage and improving immunity activity.
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Affiliation(s)
| | | | | | - Tie-Nan Bi
- Author to whom correspondence should be addressed; E-Mail: ; Tel./Fax: +86-0576-8512-0120
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20
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Poehlmann A, Kuester D, Malfertheiner P, Guenther T, Roessner A. Inflammation and Barrett's carcinogenesis. Pathol Res Pract 2012; 208:269-80. [PMID: 22541897 DOI: 10.1016/j.prp.2012.03.007] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Barrett's esophagus (BE) is one of the most common premalignant lesions in which normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium. Esophageal adenocarcinoma (EA) develops through progression from BE to low- and high-grade dysplasia (LGD/HGD) and to adenocarcinoma. It is widely accepted that inflammation can increase cancer risk, promoting tumor progression. Therefore, inflammation is regarded as the seventh hallmark of cancer. In recent years, the inflammation-cancer connection of Barrett's carcinogenesis has been intensively studied, unraveling genetic abnormalities. Besides genetic alterations, inflammation is also epigenetically linked to loss of protein expression through transcriptional silencing via promoter methylation. Key mediators linking inflammation and Barrett's carcinogenesis include reactive oxygen species (ROS), NFκB, inflammatory cytokines, prostaglandins, and specific microRNAs (miRNAs). Therefore, the decipherment of molecular pathways that contain these and novel inflammatory key mediators is of major importance for diagnosis, therapy, and prognosis. The detailed elucidation of the signaling molecules involved in Barrett's carcinogenesis will be important for the development of pharmaceutical inhibitors. We herein give an overview of the current knowledge of the inflammation-mediated genetic and epigenetic alterations involved in Barrett's carcinogenesis. We highlight the role of oxidative stress and deregulated DNA damage checkpoints besides the NFκB pathway.
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Affiliation(s)
- A Poehlmann
- Department of Pathology, Otto-von-Guericke University Magdeburg, Germany.
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21
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Long-term results of ablation with antireflux surgery for Barrett’s esophagus: a clinical and molecular biologic study. Surg Endosc 2012; 26:1892-7. [DOI: 10.1007/s00464-011-2121-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2011] [Accepted: 12/05/2011] [Indexed: 01/29/2023]
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22
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Dutta SK, Agrawal K, Girotra M, Fleisher AS, Motevalli M, Mah'moud MA, Nair PP. Barrett's esophagus and β-carotene therapy: symptomatic improvement in GERD and enhanced HSP70 expression in esophageal mucosa. Asian Pac J Cancer Prev 2012; 13:6011-6016. [PMID: 23464395 DOI: 10.7314/apjcp.2012.13.12.6011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
INTRODUCTION Epidemiological studies suggest a protective role for β-carotene with several malignancies. Esophageal adenocarcinoma frequently arises from Barrett's esophagus (BE). We postulated that β-carotene therapy maybe protective in BE. MATERIALS AND METHOD We conducted a prospective study in which 25 mg of β-carotene was administered daily for six-months to six patients. Each patient underwent upper endoscopy before and after therapy and multiple mucosal biopsies were obtained. Additionally, patients completed a gastroesophageal reflux disease (GERD) symptoms questionnaire before and after therapy and severity score was calculated. To study the effect of β-carotene at molecular level, tissue extracts of the esophageal mucosal biopsy were subjected to assessment of heat-shock protein 70 (HSP70). RESULTS A significant (p<0.05) reduction in mean GERD symptoms severity score from 7.0±2.4 to 2.7±1.7 following β-carotene therapy was noted. Measurement of Barrett's segment also revealed a significant reduction in mean length after therapy. In fact, two patients had complete disappearance of intestinal metaplasia. Furthermore, marked enhancement of HSP70 expression was demonstrated in biopsy specimens from Barrett's epithelium in four cases that were tested. CONCLUSIONS Long- term β-carotene therapy realizes amelioration of GERD symptoms along with restitution of the histological and molecular changes in esophageal mucosa of patients with BE, associated with concurrent increase in mucosal HSP70 expression.
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Affiliation(s)
- Sudhir K Dutta
- Department of Medicine, University of Maryland School of Medicine and Division Director of Gastroenterology, USA.
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23
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Schiffman SC, Li Y, Martin RCG. The association of manganese superoxide dismutase expression in Barrett's esophageal progression with MnTBAP and curcumin oil therapy. J Surg Res 2011; 176:535-41. [PMID: 22316666 DOI: 10.1016/j.jss.2011.11.1013] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2011] [Revised: 10/15/2011] [Accepted: 11/18/2011] [Indexed: 01/01/2023]
Abstract
BACKGROUND The aim of this study was to investigate the relationship between reflux induced bile insult and MnSOD expression, as well as to examine therapies to preserve MnSOD expression. Additionally, we sought to examine the relationship between MnSOD protein expression and MnSOD enzymatic activity. METHODS MnSOD protein expression was determined by Western blot assay and enzymatic activity was determined by SOD assay. The enzymatic activity of the Het-1A and Bar-T cells were compared both before and after treatments. RESULTS MnSOD expression in Het-1A cells was decreased after bile salt exposure. The cells that received MnTBAP or curcumin oil pretreatment showed increased MnSOD expression compared with control untreated cells. The Bar-T cells showed an increase in MnSOD expression after treatment with bile salts. The cells that were pretreated with MnTBAP displayed a larger increase in MnSOD expression compared with the cells that were not pretreated prior to bile salt exposure. The MnSOD activity was significantly different between the untreated cell lines (P = 0.01) and after treatment with bile salt (P = 0.03). Additionally, Bar-T cells had significantly less MnSOD activity than Het-1A cells after each of the pretreatments. CONCLUSIONS We demonstrated preservation of MnSOD expression in Het-1A cells that were pretreated with antioxidants including MnTBAP, curcumin oil, and certain berry extracts. Additionally, we demonstrated that Bar-T cells have significantly less MnSOD activity than Het-1A cells. These finding have important implications for future studies regarding chemoprevention and the treatment of esophageal cancer.
