Changes in mitochondrial stability during the progression of the Barrett's esophagus disease sequence.

N J O’Farrell,J V Reynolds,N Ravi,F Maccarthy,M Biniecka,E J Fox,J O’Sullivan,R Feighery,J J Phelan,N Lynam-Lennon,S L Picardo,D O’Toole,S A Mcgarrigle

doi:10.1186/s12885-016-2544-2

Abstract

BackgroundBarrett’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.MethodsUsing 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.ResultsBarrett’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.ConclusionsWe have demonstrated that increased mitochondrial instability and markers of cellular and mitochondrial stress are early events in the Barrett’s disease sequence.

Highlights

Barrett’s esophagus follows the classic step-wise progression of metaplasia-dysplasia-adenocarcinoma
In-vivo patient tissue assessment While there were no differences in the frequency of random mutations between specialized intestinal metaplasia (SIM) and high grade dysplasia (HGD)/esophageal adenocarcinoma (EAC) tissue (p = 1.00), interestingly, random mitochondrial deletions were significantly increased in SIM tissue compared with HGD/EAC (p = 0.043) (Fig. 2)
There was a trend towards increased mitochondrial deletions in matched-normal tissue compared with HGD/EAC cancerous tissue (p = 0.063)

Summary

Introduction

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. Esophageal cancer is one of the most rapidly increasing malignancies in the Western world [1]. Barrett’s esophagus is a pathologic precursor of esophageal adenocarcinoma. Following the classic metaplasia-dysplasia-adenocarcinoma sequence, it is speculated cancer development does not occur directly from non-dysplastic disease [4]. While Barrett’s esophagus follows this natural stepwise progression, the exact cellular instability mechanisms triggering cancer conversion are not fully elucidated

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