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Increased Toll-like receptor 5 expression indicates esophageal columnar dysplasia

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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.

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Acknowledgments

This work was supported by grants from the Emil Aaltonen Foundation (J.H.K.), Cancer Foundation of Northern Ostrobotnia (J.H.K.), Oulu University Research Foundation (J.H.K.), Georg C. and Mary Ehrnroot Foundation (J.H.K.), and the Finnish Medical Foundation (J.H.K. and H.H.). T.J.K. received travel grant from Amgen and a single lecture payment from Novartis.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Pathology, University of Oulu, P.O. Box 5000, 90014, Oulu, Finland

    Olli Helminen, Heikki Huhta, Joonas H. Kauppila & Tuomo J. Karttunen

  2. Department of Surgery, University of Oulu, 90014, Oulu, Finland

    Olli Helminen, Heikki Huhta, Heikki Takala, Petri P. Lehenkari, Juha Saarnio & Joonas H. Kauppila

  3. Oulu University Hospital, 90029, Oulu, Finland

    Olli Helminen, Heikki Huhta, Heikki Takala, Petri P. Lehenkari, Juha Saarnio, Joonas H. Kauppila & Tuomo J. Karttunen

  4. Department of Anatomy and Cell Biology, University of Oulu, 90014, Oulu, Finland

    Petri P. Lehenkari

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  1. Olli Helminen
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Correspondence to Olli Helminen.

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Joonas H. Kauppila and Tuomo J. Karttunen contributed equally to this work

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Helminen, O., Huhta, H., Takala, H. et al. Increased Toll-like receptor 5 expression indicates esophageal columnar dysplasia. Virchows Arch 464, 11–18 (2014). https://doi.org/10.1007/s00428-013-1505-2

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  • DOI: https://doi.org/10.1007/s00428-013-1505-2

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