Activation of Wnt signalling promotes development of dysplasia in Barrett's oesophagus

• Published in: The Journal of pathology 2012-09, Vol.228 (1), p.99-112
• Main Authors: Moyes, Lisa H, McEwan, Hamish, Radulescu, Sorina, Pawlikowski, Jeff, Lamm, Catherine G, Nixon, Colin, Sansom, Owen J, Going, James J, Fullarton, Grant M, Adams, Peter D
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Animals; Animals, Outbred Strains; Barrett Esophagus - metabolism; Barrett Esophagus - pathology; Barrett's oesophagus; beta Catenin - metabolism; Biological and medical sciences; Cell Nucleus - metabolism; Disease Models, Animal; Disease Progression; dysplasia; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophagus; Esophagus - metabolism; Esophagus - pathology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic; Humans; Investigative techniques, diagnostic techniques (general aspects); Ki-67 Antigen - genetics; Ki-67 Antigen - metabolism; Medical sciences; Metaplasia; Mice; Mice, Inbred C57BL; oesophageal cancer; Other diseases. Semiology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Precancerous Conditions - metabolism; Precancerous Conditions - pathology; Tumors; Wnt Signaling Pathway - physiology; Wnt signalling
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.4058

Barrett's oesophagus is a precursor of oesophageal adenocarcinoma, via intestinal metaplasia and dysplasia. Risk of cancer increases substantially with dysplasia, particularly high‐grade dysplasia. Thus, there is a clinical need to identify and treat patients with early‐stage disease (metaplasia and low‐grade dysplasia) that are at high risk of cancer. Activated Wnt signalling is critical for normal intestinal development and homeostasis, but less so for oesophageal development. Therefore, we asked whether abnormally increased Wnt signalling contributes to the development of Barrett's oesophagus (intestinal metaplasia) and/or dysplasia. Forty patients with Barrett's metaplasia, dysplasia or adenocarcinoma underwent endoscopy and biopsy. Mice with tamoxifen‐ and β‐naphthoflavone‐induced expression of activated β‐catenin were used to up‐regulate Wnt signalling in mouse oesophagus. Immunohistochemistry of β‐catenin, Ki67, a panel of Wnt target genes, and markers of intestinal metaplasia was performed on human and mouse tissues. In human tissues, expression of nuclear activated β‐catenin was found in dysplasia, particularly high grade. Barrett's metaplasia did not show high levels of activated β‐catenin. Up‐regulation of Ki67 and Wnt target genes was also mostly associated with high‐grade dysplasia. Aberrant activation of Wnt signalling in mouse oesophagus caused marked tissue disorganization with features of dysplasia, but only selected molecular indicators of metaplasia. Based on these results in human tissues and a mouse model, we conclude that abnormal activation of Wnt signalling likely plays only a minor role in initiation of Barrett's metaplasia but a more critical role in progression to dysplasia. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.