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1.
BMC Cancer ; 16: 497, 2016 07 19.
Article in English | MEDLINE | ID: mdl-27431913

ABSTRACT

BACKGROUND: Barrett's esophagus follows the classic step-wise progression of metaplasia-dysplasia-adenocarcinoma. While Barrett's esophagus is a leading known risk factor for esophageal adenocarcinoma, the pathogenesis of this disease sequence is poorly understood. Mitochondria are highly susceptible to mutations due to high levels of reactive oxygen species (ROS) coupled with low levels of DNA repair. The timing and levels of mitochondria instability and dysfunction across the Barrett's disease progression is under studied. METHODS: Using an in-vitro model representing the Barrett's esophagus disease sequence of normal squamous epithelium (HET1A), metaplasia (QH), dysplasia (Go), and esophageal adenocarcinoma (OE33), random mitochondrial mutations, deletions and surrogate markers of mitochondrial function were assessed. In-vivo and ex-vivo tissues were also assessed for instability profiles. RESULTS: Barrett's metaplastic cells demonstrated increased levels of ROS (p < 0.005) and increased levels of random mitochondrial mutations (p < 0.05) compared with all other stages of the Barrett's disease sequence in-vitro. Using patient in-vivo samples, Barrett's metaplasia tissue demonstrated significantly increased levels of random mitochondrial deletions (p = 0.043) compared with esophageal adenocarcinoma tissue, along with increased expression of cytoglobin (CYGB) (p < 0.05), a gene linked to oxidative stress, compared with all other points across the disease sequence. Using ex-vivo Barrett's metaplastic and matched normal patient tissue explants, higher levels of cytochrome c (p = 0.003), SMAC/Diablo (p = 0.008) and four inflammatory cytokines (all p values <0.05) were secreted from Barrett's metaplastic tissue compared with matched normal squamous epithelium. CONCLUSIONS: We have demonstrated that increased mitochondrial instability and markers of cellular and mitochondrial stress are early events in the Barrett's disease sequence.


Subject(s)
Adenocarcinoma/genetics , Barrett Esophagus/genetics , Gene Expression Regulation, Neoplastic , Metaplasia/genetics , Mitochondria/genetics , Mutation , Adenocarcinoma/metabolism , Barrett Esophagus/metabolism , Cell Line , Cell Line, Tumor , Cytochromes c/metabolism , Cytoglobin , Cytokines/metabolism , Disease Progression , Enzyme-Linked Immunosorbent Assay , Esophagus/metabolism , Esophagus/pathology , Globins/genetics , Globins/metabolism , Humans , Inflammation Mediators/metabolism , Metaplasia/metabolism , Mitochondria/metabolism , Mitochondrial Proteins/metabolism , Reactive Oxygen Species/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Risk Factors
2.
Cancer Lett ; 371(2): 334-46, 2016 Feb 28.
Article in English | MEDLINE | ID: mdl-26688097

ABSTRACT

In Barrett associated tumorigenesis, oxidative phosphorylation and glycolysis are reprogrammed early in the disease sequence and act mutually to promote disease progression. However, the link between energy metabolism and its connection with other central cellular processes within the Barrett microenvironment is unknown. The aim of this study was to examine the relationship between metabolism (ATP5B/GAPDH), hypoxia (HIF1α), inflammation (IL1ß/SERPINA3), p53 and obesity status using in-vivo and ex-vivo models of Barrett oesophagus. At the protein level, ATP5B (r = 0.71, P < 0.0001) and p53 (r = 0.455, P = 0.015) were found to be strongly associated with hypoxia. In addition, levels of ATP5B (r = 0.53, P = 0.0031) and GAPDH (r = -0.39, P = 0.0357) were positively associated with p53 expression. Moreover, we demonstrate that ATP5B (r = 0.8, P < 0.0001) and GAPDH (r = 0.43, P = 0.022) were positively associated with IL1ß expression. Interestingly, obesity was negatively associated with oxidative phosphorylation (r = -0.6016, P = 0.0177) but positively associated with glycolysis (r = 0.743, P = 0.0015). Comparable correlations were exhibited in the ex-vivo explant tissue between metabolism, p53, hypoxia, inflammation and angiogenesis (P < 0.05). We have shown that metabolism is closely linked with many cellular processes in the Barrett tissue microenvironment.


