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1.
Gut ; 59(2): 156-63, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19651631

ABSTRACT

BACKGROUND: Barrett's oesophagus is a common premalignant lesion caused partly by acid reflux. Although the requisite therapy, proton pump inhibitors (PPIs), have been implicated in the progression of Barrett's oesophagus in animal models, harmful effects of prolonged PPI therapy in Barrett's oesophagus is both inconclusive and controversial. We therefore aimed to test the role of PPI-induced hypergastrinaemia in vitro and see whether any biological parameters were useful surrogates of long-term therapy in man. METHODS: We undertook detailed serological and tissue assessment of gastrin and CCK(2) receptors in 90 patients randomised to different doses of PPI therapy during a detailed 2-year follow-up. We also undertook a comprehensive study of cell models to study the consequential biological effects of gastrin on the mucosa. RESULTS: Gastrin and its cognate receptor CCK(2)R were expressed highest in the stomach, then less in Barrett's oesophagus and least in squamous oesophagus (SqE) (n=20 paired t-test, p<0.01). Analysis of the change in Barrett's oesophagus segment length change in 70 patients who were randomised to high or low PPI dose showed no difference over 2 years (n=70 t-test, p=0.8). Prolonged PPI use did, however, increase the serum gastrin, (36 pg/ml+/-57 pg/ml to 103 pg/ml+/-94 pg/ml (paired t test, p<0.05)). In vitro gastrin also induced changes in OE33(E)(cckr) Barrett's oesophagus cells, but not OE21(E)(cckr) squamous cells, transfected with CCK(2)R; migration was induced by 1 ng/ml of gastrin but proliferation only increased with 100 ng/ml (paired t-test, p<0.01) and both were abolished by antagonists. CONCLUSION: While the short-term effects of gastrin enhance epithelial restitution in Barrett's oesophagus (but not squamous mucosa) there is no clinical evidence that Barrett's oesophagus length expands over time. This study, which is the largest and longest term randomised controlled trial of gastrin biology in Barrett's oesophagus, is further proof of the clinical safety of PPI therapy.


Subject(s)
Barrett Esophagus/drug therapy , Esophageal Neoplasms/drug therapy , Gastrins/biosynthesis , Precancerous Conditions/drug therapy , Proton Pump Inhibitors/therapeutic use , Adult , Aged , Barrett Esophagus/metabolism , Barrett Esophagus/pathology , Cell Movement/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Enzyme-Linked Immunosorbent Assay/methods , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/pathology , Esophagus/metabolism , Female , Gastric Mucosa/metabolism , Gastrins/genetics , Gastrins/pharmacology , Gene Expression , Humans , Male , Middle Aged , Precancerous Conditions/metabolism , Precancerous Conditions/pathology , Proton Pump Inhibitors/adverse effects , RNA, Messenger/genetics , Receptor, Cholecystokinin B/biosynthesis , Receptor, Cholecystokinin B/genetics , Reverse Transcriptase Polymerase Chain Reaction/methods , Tumor Cells, Cultured
2.
Clin Cancer Res ; 12(20 Pt 1): 5936-43, 2006 Oct 15.
Article in English | MEDLINE | ID: mdl-17062664

ABSTRACT

PURPOSE: The incidence of esophageal adenocarcinoma is rising, and survival rates remain poor. The hepatocyte growth factor (HGF) receptor Met has been detected in esophageal cancer. The perturbation of cadherin/catenin complexes has also been shown. We sought to investigate a link among Met expression, cadherin/catenin biology, and cell growth. We assessed the prognostic significance of Met expression in esophageal adenocarcinoma. EXPERIMENTAL DESIGN: Met and HGF expression in esophageal tissues were assessed using immunohistochemistry and ELISA. Met-positive cell lines (OE33 and SEG1) and a Met-negative cell line (TE7) were incubated with HGF. Real-time reverse transcription-PCR and Western blotting were used to assess levels of E-cadherin expression. Nuclear TCF/beta-catenin signaling was assessed following reporter construct transfection. Agar colony formation was used to assess anchorage-independent growth. A panel of 72 resected esophageal adenocarcinomas were assessed for Met expression by immunohistochemistry and correlated to survival data. RESULTS: An increased expression of Met was seen along the metaplasia- adenocarcinoma sequence. Met-positive cells showed reductions in E-cadherin mRNA (37% and 69%) and protein expression following stimulation with HGF (P < 0.01). OE33 and SEG-1 showed up to a 2-fold increase in the levels of beta-catenin nuclear signaling (P < 0.01). TE7 only responded when transfected to express Met; E-cadherin expression decreased by 64% (P < 0.01). HGF stimulation led to increased agar colony formation (P < 0.01). Patients with Met-positive tumors showed lower 6-month survival rates after surgical resection than those with Met-negative tumors (P < 0.05). CONCLUSIONS: Met activation induces changes consistent with early invasion, such as down-regulation of E-cadherin, increased nuclear TCF/beta-catenin signaling, and anchorage-independent growth. This is supported by ex vivo data associating Met with reduced short-term survival. Inhibitors of Met may be effective treatment for esophageal adenocarcinoma.


