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

Abstract

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.

Dickkopf-1, the Wnt antagonist, is induced by acidic pH and mediates epithelial cellular senescence in human reflux esophagitis

“…With respect to the tumorigenic nature of aberrant Wnt-signaling activation (37) and the senescenceassociated tumor suppression, Dkk1 may also play a pivotal role in esophageal carcinogenesis. Although high levels of Dkk1 expression have been reported in EAC (9) and aberrant activation of Wnt/␤-catenin signaling has been found to promote esophageal intestinal metaplasia (27) and neoplastic progression toward EAC (6,4,34), the exact role of Dkk1 during esophageal carcinogenesis remains unknown and requires further study.…”

Integrated molecular analysis reveals complex interactions between genomic and epigenomic alterations in esophageal adenocarcinomas

“…For example, the wnt/β-catenin signaling pathway plays an important role in cell-cell adhesion. Activation of β-catenin due to mutations and/or overexpression of components of the β-catenin pathway have been associated with several tumours, including colorectal cancer35, lung cancer36, breast cancer37, as well as gastric3839 and esophageal adenocarcinoma4041. Increased expression of transcription factor MYB has been reported in many human cancers42, including esophageal adenocarcinoma43.…”

Notch and Wnt signaling pathway in cancer: Crucial role and potential therapeutic targets (Review)

“…They also found that factitious expression of Wnt signal pathway in mouse oesophagus could cause tissue disorganization (125). Their results indicated that Wnt signal pathway plays an initiative effect in ESCC.…”

“…Moyes et al (125) have reported that the expression of nuclear activated β-catenin was highly expressed in high grade of dysplasia when compared with that in Barrett's metaplasia. They also found that factitious expression of Wnt signal pathway in mouse oesophagus could cause tissue disorganization (125).…”