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Affiliation(s)
- Suzanne C Schiffman
- Department of Surgical Oncology, Division of Surgical Oncology, University of Louisville, Louisville, Kentucky 40202, USA
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24
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Rantanen T, Oksala N, Honkanen T, Räsänen J, Sihvo E, Mattila J, Paimela H, Paavonen T, Salo J. The effect of fundoplication on proliferative and anti-apoptotic activity of esophageal mucosa in gastroesophageal reflux disease: 4-year follow-up study. J Dig Dis 2011; 12:263-71. [PMID: 21791020 DOI: 10.1111/j.1751-2980.2011.00508.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The capacity of fundoplication to prevent esophageal adenocarcinoma is controversial. Development of cancer is associated with proliferation and anti-apoptosis, for which little data exist as to their response to fundoplication. Therefore, we wanted to clarify the effect of fundoplication on the magnitude of Ki-67 and B-cell lymphoma 2 (Bcl-2) during 48 months of follow up. METHODS Ki-67 and Bcl-2 were assessed quantitatively from biopsies of the esophagogastric junction (EGJ) and from the distal and proximal esophagus of 20 patients with gastroesophageal reflux disease (GERD) treated by fundoplication. An upper gastrointestinal endoscopy was performed preoperatively and postoperatively at 6 months for 20 patients and 48 months for 16 patients, respectively. Ki-67 and Bcl-2 were compared to those of 7 controls. RESULTS Compared to the preoperative level, Ki-67 was elevated in the distal (P = 0.012) and proximal (P = 0.007) esophagus at 48 months. Compared to control values, Ki-67 was lower at 6 months in the EGJ (P = 0.037) and the proximal esophagus (P = 0.003) and higher at 48 months in the distal esophagus (P = 0.002). Compared to control values, Bcl-2 was lower at 6 months in the EGJ (P = 0.038). Correlations between Ki-67 and Bcl-2 were positive in the EGJ (P > 0.001) and in the distal (P = 0.001) and proximal esophagus (P = 0.013). CONCLUSION Proliferative activity after fundoplication increased during long-term follow up in the distal esophagus despite a normal fundic wrap and objective healing of GERD.
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Affiliation(s)
- Tuomo Rantanen
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere
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25
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Abstract
The incidence of esophageal adenocarcinoma (EAC) is rising rapidly in Western countries, and effective chemoprevention for this malignancy is lacking. Endoscopic surveillance of patients with Barrett's esophagus is currently employed to diagnose EAC at earlier stages, but this strategy has several limitations. Non-steroidal anti-inflammatory drugs and proton pump inhibitors are the most promising agents for prevention of EAC, and a randomized controlled trial of aspirin and esomeprazole is ongoing. Other agents under investigation include green tea, berries, and antioxidants. Cost-effectiveness analyses have shown that chemopreventive agents need to be highly effective at preventing EAC in order to have benefit beyond endoscopic surveillance.
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Affiliation(s)
- Julian A Abrams
- Division of Digestive and Liver Diseases, Columbia University Medical Center New York, NY, USA.
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26
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Yoshida N. Inflammation and oxidative stress in gastroesophageal reflux disease. J Clin Biochem Nutr 2011; 40:13-23. [PMID: 18437209 PMCID: PMC2291500 DOI: 10.3164/jcbn.40.13] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2006] [Accepted: 09/21/2006] [Indexed: 01/13/2023] Open
Abstract
The etiology of esophageal mucosal injury is complex, since it may involve the reflux of gastric acid, bile acid, and pancreatic juice, external factors such as drugs and alcohol, or functional factors such as esophagogastric motility. The mechanism of esophageal mucosal injury has gradually been understood at the molecular biological level. It is particularly important that pro-inflammatory factors, such as inflammatory cytokines (interleukin-6 and -8), leukocytes and oxidative stress, have been demonstrated to be involved in the development of gastroesophageal reflux disease (GERD) including nonerosive reflux disease (NERD). In addition, nociceptors such as acid-sensitive vanilloid receptors, protease-activated receptors and substance P have also been implicated in the pathogenesis of neurogenic inflammation in NERD patients with esophageal hypersensitivity. The development of new therapy with anti-inflammatory and anti-oxidant effects is expected to assist in the treatment of intractable NERD/GERD and the prevention of carcinogenesis.
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Affiliation(s)
- Norimasa Yoshida
- Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
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27
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Reid BJ, Kostadinov R, Maley CC. New strategies in Barrett's esophagus: integrating clonal evolutionary theory with clinical management. Clin Cancer Res 2011; 17:3512-9. [PMID: 21498395 PMCID: PMC3119197 DOI: 10.1158/1078-0432.ccr-09-2358] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Barrett's esophagus is a condition in which the normal stratified squamous epithelium of the distal esophagus is replaced by intestinal metaplasia. For more than three decades, the prevailing clinical paradigm has been that Barrett's esophagus is a complication of symptomatic reflux disease that predisposes to esophageal adenocarcinoma. However, no clinical strategy for cancer prevention or early detection based on this paradigm has been proven to reduce esophageal adenocarcinoma mortality in a randomized clinical trial in part because only about 5% to 10% of individuals with Barrett's esophagus develop esophageal adenocarcinoma. Recent research indicates that Barrett's metaplasia is an adaptation for mucosal defense in response to chronic reflux in most individuals. The risk of progressing to esophageal adenocarcinoma is determined by development of genomic instability and dynamic clonal evolution in the distal esophagus modulated by host and environmental risk and protective factors, including inherited genotype. The challenge for investigators of Barrett's esophagus lies in integrating knowledge about genomic instability and clonal evolution into clinical management to increase the lifespan and quality of life of individuals with this condition.
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Affiliation(s)
- Brian J Reid
- Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave., P.O. Box 19024, Seattle, WA 98109, USA.
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Luo C, Wu XG. Lycopene enhances antioxidant enzyme activities and immunity function in N-methyl-N'-nitro-N-nitrosoguanidine-enduced gastric cancer rats. Int J Mol Sci 2011; 12:3340-51. [PMID: 21686188 PMCID: PMC3116194 DOI: 10.3390/ijms12053340] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2011] [Revised: 04/27/2011] [Accepted: 05/17/2011] [Indexed: 01/17/2023] Open
Abstract
To investigate anticancer effect of lycopene, we examined the effects of lycopene on the oxidative injury and immunity activities of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric cancer rats. The animals were divided into five groups. Group I served as the normal control and was given corn oil orally for 20 weeks. Group II were induced with MNNG 200 mg/kg body weight by oral gavage at days 0 and 14, and saturated NaCl (1 mL per rats) was given once every three days for four weeks until the end of the experimental period. Group III, IV and V were posttreated with lycopene (50, 100 and 150 mg/kg body weight, dissolved in corn oil) from the sixth week of MNNG (as in group II) induction up to the end of the experimental period. In the presence of MNNG, MDA and immunity levels were significantly increased, whereas enzymatic (SOD, CAT, and GPx) antioxidant activities were decreased in the treated rats compared with normal control rats. Administration of lycopene to gastric carcinoma-induced rats largely up-regulated the redox status and immunity activities to decrease the risk of cancer compared to group II. We conclude that up-regulation of antioxidants and immunity by lycopene treatment might be responsible for the anticancer effect in gastric carcinoma.