Subject(s)
Adenocarcinoma/physiopathology , Esophageal Neoplasms/physiopathology , Proto-Oncogene Proteins/genetics , Receptors, Growth Factor/genetics , Adenocarcinoma/epidemiology , Adenocarcinoma/pathology , Base Sequence , Cadherins/genetics , Cell Line, Tumor , DNA Primers , Esophageal Neoplasms/epidemiology , Esophageal Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Hepatocyte Growth Factor/genetics , Humans , Incidence , Polymerase Chain Reaction , Proto-Oncogene Proteins c-met , Signal Transduction
3.
Article in English | MEDLINE | ID: mdl-16997163

ABSTRACT

Oesophageal adenocarcinoma (OA) remains one of the more deadly forms of gastro-intestinal cancer with a mortality rate exceeding 90%. The incidence of OA remains unabated and has a reported fivefold increase since 1970 [Pera M, Cameron AJ, Trastek VF, Carpenter HA & Zinsmeister AR. Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction. Gastroenterology 1993; 104(2): 510-513]. Gastro-oesophageal reflux disease and its sequelae, Barrett's oesophagus, is one of the principle risk factors in the development of OA, with a 30-fold increased risk in Barrett's patients compared with the general population [Tytgat GNJ. Does endoscopic surveillance in esophageal columnar metaplasia (Barrett's-Esophagus) have any real value. Endoscopy 1995; 27(1): 19-26]. OA is thought to be a microcosm of evolution, developing sequentially along the metaplasia-dysplasia-adenocarcinoma sequence. Progression is attributed to a series of genetic and epigenetic events that ultimately allow for clonal selection of Barrett's cells via subversion of intrinsic control mechanisms regulating cellular proliferation and/or apoptosis. This review will describe the current suppositions of the mechanisms behind the selection and subsequent expansion of Barrett's clones, and focus on some of the principle hallmarks associated with this transition.


Subject(s)
Adenocarcinoma/pathology , Barrett Esophagus/pathology , Cell Transformation, Neoplastic/metabolism , Esophageal Neoplasms/pathology , Adenocarcinoma/etiology , Adenocarcinoma/metabolism , Animals , Barrett Esophagus/complications , Barrett Esophagus/metabolism , Bile Acids and Salts/metabolism , Disease Progression , Esophageal Neoplasms/etiology , Esophageal Neoplasms/metabolism , Esophagogastric Junction/metabolism , Esophagogastric Junction/pathology , Gastrins/metabolism , Gastroesophageal Reflux/complications , Gastroesophageal Reflux/metabolism , Gastroesophageal Reflux/pathology , Humans , Inflammation Mediators/metabolism , Metaplasia/etiology , Metaplasia/metabolism , Metaplasia/pathology , Prevalence
4.
Mol Pharmacol ; 69(3): 1033-40, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16354769

ABSTRACT

The highly inducible enzyme, hemeoxygenase-1 (HO-1), metabolizes heme, thereby protecting a variety of cells against oxidative stress and apoptosis. Up-regulation by cancer chemopreventive agents has been reported, but its regulation and function in transformed cells are unclear. We compared induction by two dietary polyphenols, curcumin and epigallocatechin-3-gallate (EGCG), with that by the endogenous substrate hemin in epithelial and endothelial cells and examined the relevance to apoptosis. Curcumin or hemin (20 microM) induced HO-1 in breast cells from 5 to 24 h. Curcumin (5-40 microM) or hemin (5-100 microM) induced HO-1 and nuclear levels of nuclear factor (erythroid-derived 2)-related factor (Nrf2) in a dose-dependent manner. EGCG had no effect in breast cells, but at 30 microM, it induced nuclear translocation of Nrf2 and HO-1 expression in B-lymphoblasts. In all cases, induction was inhibited by pretreatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) or the p38 inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580). The nuclear factor-kappaB (NF-kappaB)-DNA binding inhibitor helenalin (20 microM) also prevented induction. However, wortmannin had no effect, suggesting that PI3K was not involved. Curcumin and hemin also induced nuclear Nrf2 and HO-1 effectively in wild-type mouse embryo fibroblasts (wt MEFs) and in B-Raf(-/-) MEFs but not in Nrf2(-/-) MEFs. However, EGCG (5-20 microM) induced HO-1 only in wt MEFs. Results suggest that signaling through p38 mitogen-activated protein kinase, NF-kappaB, and Nrf2 as well as other unidentified molecules is involved in HO-1 induction by hemin and both polyphenols, but cell-specific factors also play a role, particularly with respect to EGCG. Induction of HO-1 by curcumin, EGCG, or low concentrations (5-10 microM) of helenalin did not protect MDA-MB468 breast cells or B-lymphoblasts from apoptosis.


Subject(s)
Catechin/analogs & derivatives , Curcumin/pharmacology , Flavonoids/pharmacology , Heme Oxygenase-1/metabolism , Phenols/pharmacology , Animals , Apoptosis , B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , Breast/cytology , Breast/drug effects , Breast/metabolism , Catechin/pharmacology , Cell Nucleus/chemistry , Cell Nucleus/metabolism , Cells, Cultured , Diet , Fibroblasts/drug effects , Fibroblasts/metabolism , Humans , Mice , Mice, Knockout , NF-E2-Related Factor 2/metabolism , NF-kappa B/analysis , NF-kappa B/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Polyphenols , Sesquiterpenes/pharmacology , Sesquiterpenes, Guaiane , p38 Mitogen-Activated Protein Kinases/metabolism
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