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Wen H, Liu T, Liu H, Teng JH, Li SB. An improved surgical procedure to establish a gastroesophageal reflux model with a high incidence of Barrett's esophagus in rats. Exp Ther Med 2018; 16:3863-3868. [PMID: 30344662 PMCID: PMC6176162 DOI: 10.3892/etm.2018.6712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 08/02/2018] [Indexed: 11/05/2022] Open
Abstract
Barrett's esophagus (BE) is a complication of gastroesophageal reflux disease and is a precursor lesion of esophageal adenocarcinoma. In existing BE models, the incidence of BE is typically low and induction is usually time consuming. In the present study, a gastroesophageal reflux model with a high incidence of BE in rats. Rats were divided into a model group and a sham operation group, and anesthetized with an inhalation anesthesia machine. Stomach-jejunal anastomosis (SJA) and esophagus-jejunal anastomosis (EJA) were simultaneously performed in the model group. The distance between the Treitz ligament and the gastro-jejunal anastomosis was shortened to 3 cm. The distance between the SJA and the EJA was prolonged to 1–1.5 cm. However, 15/40 rats in the model group succumbed to post-surgical complications (mortality rate was 37.5%). The weight of surviving rats in the model group was significantly lower compared with the sham group rats post-surgery. Erosions and ulcers were common of the surviving rats in the model group, with an incidence of 80% (20/25). Squamous cell dysplasia was identified in 40% (10/25) of rats in model group. The modified model was well established within 16 weeks. Notably, the modified surgical procedure used enhanced the incidence of BE in rats from 47% in the EJGJ model (as establish by Zhang) to 100%. To conclude, this model can be used as a reliable animal model for basic research on BE.
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Affiliation(s)
- Hui Wen
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442002, P.R. China
| | - Tao Liu
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442002, P.R. China.,Department of Pathology, People's Hospital of Longhua, Shenzhen, Guangdong 518131, P.R. China
| | - Hua Liu
- Department of Thoracic Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442002, P.R. China
| | - Jing-Hua Teng
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442002, P.R. China
| | - Sheng-Bao Li
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442002, P.R. China
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Zeb MH, Baruah A, Kossak SK, Buttar NS. Chemoprevention in Barrett's Esophagus: Current Status. Gastroenterol Clin North Am 2015; 44:391-413. [PMID: 26021201 DOI: 10.1016/j.gtc.2015.02.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Chemoprevention in Barrett's esophagus is currently applied only in research settings. Identifying pathways that can be targeted by safe, pharmaceutical or natural compounds is key to expanding the scope of chemoprevention. Defining meaningful surrogate markers of cancer progression is critical to test the efficacy of chemopreventive approaches. Combinatorial chemoprevention that targets multiple components of the same pathway or parallel pathways could reduce the risk and improve the efficacy of chemoprevention. Here we discuss the role of chemoprevention as an independent or an adjuvant management option in BE-associated esophageal adenocarcinoma.
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Affiliation(s)
- Muhammad H Zeb
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
| | - Anushka Baruah
- Department of Internal Medicine, John H. Stroger, Jr. Hospital of Cook County, 1901 W. Harrison Street, Chicago, IL 60612, USA
| | - Sarah K Kossak
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
| | - Navtej S Buttar
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
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3
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Wang RH. From reflux esophagitis to Barrett’s esophagus and esophageal adenocarcinoma. World J Gastroenterol 2015; 21:5210-5219. [PMID: 25954094 PMCID: PMC4419061 DOI: 10.3748/wjg.v21.i17.5210] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Revised: 01/19/2015] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
The occurrence of gastroesophageal reflux disease is common in the human population. Almost all cases of esophageal adenocarcinoma are derived from Barrett’s esophagus, which is a complication of esophageal adenocarcinoma precancerous lesions. Chronic exposure of the esophagus to gastroduodenal intestinal fluid is an important determinant factor in the development of Barrett’s esophagus. The replacement of normal squamous epithelium with specific columnar epithelium in the lower esophagus induced by the chronic exposure to gastroduodenal fluid could lead to intestinal metaplasia, which is closely associated with the development of esophageal adenocarcinoma. However, the exact mechanism of injury is not completely understood. Various animal models of the developmental mechanisms of disease, and theoretical and clinical effects of drug treatment have been widely used in research. Recently, animal models employed in studies on gastroesophageal reflux injury have allowed significant progress. The advantage of using animal models lies in the ability to accurately control the experimental conditions for better evaluation of results. In this article, various modeling methods are reviewed, with discussion of the major findings on the developmental mechanism of Barrett’s esophagus, which should help to develop better prevention and treatment strategies for Barrett’s esophagus.