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Affiliation(s)
- Cong Luo
- Chemotherapy Department, Zhejiang Cancer Hospital, Hangzhou City, Zhejiang, 310022, China; E-Mail:
| | - Xian-Guo Wu
- Department of Clinical Laboratory, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou City, Zhejiang, 310009, China
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Rantanen TK, Oksala NK, Honkanen TT, Räsänen JV, Sihvo EI, Mattila JJ, Paimela HM, Paavonen TK, Salo JA. Proliferative and anti-apoptotic activity of esophageal mucosa in gastroesophageal reflux disease is not affected by fundoplication: a 4-year follow-up study. Eur Surg Res 2011; 47:5-12. [PMID: 21540613 DOI: 10.1159/000326948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2010] [Accepted: 03/02/2011] [Indexed: 11/19/2022]
Abstract
BACKGROUND The role of fundoplication in the prevention of esophageal adenocarcinoma is controversial. Development of cancer is associated with proliferation and anti-apoptosis, for which little data exist regarding their response to fundoplication. METHODS Ki-67 and Bcl-2 expression was assessed in the esophagogastric junction (EGJ) and the distal and proximal esophagus of 20 patients with gastroesophageal reflux disease (GERD) treated by fundoplication and in 7 controls. Endoscopy was performed preoperatively and 6 (20 patients) and 48 months (16 patients) postoperatively. RESULTS There were positive correlations between Ki-67 and Bcl-2 levels in the EGJ (p > 0.001) and in the distal (p = 0.001) and proximal esophagus (p = 0.013). Compared to the preoperative level, Ki-67 expression was elevated in the distal (p = 0.012) and proximal (p = 0.007) esophagus at 48 months. In addition, compared to control values, Ki-67 expression was lower at the 6-month follow-up in the EGJ (p = 0.037) and the proximal esophagus (p = 0.003), and higher at the 48-month follow-up in the distal esophagus (p = 0.002). Compared to control values, Bcl-2 was lower at 6 months in the EGJ (p = 0.038). CONCLUSIONS Proliferative activity after fundoplication increased in the long term in the distal esophagus despite a normal fundic wrap and healing of GERD.
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Affiliation(s)
- T K Rantanen
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Finland
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Goldman A, Chen HDR, Roesly HB, Hill KA, Tome ME, Dvorak B, Bernstein H, Dvorak K. Characterization of squamous esophageal cells resistant to bile acids at acidic pH: implication for Barrett's esophagus pathogenesis. Am J Physiol Gastrointest Liver Physiol 2011; 300:G292-302. [PMID: 21127259 PMCID: PMC3043651 DOI: 10.1152/ajpgi.00461.2010] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2010] [Accepted: 11/29/2010] [Indexed: 01/31/2023]
Abstract
Barrett's esophagus (BE) is a premalignant condition, where normal squamous epithelium is replaced by intestinal epithelium. BE is associated with an increased risk of developing esophageal adenocarcinoma (EAC). However, the BE cell of origin is not clear. We hypothesize that BE tissue originates from esophageal squamous cells, which can differentiate to columnar cells as a result of repeated exposure to gastric acid and bile acids, two components of refluxate implicated in BE pathology. To test this hypothesis, we repeatedly exposed squamous esophageal HET1A cells to 0.2 mM bile acid (BA) cocktail at pH 5.5 and developed an HET1AR-resistant cell line. These cells are able to survive and proliferate after repeated 2-h treatments with BA at pH 5.5. HET1AR cells are resistant to acidification and express markers of columnar differentiation, villin, CDX2, and cytokeratin 8/18. HET1AR cells have increased amounts of reactive oxygen species, concomitant with a decreased level and activity of manganese superoxide dismutase compared with parental cells. Furthermore, HET1AR cells express proteins and activate signaling pathways associated with inflammation, cell survival, and tumorigenesis that are thought to contribute to BE and EAC development. These include STAT3, NF-κB, epidermal growth factor receptor (EGFR), cyclooxygenase-2, interleukin-6, phosphorylated mammalian target of rapamycin (p-mTOR), and Mcl-1. The expression of prosurvival and inflammatory proteins and resistance to cell death could be partially modified by inhibition of STAT3 signaling. In summary, our study shows that long-term exposure of squamous cells to BA at acidic pH causes the cells to display the same characteristics and markers as BE.
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Affiliation(s)
- Aaron Goldman
- Department of Cell Biology and Anatomy, Univ. of Arizona, 1501 N. Campbell Ave. P.O. Box 245044, Tucson, AZ 85724, USA
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Rantanen T, Honkanen T, Paavonen T, Rantanen L, Oksala N. Altered expression of HSP27 and HSP70 in distal oesophageal mucosa in patients with gastro-oesophageal reflux disease subjected to fundoplication. Eur J Surg Oncol 2010; 37:168-74. [PMID: 21095095 DOI: 10.1016/j.ejso.2010.10.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2010] [Revised: 09/09/2010] [Accepted: 10/26/2010] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Gastro-oesophageal reflux disease (GERD) is a risk factor for oesophageal adenocarcinoma. Although fundoplication cures reflux symptoms and oesophagitis, it remains controversial whether it is capable of preventing the development of oesophageal adenocarcinoma. Hsp27 and Hsp70 are associated with the development of cancer, whereas the effect of fundoplication on them is not known. METHODS The expression of Hsp27 and Hsp70 was assessed semiquantitatively from biopsies of oesophageal mucosa for a prospective cohort of 19 patients with GERD treated with fundoplication and 7 controls without GERD. Upper gastrointestinal endoscopy with biopsies from the oesophagogastric junction (EGJ) and the distal and proximal oesophagus were performed preoperatively (19 patients) and after recovery from GERD at 6 (19 patients) and 48 months (16 patients) postoperatively. RESULTS The expressions of both Hsp27 (p = 0.001) and Hsp70 (p = 0.002) in the distal oesophagus were lower in patients preoperatively and at 48 months postoperatively (p < 0.001 for both) than in controls. The patients' Hsp27 and Hsp70 levels were lower preoperatively in the proximal oesophagus (p = 0.048 for both) than in controls. Both Hsp27 (p = 0.002) and Hsp70 (p = 0.003) were lower in the distal oesophagus preoperatively and at 48 months postoperatively (p = 0.003 for Hsp27, p = 0.004 for Hsp70) than in the proximal oesophagus. CONCLUSIONS Our results indicate that there may be some factor interfering with the mucosal defence system of the distal oesophagus in GERD that is uninfluenced by fundoplication and not associated with the acid-reflux-normalizing effect.
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Affiliation(s)
- T Rantanen
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland.
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Bower MR, Aiyer HS, Li Y, Martin RCG. Chemoprotective effects of curcumin in esophageal epithelial cells exposed to bile acids. World J Gastroenterol 2010; 16:4152-8. [PMID: 20806431 PMCID: PMC2932918 DOI: 10.3748/wjg.v16.i33.4152] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the ability of curcumin to counteract the impact of bile acids on gene expression of esophageal epithelial cells.
METHODS: An esophageal epithelial cell line (HET-1A) was treated with curcumin in the presence of deoxycholic acid. Cell proliferation and viability assays were used to establish an appropriate dose range for curcumin. The combined and individual effects of curcumin and bile acid on cyclooxygenase-2 (COX-2) and superoxide dismutase (SOD-1 and SOD-2) gene expression were also assessed.
