Increased Toll-like receptor 5 expression indicates esophageal columnar dysplasia

Abstract

Toll-like receptor 5 (TLR5) is an immune receptor, which recognizes bacterial flagellin. Increased expression has been reported in various premalignant and malignant lesions indicating a role in carcinogenesis. We assessed the expression of TLR5 in normal esophageal squamous epithelium, Barrett's esophagus with and without dysplasia, and in esophageal adenocarcinoma. Specimens with normal esophagus (n=93), gastric (n=75) or intestinal metaplasia (n=53) without dysplasia, and low-grade (n=56) or high-grade dysplasia (n=33) and esophageal adenocarcinoma (n=94) were studied. TLR5 immunohistochemical stainings were analyzed for the proportion of positive cells and the intensity of expression. In normal squamous epithelium, only the basal third showed TLR5 expression. In esophageal gastric or intestinal metaplasia, expression was present in majority of the cells but significantly weaker (p<0.001) than in dysplastic epithelium. In dysplasia, expression extended to the apical cytoplasm, contrasting basolateral expression in non-dysplastic columnar epithelium. Receiver operating characteristic curve analysis showed that moderate to high expression intensity of TLR5 indicates low-grade dysplasia with 86 % sensitivity and 83 % specificity. Carcinomas showed increased expression in comparison with non-dysplastic columnar epithelium, but there was no association with prognosis. Our results indicate that the esophageal columnar dysplasia is associated with clear increase of TLR5 expression and dissolution of regular polarized expression. TLR5 staining provides a possible biomarker for the recognition of low-grade dysplasia. In addition, the findings suggest a role for abnormal expression of TLR5 in the pathogenesis of esophageal adenocarcinoma and suggest importance of altered microbiome in the pathogenesis of complications of Barrett's esophagus.

Nucleic acid-sensing toll-like receptors 3, 7 and 8 in esophageal epithelium, barrett’s esophagus, dysplasia and adenocarcinoma

“…Nuclear expression of TLR8 associated to distant metastases and poor cancer prognosis. These findings indicate that in addition to flagellin sensing TLR5 11 and bacterial DNA sensing TLR9, 7 also other nucleotide sensing TLRs are involved in pathogenesis and progression of Barrett's esophagus.…”

“…7,11 In cases of more extensive differences between the investigators, a consensus would be reached by discussion with a third investigator (T. J. K.). None of the differences between the assessments exceeded these predetermined values.…”

“…The material has been earlier described elsewhere. 11 The median age of the cancer patients was 64 y (range 43-90). The median follow-up time was 36 mo (range 0-288 mo).…”

“…The intensity and extent of different TLR expression in all epithelial cells in the each type of lesion, including normal squamous epithelium, columnar metaplasia and dysplasia, and carcinoma, was assessed semiquantitatively by two independent investigators (O. H and H. H.), as described previously. 7,11 For interobserver calibration, a training set of samples were jointly evaluated and scored. The investigators were blinded to the clinical data and each other's assessments.…”

Association between Toll-like receptor 7 Gln11Leu single-nucleotide polymorphism and basal cell carcinoma

“…The role of TLRs in cancer is therefore ambiguous. TLRs have been found to be overexpressed in certain pre-malignant conditions and neoplasia (25)(26)(27)(28), responsible for increasing angiogenic and metastatic potential of tumors activating nitric oxide synthase 2 and cyclooxygenase 2, and upregulating vascular endothelial growth factor and transforming growth factor-β within the tumor microenvironment (29)(30)(31). By contrast, TLRs can cause tumor inhibition (32)(33)(34)(35) and TLR ligands can have an anticancer effect, as demonstrated by studies on TLR7/8 and TLR9 agonists (36)(37)(38).…”