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Baruah A, Buttar NS. Chemoprevention in Barrett's oesophagus. Best Pract Res Clin Gastroenterol 2015; 29:151-65. [PMID: 25743463 DOI: 10.1016/j.bpg.2014.12.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 12/11/2014] [Indexed: 01/31/2023]
Abstract
Increasing incidence of oesophageal adenocarcinoma along with poor survival entails novel preventive strategies. Agents that target pro-oncogenic pathways in Barrett's mucosa could halt this neoplastic transformation. In this review, we will use epidemiological associations and molecular mechanisms to identify novel chemoprevention targets in Barrett's oesophagus. We will also discuss recent chemoprevention trials.
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Affiliation(s)
- Anushka Baruah
- Mayo Clinic College of Medicine, Department of Gastroenterology and Hepatology, Rochester, MN, USA
| | - Navtej S Buttar
- Mayo Clinic College of Medicine, Department of Gastroenterology and Hepatology, Rochester, MN, USA.
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Gronnier C, Bruyère E, Piessen G, Briez N, Bot J, Buob D, Leteurtre E, Van Seuningen I, Mariette C. Operatively induced chronic reflux in rats: a suitable model for studying esophageal carcinogenesis? Surgery 2013; 154:955-67. [PMID: 24084597 DOI: 10.1016/j.surg.2013.05.029] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Accepted: 05/16/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND The mechanisms of esophageal reflux leading to esophageal adenocarcinoma (EA) remain poorly understood. This study appraises critically an operatively induced chronic reflux rat model. METHODS We randomized 108 Sprague-Dawley rats into 2 experimental groups; one was performing esophagoduodenal (ED) anastomosis with or without gastrectomy to induce duodeno-esophageal reflux (DER group; n = 63), and the other involved duodeno-gastro-esophageal reflux (DGER group; n = 45). Control groups included (i) Roux-en-Y esophagojejunal anastomosis, (ii) laparotomy alone, (iii) subtotal gastrectomy to induce duodenogastric reflux (DGR group), and (iv) the same procedure as in the DGER group plus proton pump inhibition (PPI group). The esophagus underwent histologic and molecular analyses. RESULTS The prevalence of Barrett's esophagus (BE), dysplasia, and EA in the experimental groups was 41%, 7%, and 11%, respectively. Histologic and molecular analyses in groups DER, DGER, and DGR suggested that BE occurred through de novo intestinal metaplasia and proximal migration of duodenal cells. No distant metastases were identified. The molecular characteristics of both BE and EA were similar to humans. BE was more common, and dysplasia and EA less frequent in the DER group when compared with the DGER group (44% vs 24% [P = .038] and 7% vs 25% [P = .012], respectively). Compared with the DGER group, carcinogenic sequence occurred less frequently in the PPI-treated group (P = .019). CONCLUSION Despite pathophysiologic differences with humans, the rat model of esophagoduodenostomy reproduces accurately histologic and molecular lesions in the carcinogenetic sequence of BE and allowed us to identify novel, tumor-associated proteins that may be potential biomarkers and new therapeutic targets in EA.