RESULTS: Curcumin in a dose range of 10-100 μmol/L displayed minimal inhibition of HET-1A cell viability. Deoxycholic acid at a concentration of 200 μmol/L caused a 2.4-fold increase in COX-2 gene expression compared to vehicle control. The increased expression of COX-2 induced by deoxycholic acid was partially reversed by the addition of curcumin, and curcumin reduced COX-2 expression 3.3- to 1.3-fold. HET-1A cells exposed to bile acid yielded reduced expression of SOD-1 and SOD-2 genes with the exception that high dose deoxycholic acid at 200 μmol/L led to a 3-fold increase in SOD-2 expression. The addition of curcumin treatment partially reversed the bile acid-induced reduction in SOD-1 expression at all concentrations of curcumin tested.
CONCLUSION: Curcumin reverses bile acid suppression of gene expression of SOD-1. Curcumin is also able to inhibit bile acid induction of COX-2 gene expression.
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Lai LA, Kostadinov R, Barrett MT, Peiffer DA, Pokholok D, Odze R, Sanchez CA, Maley CC, Reid BJ, Gunderson KL, Rabinovitch PS. Deletion at fragile sites is a common and early event in Barrett's esophagus. Mol Cancer Res 2010; 8:1084-94. [PMID: 20647332 PMCID: PMC3100793 DOI: 10.1158/1541-7786.mcr-09-0529] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Barrett's esophagus (BE) is a premalignant intermediate to esophageal adenocarcinoma, which develops in the context of chronic inflammation and exposure to bile and acid. We asked whether there might be common genomic alterations that could be identified as potential clinical biomarker(s) for BE by whole genome profiling. We detected copy number alterations and/or loss of heterozygosity at 56 fragile sites in 20 patients with premalignant BE. Chromosomal fragile sites are particularly sensitive to DNA breaks and are frequent sites of rearrangement or loss in many human cancers. Seventy-eight percent of all genomic alterations detected by array-CGH were associated with fragile sites. Copy number losses in early BE were observed at particularly high frequency at FRA3B (81%), FRA9A/C (71.4%), FRA5E (52.4%), and FRA 4D (52.4%), and at lower frequencies in other fragile sites, including FRA1K (42.9%), FRAXC (42.9%), FRA 12B (33.3%), and FRA16D (33.3%). Due to the consistency of the region of copy number loss, we were able to verify these results by quantitative PCR, which detected the loss of FRA3B and FRA16D, in 83% and 40% of early molecular stage BE patients, respectively. Loss of heterozygosity in these cases was confirmed through pyrosequencing at FRA3B and FRA16D (75% and 70%, respectively). Deletion and genomic instability at FRA3B and other fragile sites could thus be a biomarker of genetic damage in BE patients and a potential biomarker of cancer risk.
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Affiliation(s)
- Lisa A. Lai
- Department of Pathology, University of Washington, Seattle, Washington
| | - Rumen Kostadinov
- Molecular & Cellular Oncogenesis Program, Systems Biology Division, Wistar Institute, Philadelphia, Pennsylvania
| | - Michael T. Barrett
- Pharmaceutical Genomics Division, Translational Genomics Research Institute, Scottsdale, Arizona
| | | | | | - Robert Odze
- Department of Pathology, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Carissa A. Sanchez
- Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Carlo C. Maley
- Molecular & Cellular Oncogenesis Program, Systems Biology Division, Wistar Institute, Philadelphia, Pennsylvania
| | - Brian J. Reid
- Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
- Department of Medicine, University of Washington, Seattle, Washington
- Department of Genome Sciences, University of Washington, Seattle, Washington
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Rieder F, Biancani P, Harnett K, Yerian L, Falk GW. Inflammatory mediators in gastroesophageal reflux disease: impact on esophageal motility, fibrosis, and carcinogenesis. Am J Physiol Gastrointest Liver Physiol 2010; 298:G571-81. [PMID: 20299604 PMCID: PMC2867418 DOI: 10.1152/ajpgi.00454.2009] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Gastroesophageal reflux disease (GERD) is one of the most common problems in clinical practice today. It is widely believed that functional and structural abnormalities of the gastroesophageal junction as well as an abnormal exposure to gastroduodenal contents are the main contributors to its pathogenesis. Novel findings of the inflammatory process in GERD suggest a far more complex process involving multifaceted inflammatory mechanisms. This review summarizes knowledge about the expression of inflammatory mediators in GERD and their potential cellular sources and provides an integrated concept of disease pathogenesis. In addition we evaluate the contribution of inflammatory mediators to well-known complications of GERD, namely motility abnormalities, fibrosis, and carcinogenesis. Novel findings regarding the pathophysiology of esophageal inflammation should enhance our understanding of GERD and its complications and provide new treatment insights.
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Affiliation(s)
- Florian Rieder
- Dept. of Gastroenterology and Hepatology, NC22, Cleveland Clinic Foundation; 9500 Euclid Ave., Cleveland, OH, 44195.
| | - Piero Biancani
- 4Department of Medicine, Rhode Island Hospital and Brown University, Providence, Rhode Island
| | - Karen Harnett
- 4Department of Medicine, Rhode Island Hospital and Brown University, Providence, Rhode Island
| | - Lisa Yerian
- 3Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio; and
| | - Gary W. Falk
- 2Department of Gastroenterology and Hepatology, and
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Reid BJ, Li X, Galipeau PC, Vaughan TL. Barrett's oesophagus and oesophageal adenocarcinoma: time for a new synthesis. Nat Rev Cancer 2010; 10:87-101. [PMID: 20094044 PMCID: PMC2879265 DOI: 10.1038/nrc2773] [Citation(s) in RCA: 293] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The public health importance of Barrett's oesophagus lies in its association with oesophageal adenocarcinoma. The incidence of oesophageal adenocarcinoma has risen at an alarming rate over the past four decades in many regions of the Western world, and there are indications that the incidence of this disease is on the rise in Asian populations in which it has been rare. Much has been learned of host and environmental risk factors that affect the incidence of oesophageal adenocarcinoma, and data indicate that patients with Barrett's oesophagus rarely develop oesophageal adenocarcinoma. Given that 95% of oesophageal adenocarcinomas arise in individuals without a prior diagnosis of Barrett's oesophagus, what strategies can be used to reduce late diagnosis of oesophageal adenocarcinoma?
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Affiliation(s)
- Brian J Reid
- Divisions of Public Health Sciences and Human Biology, Fred Hutchinson Cancer Research Center, University of Washington, 98109 Seattle, USA.
