Abstract
BackgroundToll-like receptors (TLRs) recognize microbial and endogenous ligands and have already shown to play a role in esophageal cancer. In this study, we evaluated especially TLRs that sense bacterial cell wall components in Barrett's esophagus, dysplasia and esophageal adenocarcinoma.MethodsTLRs 1, 2, 4 and 6 were stained immunohistochemically and assessed in esophageal specimens from patients with esophageal dysplasia (n = 30) or adenocarcinoma (n = 99). Structures and lesions were evaluated including normal esophagus (n = 88), gastric (n = 67) or intestinal metaplasia (n = 51) without dysplasia, and low-grade (n = 42) or high-grade dysplasia (n = 37), and esophageal adenocarcinoma (n = 99).ResultsWe found TLR1, TLR2, TLR4 and TLR6 expression in all lesions. TLR expression increased in Barrett's mucosa and dysplasia. There was profound increase of TLR expression from gastric- to intestinal-type columnar epithelium. In cancers, high nuclear and cytoplasmic staining of TLR4 associated with metastatic disease and poor prognosis.ConclusionsTLR1, TLR2, TLR4 and TLR6 are upregulated during malignant changes of esophageal columnar epithelium. Increased TLR4 expression associates with advanced stage and poor prognosis in esophageal adenocarcinoma.
Highlights
The best characterized pathway is correlation between gastric cancer and Helicobacter pylori infection [4], where aberrant Toll-like receptors (TLRs) expression is involved [5].Esophageal microbiome shows characteristic features in Barrett’s esophagus and esophageal adenocarcinoma, but their actual pathogenetic significance is not known [6].In esophageal epithelium, TLR9 expression increases during premalignant and malignant changes [7,8,9] and TLR9 activation stimulates invasion in esophageal adenocarcinoma cells [10]
The aim of this study was to assess the expression of TLRs 1, 2, 4 or 6 in different stages of esophageal metaplasia-dysplasia-adenocarcinoma-sequence
We demonstrate widespread expression of TLRs 1, 2, 4 and 6 in normal esophageal squamous epithelium, columnar metaplasia and dysplasia of Barrett’s esophagus, as well as esophageal adenocarcinoma
Summary
The best characterized pathway is correlation between gastric cancer and Helicobacter pylori infection [4], where aberrant TLR expression is involved [5].Esophageal microbiome shows characteristic features in Barrett’s esophagus and esophageal adenocarcinoma, but their actual pathogenetic significance is not known [6].In esophageal epithelium, TLR9 expression increases during premalignant and malignant changes [7,8,9] and TLR9 activation stimulates invasion in esophageal adenocarcinoma cells [10]. Epithelial TLR5 expression increases along with development esophageal columnar dysplasia and is a marker of dysplasia [11]. Tolllike receptor 4, for example recognizes lipopolysaccharide and TLRs 1, 2 and 6 form heterodimers to recognize different kinds of lipopeptides, which are components of bacterial cell wall [1]. Bacteria-recognizing TLRs are found, in immune cells, and in epithelial cells and fibroblasts. Epithelial cells sense luminal pathogens via TLRs and activate immune cells and consequent inflammation [2]. Toll-like receptors (TLRs) recognize microbial and endogenous ligands and have already shown to play a role in esophageal cancer. We evaluated especially TLRs that sense bacterial cell wall components in Barrett’s esophagus, dysplasia and esophageal adenocarcinoma
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