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Affiliation(s)
- Caroline Gronnier
- Inserm, UMR837, Jean-Pierre Aubert Research Center, Team 5 "Mucins, epithelial differentiation and carcinogenesis", Lille, France; Université Lille Nord de France, Lille, France; Department of Digestive and Oncological Surgery, University Hospital Claude Huriez, Centre Hospitalier Régional et Universitaire de Lille, Lille, France
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6
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[Barrett's esophagus: analyses from human and experimental animal studies]. DER PATHOLOGE 2013; 34:138-47. [PMID: 23430135 DOI: 10.1007/s00292-012-1731-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Whereas attention in the past has been focused on goblet cells as the primary marker for Barrett's esophagus (BE), the recent change in the definition now includes the non-goblet cell columnar cell-lined esophagus. In the present study the histological features of neoplasia of the lower esophagus and esophago-gastric junction in a German cohort were examined using immunohistochemical staining for MUC, CD10, intestinal and gastric type major tight junction proteins (claudins). Experimental studies using rat duodenogastric content reflux models have also been performed and data show that most neoplastic lesions of the esophageal glands in humans express gastric mucin phenotypes. Cardiac type mucosa was the main histological type in the surrounding mucosa of neoplastic lesions; however, most cardiac type mucosa has intestinal type tight junction proteins. BE with goblet cells has been reported to originate from stem cells located in the basal layer of esophageal squamous cell epithelium in previous models. However, the cardiac type mucosa seems to develop from the site of the stomach and not from the basal layer of esophageal squamous cell epithelium according to our model.
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Endo H, Iijima K, Asanuma K, Ara N, Ito H, Asano N, Uno K, Koike T, Imatani A, Shimosegawa T. Exogenous luminal nitric oxide exposure accelerates columnar transformation of rat esophagus. Int J Cancer 2010; 127:2009-2019. [PMID: 20131319 DOI: 10.1002/ijc.25227] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Exposure of the esophageal mucosa to refluxed gastroduodenal contents is recognized to be an important risk factor for Barrett's esophagus (BE). At the human gastroesophageal junction, nitric oxide is generated luminally through the enterosalivary recirculation of dietary nitrate, and in cases with gastroesophageal reflux, the site of luminal nitric oxide generation could shift to the distal esophagus. The aim of this study is to investigate whether exogenous luminal nitric oxide could promote the development of BE in rats. Sodium nitrite plus ascorbic acid were administered to a rat surgical model of BE, in which the gastroduodenal contents were refluxed into the esophagus to generate exogenous luminal nitric oxide in the esophagus by the acid-catalyzed chemical reaction between the 2 reagents. The emergence of BE was evaluated histologically in the early phase (several weeks) after the surgery with or without exogenous nitric oxide administration. To elucidate the histogenesis of BE, CDX2, MUC2 and MUC6 expressions were investigated immunohistochemically. Coadministration of sodium nitrite plus ascorbic acid significantly accelerated the timing of emergence and increased the area of BE compared with controls. Administration of either reagent alone did not show any promotive effects on BE formation. Immunohistochemically, the columnar epithelium thus induced was similar to the specialized intestinal metaplasia in human BE. The results of this animal model study suggest that exogenous luminal nitric oxide could be involved in the pathogenesis of the columnar transformation of the esophagus. Further studies in human are warranted.
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Affiliation(s)
- Hiroyuki Endo
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
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Aiyer HS, Li Y, Martin RCG. Diet composition affects surgery-associated weight loss in rats with a compromised alimentary tract. J Surg Res 2009; 168:42-8. [PMID: 19932903 DOI: 10.1016/j.jss.2009.08.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2009] [Revised: 06/23/2009] [Accepted: 08/03/2009] [Indexed: 12/17/2022]
Abstract
BACKGROUND Esophageal adenocarcinoma (EAC) is the fastest growing cancer in terms of incidence and has a high mortality rate. The animal model to study EAC uses esophagoduodenal anastomosis (EDA) to induce mixed-reflux (bile/acid) causing esophagitis, Barrett's esophagus, and EAC sequence within 6 mo. However, the lack of fully functional stomach in these rats leads to the development of malnutrition. METHODS We have assessed the ability of a chemically pure, purified ingredient diet (AIN-93M) to reduce surgery-associated malnutrition in rats that have undergone the EDA-surgery. Animals were either sham- (SH) or EDA-operated and fed either a grain-based rodent diet (RD) (SH-RD, n=3; EDA-RD, n=10) or a purified diet (PD) (SH-PD, n=4; EDA-PD, n=11). The animals were weighed periodically for assessment of weight gain and euthanized at the end of 24 wk to measure esophageal tumor incidence. RESULTS Animals that underwent sham surgery continued to gain weight throughout the study period and no tumors were detected. The EDA-operated animals had significantly lower weight gain compared with sham animals. There was no significant difference in weight gain among EDA animals fed two different types of diets until 9 wk after the surgery. After 9 wk, EDA-RD continued to lose weight significantly, whereas the weight loss leveled in EDA-PD (P<0.001). At termination, neither tissue histopathology nor tumor incidence was significantly different between the groups. CONCLUSION These results show that compared with a natural ingredient diet, a purified ingredient diet can reduce surgery-associated weight loss in rats with a compromised alimentary tract. This reduction in malnutrition has the potential to reduce the confounding effects of weight loss on future animal studies reported.