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36
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Kadioglu E, Sardas S, Ergun M, Unal S, Karakaya AE. The role of oxidative DNA damage, DNA repair, GSTM1, SOD2 and OGG1 polymorphisms in individual susceptibility to Barrett’s esophagus. Toxicol Ind Health 2010; 26:67-79. [DOI: 10.1177/0748233709359278] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Determination of the genetic alterations, which play a role in the etiology of Barrett’s esophagus (BE), could help identify high-risk individuals for esophageal adenocarcinoma (EA). The aim of the present study was to investigate the role of oxidative DNA damage, glutathione (GSH) concentration as oxidative stress parameters and DNA repair capacity, GSTM1, SOD1 Ala16Val and OGG1 Ser326Cys genetic polymorphisms as individual susceptibility parameters in the etiology of BE. The study groups comprised BE patients who were clinically diagnosed (n = 40) and a healthy control group (n = 40). Basal DNA damage, pyrimidine and purine base damage after H2O2 induction, H 2O2 sensitivity, DNA repair capacity, oxidized pyrimidine and purine base damage repair were evaluated in peripheral blood lymphocytes with a modified comet assay using specific endonucleases (Endo III and Fpg). Polymerase chain reaction—restriction length polymorphism (PCR-RFLP)-based assays were used for genotyping. The patient group showed elevated levels of basal DNA damage, pyrimidine base damage and H2O2 sensitivity as compared to controls (p < .05). DNA repair capacity, oxidized pyrimidine and purine base damage repair capacity, were not statistically different between patients and controls. GSH concentration was found to be significantly lower in smoking patients than in the controls (p < .05). None of the genetic variations changed the risk of having BE disease. However, patients carrying the variant OGG1 Cys allele showed elevated levels of pyrimidine base damage as compared to patients carrying the wild-type OGG1 Ser (p < .05). The results of this study point to a role of oxidative DNA damage in BE. However, DNA repair capacity, GSTM1, SOD1 Ala16Val and OGG1 Ser326Cys genetic polymorphisms appeared to play no role in the individual susceptibility to this disease.
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Affiliation(s)
- Ela Kadioglu
- Toxicology Department, Faculty of Pharmacy, Gazi University, Hipodrom, Ankara, Turkey,
| | - Semra Sardas
- Toxicology Department, Faculty of Pharmacy, Marmara University, Istanbul, Turkey
| | - Meltem Ergun
- Gastroenterology Department, Faculty of Medicine, Gazi University, Beşevler, Ankara, Turkey
| | - Selahattin Unal
- Gastroenterology Department, Faculty of Medicine, Gazi University, Beşevler, Ankara, Turkey
| | - Ali Esat Karakaya
- Toxicology Department, Faculty of Pharmacy, Gazi University, Hipodrom, Ankara, Turkey
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Abstract
Carcinoma of the oesophagus including carcinoma of gastro-oesophageal junction are rapidly increasing in incidence. During recent years there have been changes in the knowledge surrounding biology of the disease progression. Identification of dysplasia in mucosal biopsies is the most reliable pathologic indicator of an increased risk of development of squamous cell carcinoma and passes through the sequence of chronic esophagitis, low-grade and high-grade dysplasia and invasive carcinoma. Although Barrett's esophagus is a precursor to esophageal adenocarcinoma and have a well described sequence of carcinogenesis: the Barrett's metaplasia-dysplasia-adenocarcinoma sequence, not all patients with this disorder require intensive surveillance. The natural history of dysplasia is poorly understood, particularly in low-risk regions, and prospective follow-up studies are needed. Adjunctive methods to improve reproducibility, such as immunostaining for alpha-methylacyl-coenzyme A racemase (AMACR), show promise, but require confirmation in larger studies. In addition, several controversial methods such as detection of p16, p53, and DNA content abnormalities may help identify patients at particularly high risk for progression to cancer, but these techniques are not yet widely available for routine clinical application. More studies are needed to define other early nonmorphologic biomarkers for risk of squamous cell carcinoma. Recent evidence regarding the importance of several histopathologically derived prognostic factors, such as circumferential resection margin status and lymph node metastases are evaluated, including lymph node micrometastases and the sentinel node concept. With the rising use of multimodal treatments for oesophageal cancer it is important that the response of the tumour to this therapy can be carefully documented by histopathology.
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38
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Stairs DB, Kong J, Lynch JP. Cdx genes, inflammation, and the pathogenesis of intestinal metaplasia. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2010; 96:231-70. [PMID: 21075347 PMCID: PMC6005371 DOI: 10.1016/b978-0-12-381280-3.00010-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Intestinal metaplasia (IM) is a biologically interesting and clinically relevant condition in which one differentiated type of epithelium is replaced by another that is morphologically similar to normal intestinal epithelium. Two classic examples of this are gastric IM and Barrett's esophagus (BE). In both, a chronic inflammatory microenvironment, provoked either by Helicobacter pylori infection of the stomach or acid and bile reflux into the esophagus, precedes the metaplasia. The Caudal-related homeodomain transcription factors Cdx1 and Cdx2 are critical regulators of the normal intestinal epithelial cell phenotype. Ectopic expression of Cdx1 and Cdx2 occurs in both gastric IM as well as in BE. This expression precedes the onset of the metaplasia and implies a causal role for these factors in this process. We review the observations regarding the role of chronic inflammation and the Cdx transcription factors in the pathogenesis of gastric IM and BE.
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Affiliation(s)
- Douglas B Stairs
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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di Pietro M, Fitzgerald RC. Barrett's oesophagus: an ideal model to study cancer genetics. Hum Genet 2009; 126:233-46. [PMID: 19365640 DOI: 10.1007/s00439-009-0665-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2009] [Accepted: 04/01/2009] [Indexed: 12/16/2022]
Abstract
Chronic gastro-oesophageal reflux disease can induce a metaplastic change of the distal oesophagus called Barrett's oesophagus whereby the normal squamous epithelium is substituted by a columnar epithelium. Patients with Barrett's oesophagus are at increased risk of oesophageal adenocarcinoma which occurs through dysplastic stages with increasing degree of cellular and architectural disorganization. Barrett's oesophagus represents an ideal model to study the genetic events supporting the onset of an invasive tumour since patients with this condition are surveilled with endoscopic tissue sampling until high grade dysplasia or intramucosal carcinoma develop. However, due to the relatively low incidence of this disease compared to other cancers, i.e. colon and breast, it is only recently that researchers have concentrated on understanding the genetic events supporting the onset of Barrett's and its transformation to cancer. Here, we review the knowledge acquired so far on the genetic and molecular alterations along the oesophageal metaplasia-dysplasia-carcinoma sequence.
