University Department of Surgery, Royal Infirmary, Glasgow, UK.
J Pathol. 2012 Sep;228(1):99-112. doi: 10.1002/path.4058. Epub 2012 Jul 18.
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.
巴雷特食管是食管腺癌的前身，通过肠化生和异型增生。异型增生，尤其是高级别异型增生，癌症风险显著增加。因此，临床上需要识别和治疗具有高癌症风险的早期疾病（化生和低级别异型增生）患者。激活的 Wnt 信号对于正常的肠道发育和稳态至关重要，但对于食管发育则不太重要。因此，我们想知道异常增加的 Wnt 信号是否会导致 Barrett 食管（肠化生）和/或异型增生的发展。40 名患有 Barrett 化生、异型增生或腺癌的患者接受了内镜和活检。使用他莫昔芬和β-萘黄酮诱导激活β-catenin表达的小鼠来上调小鼠食管中的 Wnt 信号。对人类和小鼠组织进行β-catenin、Ki67、Wnt 靶基因的表达以及肠化生标志物的免疫组织化学检测。在人类组织中，发现异型增生，特别是高级别异型增生，存在核激活β-catenin的表达。Barrett 化生没有显示高水平的激活β-catenin。Ki67 和 Wnt 靶基因的上调也主要与高级别异型增生相关。在小鼠食管中上调 Wnt 信号导致组织明显紊乱，具有异型增生的特征，但只有选择的化生分子标志物。基于这些人类组织和小鼠模型的结果，我们得出结论，Wnt 信号的异常激活可能仅在 Barrett 化生的起始中起次要作用，但在进展为异型增生中起更关键的作用。