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Affiliation(s)
- Harini S Aiyer
- Division of Surgical Oncology, Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA
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Murphy JO, Ravi N, Byrne PJ, McDonald GSA, Reynolds JV. Neither Antioxidants nor COX-2 Inhibition Protect Against Esophageal Inflammation in an Experimental Model of Severe Reflux. J Surg Res 2008; 145:33-40. [PMID: 17727884 DOI: 10.1016/j.jss.2006.07.053] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2006] [Revised: 06/19/2006] [Accepted: 07/17/2006] [Indexed: 01/27/2023]
Abstract
BACKGROUND Reflux-induced injury and oxidative stress result in esophageal inflammation and the potential for progression to intestinal metaplasia and adenocarcinoma. Proton-pump inhibitors represent the standard medical approach, but anti-inflammatories and antioxidants offer novel therapeutic possibilities. MATERIALS AND METHODS Six weeks after an esophagojejunostomy reflux procedure, female Wistar rats (n = 100) were randomized to receive either an antioxidant (vitamin C, 8 mg or 28 mg/day), a cyclooxygenase-2 (COX-2) inhibitor (rofecoxib, 1 mg/day), or no therapy. After sacrifice 16 weeks later, esophageal injury was scored using pathologic and image analysis scoring. RESULTS Esophagitis was present in all 63 animals completing the study and was severe in 27 (43%). No animal developed metaplasia or tumor. The extent of inflammation and esophageal ulceration were not significantly different between experimental groups. CONCLUSIONS In this model of reflux injury, antioxidants and COX-2 inhibitors failed to ameliorate the severe inflammation induced. Further experimental designs should evaluate these novel approaches in less severe experimental models.
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Affiliation(s)
- James O Murphy
- Department of Surgery, St. James's Hospital and Trinity College, Dublin, Ireland
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10
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Zhang T, Zhang F, Han Y, Gu Z, Zhou Y, Cheng Q, Zhu Y, Zhang C, Wang Y. A rat surgical model of esophageal metaplasia and adenocarcinoma-induced by mixed reflux of gastric acid and duodenal contents. Dig Dis Sci 2007; 52:3202-8. [PMID: 17393326 DOI: 10.1007/s10620-007-9774-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2006] [Accepted: 01/18/2007] [Indexed: 12/17/2022]
Abstract
Recent clinical data have revealed that mixed reflux (MR) of gastric acid and duodenal contents frequently occurs in patients with gastroesophageal reflux disease and a progressive increase of MR occurs with increasing severity across gastroesophageal reflux disease. Herein we report a novel rat surgical model in which esophageal metaplasia and adenocarcinoma develop as complications of MR. The model was created by performing an esophagojejunostomy and a gastrojejunostomy 5 mm proximal to the esophagojejunal anastomosis in 40 rats. Severe inflammatory and proliferative changes, high prevalence of esophageal metaplasia (78%), and adenocarcinoma (50%) were observed in the lower part of the esophagus of rats 20 weeks after surgery. The resulting esophageal lesions resembled those described in humans and supported a progression from intestinal metaplasia to dysplasia and, ultimately, esophageal adenocarcinoma. Such a model may provide a useful tool in study of human reflux-induced carcinogenesis.