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40
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Abdel-Latif MMM, Duggan S, Reynolds JV, Kelleher D. Inflammation and esophageal carcinogenesis. Curr Opin Pharmacol 2009; 9:396-404. [PMID: 19596608 DOI: 10.1016/j.coph.2009.06.010] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2009] [Revised: 06/08/2009] [Accepted: 06/10/2009] [Indexed: 02/06/2023]
Abstract
The incidence of esophageal adenocarcinoma is increasing largely in Western populations, and patients diagnosed with this cancer continue to have a poor prognosis. The major risk factors are gastroesophageal reflux disease and Barrett's esophagus, both of which are associated with inflammation of the esophageal squamous epithelium, a condition called reflux esophagitis. The cellular mechanisms contributing to cancer development in the esophagus are poorly understood. The chronic inflammation that is present in Barrett's esophagus creates an environment suitable for DNA damage and altered expression of genes involved in cellular proliferation and inhibition of apoptosis. Key players in the inflammatory cascade include generation of free radicals, activation of kinases pathways and transcription factors, and production of cytokines and inflammatory enzymes. The current review highlights the link between reflux-induced inflammation and esophageal carcinogenesis. Understanding the molecular pathways involved in inflammation-associated esophageal tumorigenesis could enable the development of targeted therapies and offer a better therapeutic treatment in esophageal cancer.
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Affiliation(s)
- Mohamed M M Abdel-Latif
- Department of Clinical Medicine, Trinity Centre for Health Sciences, St. James's Hospital, Dublin 8, Ireland.
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41
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Sun L, König IR, Homann N. Manganese superoxide dismutase (MnSOD) polymorphism, alcohol, cigarette smoking and risk of oesophageal cancer. Alcohol Alcohol 2009; 44:353-7. [PMID: 19451660 DOI: 10.1093/alcalc/agp025] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
AIMS Alcohol, tobacco smoke and Barrett's oesophagus as a consequence of gastro-oesophageal reflux are the main risk factors in oesophageal carcinogenesis. All risk factors may induce oxidative stress. Manganese superoxide dismutase (MnSOD) is one important repair enzyme for reactive oxidative stress (ROS)-induced damage. MnSOD polymorphisms in the -9 position of the signal sequence of the protein may lead to critical enzyme deficiency. The aim of the present study was to investigate the role of polymorphisms of MnSOD in patients with oesophageal cancer [n = 170, 61 patients with adenocarcinoma (AC), 109 patients with squamous cell carcinoma (SCC)] compared to heavy drinkers (n = 160) and healthy blood donors (n = 400). METHODS Genotyping was performed by PCR-RFLP analysis using genomic DNA extracted from whole blood. RESULTS The Ala/Ala genotype was 27.7% in cancer patients (29.5% AC, 26.6% SCC), 23.1% in patients with heavy alcohol abuse and 12.5% in the group of healthy blood donors. These results were not statistically significant after multivariate analysis controlling for age, sex, alcohol, cigarettes and interactions (odds ratio 0.92, 95% confidence interval = 0.63-1.36, for cancer patients versus heavy drinkers; odds ratio 1.02, 95% confidence interval = 0.51-2.03, for cancer patients versus blood donors; analysis by logistic regression). Subjects with an Ala/Ala genotype (81.3 g/day) had a significantly higher alcohol intake than those with Val/Ala (63.9 g/day) or Val/Val (53.8 g/day) genotype (P < 0.00001 by the Kruskal-Wallis test). CONCLUSIONS MnSOD polymorphisms play no role in the genetic predisposition to oesophageal cancer. However, our data suggest a complex gene-to-phenotype interaction between the MnSOD genotype and alcohol misuse.
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Affiliation(s)
- L Sun
- Department of Medicine I, University Hospital of Schleswig Holstein, Campus Lübeck, Germany
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Pan J, Lin J, Izzo JG, Liu Y, Xing J, Huang M, Ajani JA, Wu X. Genetic susceptibility to esophageal cancer: the role of the nucleotide excision repair pathway. Carcinogenesis 2009; 30:785-92. [PMID: 19270000 PMCID: PMC2675653 DOI: 10.1093/carcin/bgp058] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2008] [Revised: 03/02/2009] [Accepted: 03/03/2009] [Indexed: 12/14/2022] Open
Abstract
In this case-control study with 387 White esophageal patients and 462 White controls matched to cases by age and sex, we evaluated the associations between 13 potential functional polymorphisms in eight major nucleotide excision repair (NER) genes and esophageal cancer risk. In individual single nucleotide polymorphism analysis, after adjustment for multiple comparisons, the heterozygous GT genotype of the ERCC1 3' untranslated region (UTR) was associated with an increased risk, whereas the homozygous variant genotype TT was associated with 60% reduction in risk with an odds ratio (OR) of 0.40 (95% confidence interval [CI] = 0.19-0.86). The heterozygous AG genotype of XPA 5' UTR was at 2.11-fold increased risk (95% CI = 1.33-3.35) and the risk reached 3.10-fold (95% CI = 1.94-4.95) for the homozygous variant GG genotype. These associations were also significant when restricted the analyses in patients with esophageal adenocarcinoma. Further, the CT genotype of the RAD23B Ala249Val was associated with increased esophageal cancer risk (OR = 1.44; 95% CI = 1.05-1.97), whereas the poly-AT-/+ genotype of the XPC intron 9 conferred a decreased risk (OR = 0.71, 95% CI = 0.51-0.97). In joint analysis, individuals carrying 1 (OR = 2.64, 95% CI = 1.57-4.52) and > or = 2 (OR = 2.74, 95% CI = 1.58-4.75) unfavorable genotypes exhibited significantly increased risk for esophageal cancer risk with significant dose-response trend (P for trend = 0.006). The pathway-based risk was more evident in ever smokers, overweight/obese individuals, men and ever drinkers. Our results support the hypothesis that increasing numbers of unfavorable genotypes in the NER predispose susceptible individuals to increased risk of esophageal cancer. These findings warrant further replications in different populations.
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Affiliation(s)
- Jennifer Pan
- Department of Epidemiology
- Department of Gastrointestinal Medical Oncology
| | | | - Julie G. Izzo
- Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
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Hao J, Zhang B, Liu B, Lee M, Hao X, Reuhl KR, Chen X, Yang CS. Effect of alpha-tocopherol, N-acetylcysteine and omeprazole on esophageal adenocarcinoma formation in a rat surgical model. Int J Cancer 2009; 124:1270-5. [PMID: 19058177 PMCID: PMC2677378 DOI: 10.1002/ijc.24077] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
We previously demonstrated that oxidative stress subsequent to gastroesophageal reflux is an important driving force of esophageal adenocarcinoma (EAC) formation in the esophagogastroduodenal anastomosis (EGDA) rat model. This study investigated the possible tumor inhibitory effects of 2 antioxidants, alpha-tocopherol (389 and 778 ppm), N-acetylcysteine (NAC, 500 and 1,000 ppm), and their combination (389 and 500 ppm, respectively), as well as an antacid therapeutic agent, omeprazole (1,400 ppm). The rats were fed experimental diets 2 weeks after EGDA. All the animals were sacrificed 40 weeks after EGDA and the esophagi were harvested for histopathological examination. alpha-Tocopherol dose-dependently decreased the incidence of EAC (p = 0.03), with 778 ppm alpha-tocopherol reducing the incidence of EAC to 59% (16/27) in comparison with 84% (26/31) in the control group (p = 0.04). Supplementation of alpha-tocopherol also increased the serum concentration of alpha-tocopherol. NAC at 500 and 1,000 ppm did not significantly decrease EAC incidence; however, the combination of alpha-tocopherol 389 ppm and NAC 500 ppm significantly reduced the incidence of EAC to 55% (15/27) (p = 0.02). alpha-Tocopherol alone or in combination with NAC significantly reduced the number of infiltrating cells positively stained for 4-hydroxynonenal. Omeprazole showed only a slight nonsignificant inhibitory effect at the dose given. Our results suggest that supplementation with alpha-tocopherol inhibits the development of EAC in the rat EGDA model and similar inhibitory effect can be achieved when a lower dose of alpha-tocopherol is used in combination with NAC.