Subject(s)
Barrett Esophagus/metabolism , Cell Communication , Cellular Microenvironment , Esophagus/metabolism , Aged , Barrett Esophagus/pathology , Barrett Esophagus/physiopathology , Biomarkers/metabolism , Cell Hypoxia , Cell Line , Esophagus/blood supply , Esophagus/pathology , Female , Glyceraldehyde-3-Phosphate Dehydrogenases/metabolism , Glycolysis , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Inflammation/metabolism , Inflammation Mediators/metabolism , Interleukin-1beta/metabolism , Male , Middle Aged , Mitochondrial Proton-Translocating ATPases/metabolism , Neovascularization, Pathologic , Obesity/metabolism , Oxidative Phosphorylation , Prospective Studies , Serpins/metabolism , Signal Transduction , Tumor Suppressor Protein p53/metabolism
3.
Dis Esophagus ; 28(2): 121-6, 2015.
Article in English | MEDLINE | ID: mdl-24428806

ABSTRACT

Barrett's esophagus (BE) arising from chronic gastro-oesophageal reflux (GERD) is the main pathologic precursor of esophageal adenocarcinoma (EAC). The risk of progression to high-grade dysplasia (HGD) and EAC is unclear, and recent population studies from Denmark and Northern Ireland suggest that this has been overestimated in the past. No data exist from the Republic of Ireland. A detailed clinical, endoscopic, and pathologic database was established in one center as a proposed pilot for a national registry, and initial and follow-up data were abstracted by a data manager. One thousand ninety-three patients were registered, 60 patients with HGD were excluded, leaving 1033, with a median age of 59 and 2 : 1 male to female ratio, and 3599 person-years of follow-up. The overall incidence of HGD/EAC was 1.33% per year overall, 0.85% if the first year is excluded. Within the first year after index endoscopy, 18 cases of HGD or EAC were identified, and 30 following the first year. Low-grade dysplasia (LGD) on index endoscopy was associated with an incidence of progression of 6.5% per year, and 3.1% when tertiary referrals were excluded. These data provide important demographic and clinical information on the population of Irish patients with BE, with incidence rates of progression higher than recently published population-based registry series, perhaps relating to sampling and pathological assessment. Low-grade dysplasia on initial biopsy is a significant proxy marker of risk of progression.


Subject(s)
Adenocarcinoma/epidemiology , Barrett Esophagus/epidemiology , Esophageal Neoplasms/epidemiology , Registries/statistics & numerical data , Age Distribution , Aged , Aged, 80 and over , Barrett Esophagus/pathology , Biopsy/statistics & numerical data , Disease Progression , Esophagus/pathology , Female , Humans , Incidence , Ireland/epidemiology , Male , Middle Aged , Prospective Studies , Risk , Sex Distribution
4.
Cancer Lett ; 354(1): 122-31, 2014 Nov 01.
Article in English | MEDLINE | ID: mdl-25107643

ABSTRACT

Contemporary clinical management of Barrett's oesophagus has highlighted the lack of accurate predictive markers of disease progression to oesophageal cancer. This study aims to examine alterations in mitochondrial energy metabolism profiles across the entire disease progression sequence in Barrett's oesophagus. An in-vitro model was used to screen 84 genes associated with mitochondrial energy metabolism. Three energy metabolism genes (ATP12A, COX4I2, COX8C) were significantly altered across the in-vitro Barrett's disease sequence. In-vivo validations across the Barrett's sequence demonstrated differential expression of these genes. Tissue microarrays demonstrated significant alterations in both epithelial and stromal oxidative phosphorylation (ATP5B and Hsp60) and glycolytic (PKM2 and GAPDH) protein markers across the in-vivo Barrett's sequence. Levels of ATP5B in sequential follow up surveillance biopsy material segregated Barrett's non progressors and progressors to HGD and cancer. Utilising the Seahorse XF24 flux analyser, in-vitro Barrett's and adenocarcinoma cells exhibited altered levels of various oxidative parameters. We show for the first time that mitochondrial energy metabolism is differentially altered across the metaplasia-dysplasia-adenocarcinoma sequence and that oxidative phosphorylation profiles have predictive value in segregating Barrett's non progressors and progressors to adenocarcinoma.


Subject(s)
Adenocarcinoma/metabolism , Barrett Esophagus/metabolism , Gene Expression Regulation, Neoplastic , Mitochondria/metabolism , Barrett Esophagus/pathology , Biopsy , Cell Line, Tumor , Disease Progression , Electron Transport Complex IV/metabolism , Energy Metabolism , Gene Expression Profiling , Glycolysis , H(+)-K(+)-Exchanging ATPase/metabolism , Humans , Metaplasia/metabolism , Oligonucleotide Array Sequence Analysis , Oxygen/chemistry , Phosphorylation
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