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Affiliation(s)
- Tao Zhang
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, China
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11
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Murphy JO, Ravi N, Byrne PJ, McDonald GSA, Reynolds JV. Neither Antioxidants nor COX-2 Inhibition Protect Against Esophageal Inflammation in an Experimental Model of Severe Reflux. J Surg Res 2007; 142:20-7. [PMID: 17543990 DOI: 10.1016/j.jss.2007.01.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2006] [Indexed: 01/27/2023]
Abstract
BACKGROUND Reflux-induced injury and oxidative stress result in esophageal inflammation and the potential for progression to intestinal metaplasia and adenocarcinoma. Proton-pump inhibitors represent the standard medical approach, but anti-inflammatories and antioxidants offer novel therapeutic possibilities. MATERIALS AND METHODS Six weeks after an esophagojejunostomy reflux procedure, female Wistar rats (n = 100) were randomized to receive either an antioxidant (vitamin C, 8 mg or 28 mg/day), a cyclooxygenase-2 (COX-2) inhibitor (rofecoxib, 1 mg/day), or no therapy. After sacrifice 16 weeks later, esophageal injury was scored using pathologic and image analysis scoring. RESULTS Esophagitis was present in all 63 animals completing the study and severe in 27 (43%). No animal developed metaplasia or tumor. The extent of inflammation and esophageal ulceration were not significantly different between experimental groups. CONCLUSIONS In this model of reflux injury, antioxidants and COX-2 inhibitors failed to ameliorate the severe inflammation induced. Further experimental designs should evaluate these novel approaches in less severe experimental models.
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Affiliation(s)
- James O Murphy
- Department of Surgery, St James's Hospital and Trinity College, Dublin, Ireland
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Sital RR, Kusters JG, De Rooij FWM, Kuipers EJ, Siersema PD. Bile acids and Barrett's oesophagus: a sine qua non or coincidence? Scand J Gastroenterol 2007:11-7. [PMID: 16782617 DOI: 10.1080/00365520600664219] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
BACKGROUND Barrett's oesophagus (BO), a premalignant condition associated with the development of oesophageal adenocarcinoma (OAC), is thought to be a consequence of chronic duodeno-gastro-oesophageal reflux. Of the refluxates, bile acids, either alone or in combination with acid, are probably the most important. METHODS Analysis of the literature on the role played by bile acids in inducing BO and/or progression to OAC. RESULTS Combined pH and Bilitec 2000 (as a measure of bile reflux) monitoring and oesophageal aspiration studies in humans suggest a combined role for bile acids, particularly taurine conjugated bile acids, in causing oesophageal mucosal injury. Evidence from animal models has demonstrated that duodenal juice alone is also able to induce BO and/or OAC. Likewise, ex vivo studies with biopsies from BO patients show that increased proliferation and cyclo-oxygenase-2 expression are present after a pulsed exposure to acid or conjugated bile acids, but not if acid and bile acids are combined. Proton-pump inhibitors (PPIs) have been shown to decrease the biliary component of the refluxate. There is some evidence that PPIs are able to reduce neoplastic progression in BO. On the other hand, chronic PPIs can also stimulate bacterial overgrowth, which can result in increased production of secondary bile acids, particularly deoxycholic acid, in the stomach. Deoxycholic acid has been demonstrated to have a tumour-promoting capacity. CONCLUSIONS It is unknown what factors of the refluxate (acid and/or bile) induce BO and/or promote carcinogenesis, but there is evidence that secondary bile acids play a role. A better understanding of the molecular steps involved in the induction of BO, and the role of bile acids herein, may identify targets at which preventive therapies can be directed.