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Affiliation(s)
- Jing Hao
- Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, New Jersey 08854
| | - Bin Zhang
- Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, New Jersey 08854
| | - Ba Liu
- Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, New Jersey 08854
| | - Maojung Lee
- Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, New Jersey 08854
| | - Xingpei Hao
- Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, New Jersey 08854
| | - Kenneth R. Reuhl
- Department of Pharmacology & Toxicology, Rutgers University, New Brunswick, NJ 08854
| | - Xiaoxin Chen
- Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, New Jersey 08854
- Cancer Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, 700 George Street, Durham, NC 27707
| | - Chung S Yang
- Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, New Jersey 08854
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Ekambaram G, Rajendran P, Magesh V, Sakthisekaran D. Naringenin reduces tumor size and weight lost in N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats. Nutr Res 2009; 28:106-12. [PMID: 19083396 DOI: 10.1016/j.nutres.2007.12.002] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2007] [Revised: 12/01/2007] [Accepted: 12/04/2007] [Indexed: 02/08/2023]
Abstract
Carcinoma of the stomach is reportedly the second most common cancerous condition affecting the general population. Administration of antioxidants is reported to effectively alleviate the risk of gastric carcinoma. Therefore, we assessed the protective role of naringenin, an antioxidant and naturally occurring citrus flavanone, on gastric carcinogenesis induced by MNNG (200 mg/kg body weight) and S-NaCl (1 mL per rat) in Wistar rats (obtained from the Central Animal House Facility, University of Madras, Taramani Campus, Chennai, India). The animals were divided into 5 groups, and the effects of naringenin on simultaneous and posttreated stages of MNNG were tested. Cancer risk was analyzed along with their antioxidant status. The LPO levels in the experimental groups were assessed as an index of oxidative milieu. Altered redox status was subsequently investigated by assaying the superoxide and hydroxyl radicals, the enzymatic antioxidants (SOD, CAT, GPx), and the nonenzymatic antioxidants viz reduced GSH, vitamin C, and vitamin E. In the presence of MNNG, cancer incidence and LPO levels were significantly increased, whereas enzymatic (SOD, CAT, and GPx) and nonenzymatic antioxidant activities (GSH, Vitamins C, and E) were decreased in the treated rats compared with control rats. Administration of naringenin to gastric carcinoma-induced rats largely up-regulated the redox status to decrease the risk of cancer. We conclude that up-regulation of antioxidants by naringenin treatment might be responsible for the anticancer effect in gastric carcinoma.
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Affiliation(s)
- Ganapathy Ekambaram
- Department of Medical Biochemistry, Dr A.L. Mudaliyar Postgraduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600 113, India
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Sturmey RG, Wild CP, Hardie LJ. Removal of red light minimizes methylene blue-stimulated DNA damage in oesophageal cells: implications for chromoendoscopy. Mutagenesis 2009; 24:253-8. [DOI: 10.1093/mutage/gep004] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
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Moriyama N, Amano Y, Mishima Y, Okita K, Takahashi Y, Yuki T, Ishimura N, Ishihara S, Kinoshita Y. What is the clinical significance of stromal angiogenesis in Barrett's esophagus? J Gastroenterol Hepatol 2008; 23 Suppl 2:S210-5. [PMID: 19120900 DOI: 10.1111/j.1440-1746.2008.05440.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Enriched blood vessels occur in the stroma of Barrett's esophagus and are related to the ease of tumor invasion in the early stage of the cancer. Hypoxia-inducible factor (HIF) is closely related with angiogenesis through expression of vascular endothelial growth factor. The aim of the present study was to determine the predictors for angiogenesis in Barrett's esophagus and evaluate their clinical significance. METHODS Between December 2003 and May 2004, 209 patients with endoscopically and histologically proven Barrett's esophagus were enrolled. Before endoscopic examination, all participants answered structured questionnaires for gastroesophageal reflux symptoms and drug usage. HIF-1alpha and COX-2 protein expressions, cellular proliferation, and apoptosis were investigated immunohistochemically in biopsy samples taken from the esophagus of each patient. The degree of angiogenesis was determined by CD34 immunostaining analysis. Predictors for angiogenesis were evaluated with multivariate logistic regression analysis. RESULTS Sixty (28.7%) of the 209 enrolled patients with Barrett's esophagus had a high CD34 score. Factors proven as positive predictors for a high CD34 score were presence of gastroesophageal reflux symptoms, reflux esophagitis, COX-2 protein expression, and the proliferating cell nuclear antigen (PCNA) index. Administration of proton-pump inhibitors and HIF-1alpha protein expression were not predictors. CONCLUSIONS Reflux esophagitis and gastroesophageal reflux symptoms were positive predictors for enriched angiogenesis in the stromal portion of Barrett's esophagus, which has malignant potential because the epithelial cells express COX-2 and have accelerated cellular proliferation.
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Affiliation(s)
- Nobuyuki Moriyama
- Department of Gastroenterology and Hepatology, Shimane University, School of Medicine, Izumo-shi, Shimane Japan
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Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for preventing gastrointestinal cancers. Cochrane Database Syst Rev 2008:CD004183. [PMID: 18677777 DOI: 10.1002/14651858.cd004183.pub3] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Oxidative stress may cause gastrointestinal cancers. The evidence on whether antioxidant supplements are effective in preventing gastrointestinal cancers is contradictory. OBJECTIVES To assess the beneficial and harmful effects of antioxidant supplements in preventing gastrointestinal cancers. SEARCH STRATEGY We identified trials through the trials registers of the four Cochrane Review Groups on gastrointestinal diseases, The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 2, 2007), MEDLINE, EMBASE, LILACS, SCI-EXPANDED, and The Chinese Biomedical Database from inception to October 2007. We scanned reference lists and contacted pharmaceutical companies. SELECTION CRITERIA Randomised trials comparing antioxidant supplements to placebo/no intervention examining occurrence of gastrointestinal cancers. DATA COLLECTION AND ANALYSIS Two authors (GB and DN) independently selected trials for inclusion and extracted data. Outcome measures were gastrointestinal cancers, overall mortality, and adverse effects. Outcomes were reported as relative risks (RR) with 95% confidence interval (CI) based on random-effects and fixed-effect model meta-analysis. Meta-regression assessed the effect of covariates across the trials. MAIN RESULTS We identified 20 randomised trials (211,818 participants), assessing beta-carotene (12 trials), vitamin A (4 trials), vitamin C (8 trials), vitamin E (10 trials), and selenium (9 trials). Trials quality was generally high. Heterogeneity was low to moderate. Antioxidant supplements were without significant effects on gastrointestinal cancers (RR 0.94, 95% CI 0.83 to 1.06). However, there was significant heterogeneity (I(2) = 54.0%, P = 0.003). The heterogeneity may have been explained by bias risk (low-bias risk trials RR 1.04, 95% CI 0.96 to 1.13 compared to high-bias risk trials RR 0.59, 95% CI 0.43 to 0.80; test of interaction P < 0.0005), and type of antioxidant supplement (beta-carotene potentially increasing and selenium potentially decreasing cancer risk). The antioxidant supplements had no significant effects on mortality in a random-effects model meta-analysis (RR 1.02, 95% CI 0.97 to 1.07, I(2) = 53.5%), but significantly increased mortality in a fixed-effect model meta-analysis (RR 1.04, 95% CI 1.02 to 1.07). Beta-carotene in combination with vitamin A (RR 1.16, 95% CI 1.09 to 1.23) and vitamin E (RR 1.06, 95% CI 1.02 to 1.11) significantly increased mortality. Increased yellowing of the skin and belching were non-serious adverse effects of beta-carotene. In five trials (four with high risk of bias), selenium seemed to show significant beneficial effect on gastrointestinal cancer occurrence (RR 0.59, 95% CI 0.46 to 0.75, I(2) = 0%). AUTHORS' CONCLUSIONS We could not find convincing evidence that antioxidant supplements prevent gastrointestinal cancers. On the contrary, antioxidant supplements seem to increase overall mortality. The potential cancer preventive effect of selenium should be tested in adequately conducted randomised trials.
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Affiliation(s)
- Goran Bjelakovic
- Copenhagen Trial Unit, Centre for Clinical Intervention Research,, Department 3344, Rigshospitalet, Copenhagen University Hospital,, Blegdamsvej 9, Copenhagen, Denmark, DK-2100.
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De Jonge PJF, Siersema PD, Van Breda SGJ, Van Zoest KPM, Bac DJ, Leeuwenburgh I, Ouwendijk RJT, Van Dekken H, Kusters JG, Kuipers EJ. Proton pump inhibitor therapy in gastro-oesophageal reflux disease decreases the oesophageal immune response but does not reduce the formation of DNA adducts. Aliment Pharmacol Ther 2008; 28:127-36. [PMID: 18384663 DOI: 10.1111/j.1365-2036.2008.03699.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Chronic oesophageal inflammation and related oxidative stress are important in the pathogenesis of erosive oesophagitis (EO) and its malignant progression. AIM To study the effect of proton pump inhibitors (PPIs) on oesophageal cellular immune response and oxidative damage in EO patients. METHODS Forty gastro-oesophageal reflux disease (GERD) patients [non-erosive reflux disease (NERD): 15, EO: 25] were included, after 7 days off antisuppressive drugs. EO patients were randomized to 20-mg rabeprazole once daily for either 4 or 8 weeks with baseline and follow-up endoscopy with distal oesophageal biopsies. T lymphocytes, macrophages and mast cells were quantified by immunohistochemistry. DNA adducts were measured by analysis of 8-oxo-deoxyguanosine levels. RESULTS Erosive oesophagitis patients had more T lymphocytes and CD8(+) T lymphocytes in squamous epithelium than NERD patients (P = 0.001, P = 0.002, respectively). Levels of DNA adducts between both groups were, however, not different (P = 0.99). Four- and eight-week rabeprazole treatment in EO patients resulted in a significant decrease in number of T lymphocytes and CD8(+) T lymphocytes (all P < 0.05). PPIs did not, however, affect levels of DNA adducts. CONCLUSIONS Short-term PPI therapy in EO patients reduces the oesophageal cellular immune response, but does not change oxidative damage. PPI therapy may therefore not be effective in reducing the risk of oesophageal cancer in GERD patients.
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Affiliation(s)
- P J F De Jonge
- Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands.
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Risques RA, Vaughan TL, Li X, Odze RD, Blount PL, Ayub K, Gallaher JL, Reid BJ, Rabinovitch PS. Leukocyte telomere length predicts cancer risk in Barrett's esophagus. Cancer Epidemiol Biomarkers Prev 2008; 16:2649-55. [PMID: 18086770 DOI: 10.1158/1055-9965.epi-07-0624] [Citation(s) in RCA: 121] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
PURPOSE Leukocyte telomere length has gained attention as a marker of oxidative damage and age-related diseases, including cancer. We hypothesize that leukocyte telomere length might be able to predict future risk of cancer and examined this in a cohort of patients with Barrett's esophagus, who are at increased risk of esophageal adenocarcinoma and thus were enrolled in a long-term cancer surveillance program. PATIENTS AND METHODS In this prospective study, telomere length was measured by quantitative PCR in baseline blood samples in a cohort of 300 patients with Barrett's esophagus followed for a mean of 5.8 years. Leukocyte telomere length hazard ratios (HR) for risk of esophageal adenocarcinoma were calculated using multivariate Cox models. RESULTS Shorter telomeres were associated with increased esophageal adenocarcinoma risk (age-adjusted HR between top and bottom quartiles of telomere length, 3.45; 95% confidence interval, 1.35-8.78; P = 0.009). This association was still significant when individually or simultaneously adjusted for age, gender, nonsteroidal anti-inflammatory drug (NSAID) use, cigarette smoking, and waist-to-hip ratio (HR, 4.18; 95% confidence interval, 1.60-10.94; P = 0.004). The relationship between telomere length and cancer risk was particularly strong among NSAID nonusers, ever smokers, and patients with low waist-to-hip ratio. CONCLUSION Leukocyte telomere length predicts risk of esophageal adenocarcinoma in patients with Barrett's esophagus independently of smoking, obesity, and NSAID use. These results show the ability of leukocyte telomere length to predict the risk of future cancer and suggest that it might also have predictive value in other cancers arising in a setting of chronic inflammation.
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Affiliation(s)
- Rosa Ana Risques
- Department of Pathology, University of Washington, Seattle, WA 98195-7705, USA
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Schlöbe D, Hölzle D, Hatz D, von Meyer L, Tricker AR, Richter E. 4-Hydroxy-1-(3-pyridyl)-1-butanone-releasing DNA adducts in lung, lower esophagus and cardia of sudden death victims. Toxicology 2008; 245:154-61. [DOI: 10.1016/j.tox.2007.12.021] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2007] [Revised: 12/18/2007] [Accepted: 12/19/2007] [Indexed: 01/28/2023]
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