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Affiliation(s)
- Rudy R Sital
- Department of Gastroenterology and Hepatology and Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
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Li Y, Wo JM, Ellis S, Ray MB, Jones W, Martin RCG. Morphological transformation in esophageal submucosa by bone marrow cells: esophageal implantation under external esophageal perfusion. Stem Cells Dev 2007; 15:697-705. [PMID: 17105405 DOI: 10.1089/scd.2006.15.697] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Accumulating clinical and experimental studies indicate that Barrett's esophagus might arise through multipotential stem cells under the stress of gastroesophageal reflux. Previously, we have presented a novel external pump perfusion rat model and demonstrated that perfusion with both acid and bile can induce severe esophagitis in 1 week with a similarly pathological change seen in humans. The aim of this study was to investigate the histological changes of esophagus after bone marrow cell engraftment with bile and acid perfusion. The external pump perfusion procedure involved implantation of a microosmotic pump for esophageal perfusion. Bone marrow cells were obtained by flushing of the femur marrow, and the cell suspension was injected between the esophageal muscular and inner mucosa layer. Histological changes were determined after 4 weeks of perfusion. Proliferating cell nuclear antigen, 8-hydroxy-deoxyguanosine, manganese superoxide dismutase, and apoptosis were measured by immunohistochemical staining and TUNEL assay, respectively. Severe esophagitis was seen in both acid and bile perfusion. Bone marrow engraftment and potentiation was seen in both the acid and bile perfusion, when compared to saline controls. Glandular-like cells in submucosa, consistent with intestinal metaplasia, confirmed by Alcin Blue-PAS staining were observed after bone marrow esophageal implantation along with bile perfusion, but not with acid perfusion and controls. Bone marrow implantation in conjunction with esophageal reflux injury contributes to abnormal histological changes consistent with early Barrett's esophageal changes. Engrafted bone marrow cells proliferate under oxidative stress conditions with bile perfusion.
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Affiliation(s)
- Yan Li
- Division of Surgical Oncology, University of Louisville School of Medicine, Louisville, KY 40202, USA
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Saygili EI, Akcay T, Dinçer Y, Obek C, Kural AR, Cakalir C. Methylguanine DNA methyl transferase activities, glutathione s transferase and nitric oxide in bladder cancer patients. Cancer Invest 2006; 24:256-60. [PMID: 16809152 DOI: 10.1080/07357900600634120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Tumor formation is a multistep process that can be divided in to the stages of tumor initiation, promotion, and progression. DNA repair protein; MGMT is a key suicide enzyme that repairs the mispairing base methylguanine, which is induced in DNA as a minor lesion. The glutathione S transferases (GSTs) are a family of enzymes that are important to protect against alkylating agents. Nitric oxide, contributes to the regulation of tumor angiogenesis. A substantial body of experimental evidence supports the hypothesis that tumor angiogenesis is fundamental for the growth and metastasis of solid tumors. We measured the activities of GST, MGMT, and levels of NO3-/NO2- in the leukocytes from patients with bladder carcinoma and healthy controls and activities of MGMT in the tissue from patients with bladder carcinoma and adjacent normal tissue in bladder. Both GST and tissue MGMT activites were significantly increased in the patient group. There was no significant difference between controls and patients for MGMT activity in peripheral blood leukocytes (PBL). Nitrate/nitrite levels in PBL, there was no significant difference between controls and patients. Nitrate/nitrite levels were increased in G2-G3 tumors. In conclusion, we determined high concentrations of nitrite in leukocytes are suspected alkylation damage by induction nitrosamine. Increased DNA alkylation damage may lead the stimulation of MGMT and GST.
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Affiliation(s)
- E Ilker Saygili
- Departments of Biochemistry, Cerrahpaşa Medical School, Istanbul University, Istanbul, Turkey
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Buttar NS, Wang KK. Mechanisms of disease: Carcinogenesis in Barrett's esophagus. ACTA ACUST UNITED AC 2005; 1:106-12. [PMID: 16265072 DOI: 10.1038/ncpgasthep0057] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2004] [Accepted: 10/29/2004] [Indexed: 02/02/2023]
Abstract
The pathogenesis of cancer in Barrett's esophagus is multifactorial. Gastroesophageal reflux seems to be important in the initiation of Barrett's esophagus, but its role in promoting carcinogenesis has yet to be established. Diet, lifestyle and carcinogens, especially the nitrates, may be important in the development of carcinogenesis, and require further investigation. Inhibition of reflux-stimulated inflammatory changes, for example by inhibiting cyclooxygenase, holds promise for decreasing cancer progression. Similarly, dietary and lifestyle modification used in the management of reflux may also help to prevent the development of esophageal cancer. The molecular changes that are associated with the development of cancer in Barrett's esophagus offer several potential areas of intervention to prevent and manage esophageal cancer. Limiting cell growth, increasing apoptosis of damaged cells, limiting cell invasion and angiogenesis factors could be useful to accomplish this goal. Having a greater understanding of the pathogenesis of this condition can only help to develop more management options in the future.
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Ye W, Held M, Lagergren J, Engstrand L, Blot WJ, McLaughlin JK, Nyrén O. Helicobacter pylori infection and gastric atrophy: risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia. J Natl Cancer Inst 2004; 96:388-96. [PMID: 14996860 DOI: 10.1093/jnci/djh057] [Citation(s) in RCA: 243] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND An inverse association between Helicobacter pylori infection and esophageal adenocarcinoma has been reported that may be attributed to reduced acidity from inducing atrophic gastritis and from producing ammonia. We examined associations between H. pylori infection, gastric atrophy, and the risk of esophageal adenocarcinoma, esophageal squamous-cell carcinoma, and gastric cardia adenocarcinoma in a large population-based case-control study in Sweden. METHODS Self-reported data were obtained during interviews, and serum was collected from 97 patients with incident esophageal adenocarcinoma, 85 patients with incident esophageal squamous-cell carcinoma, 133 patients with incident gastric cardia adenocarcinoma, and 499 randomly selected control subjects. Serum antibodies against whole H. pylori cell-surface antigens (HP-CSAs) and cytotoxin-associated gene A (CagA) antigens were assessed by an IgG enzyme-linked immunosorbent assay and immunoblotting, respectively. Gastric atrophy was assessed by serum levels of pepsinogen I. Multivariable logistic regression with adjustment for potential confounding factors was used to evaluate associations. RESULTS H. pylori infection, assayed by HP-CSA or CagA antibodies, was statistically significantly associated with a reduced risk for esophageal adenocarcinoma (for HP-CSA antibodies, odds ratio [OR] = 0.3, 95% confidence interval [CI] = 0.2 to 0.6; for CagA antibodies, OR = 0.5, 95% CI = 0.3 to 0.8; for both, OR = 0.2, 95% CI = 0.1 to 0.5). Gastric atrophy was not associated with the risk for esophageal adenocarcinoma (OR = 1.1, 95% CI = 0.5 to 2.5). Serum CagA antibodies and gastric atrophy were associated with an increased risk for esophageal squamous-cell carcinoma (OR = 2.1, 95% CI = 1.1 to 4.0, and OR = 4.3, 95% CI = 1.9 to 9.6, respectively). The risk of gastric cardia adenocarcinoma was not associated with H. pylori infection. However, gastric atrophy was associated with an increased risk for gastric cardia adenocarcinoma (OR = 4.5, 95% CI = 2.5 to 7.8). CONCLUSIONS Infection with H. pylori may reduce the risk of esophageal adenocarcinoma, but it is unlikely to do so by atrophy-reduced acidity. Gastric atrophy and infection with CagA-positive strains of H. pylori may increase the risk for esophageal squamous-cell carcinoma.
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Affiliation(s)
- Weimin Ye
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
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Abstract
Columnar-lined lower esophagus (CLE) or Barrett's esophagus (BE) is caused by chronic reflux of the gastrointestinal tract and can progress to invasive adenocarcinoma. However, the pathophysiology, cell of origin, and management of this condition is incompletely understood. This review evaluates the role of in vivo models in resolving these debates. A search was performed on the Ovid and Pub Medline for 1964-2001 and Cochrane Collaboration. The keywords used were adenocarcinoma, animal model, Barrett's esophagus, columnar-lined esophagus, esophageal neoplasms, and esophageal carcinogenesis. All relevant papers were scrutinized and an attempt at tabulation was made. In vivo models have been used at several stages of debate on the pathophysiology of BE. They provide conclusive evidence for its acquired nature secondary to duodenogastroesophageal reflux. The cell of origin of experimental BE may arise from adjacent columnar epithelium, basal layer multipotent cells, or esophageal glands. Experimental work on BE is lacking in assessing therapeutic modalities.
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Affiliation(s)
- Y Koak
- Department of Surgery, Royal Free and University College School of Medicine, Rowland Hill Street, London, UK.
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