Department of Human Pathology, Kanazawa University Graduate School of Medicine, 13-1 Takara-machi, Kanazawa 920-8640, Japan.
Am J Pathol. 2010 Jul;177(1):141-52. doi: 10.2353/ajpath.2010.090747. Epub 2010 May 20.
Epithelial-mesenchymal transition is an important mechanism behind initiation of cancer invasion and metastasis. This study was performed to clarify the involvement of epithelial-mesenchymal transition in the progression of cholangiocarcinoma. Cholangiocarcinoma cell lines, CCKS-1 and TFK-1, were treated with transforming growth factor-beta1 (TGF-beta1), and the phenotypic changes and invasive activity were examined. Immunohistochemical analysis was performed using tissue sections of cholangiocarcinoma. In vitro, TGF-beta1 induced mesenchymal features in CCKS-1 and TFK-1 characterized by the reduction of E-cadherin and cytokeratin 19 expression and the induction of mesenchymal markers, such as vimentin and S100A4. TGF-beta1 also induced the nuclear expression of Snail, and the invasive activity was significantly increased in both cell lines. Studies using a mouse xenograft model showed that TGF-beta1 worsened the peritoneal dissemination of CCKS-1. All these changes by TGF-beta1 were inhibited by the simultaneous administration of soluble TGF-beta type II receptor. In vivo, six (16%) of 37 cholangiocarcinoma cases showed marked immunoreactivity of Snail in their nuclei. In these six cases, the immuno-expression of cytokeratin 19 was significantly reduced, and the expression of vimentin was significantly increased. The Snail expression significantly correlated with the lymph node metastasis and a poor survival rate of the patients. These results suggest that epithelial-mesenchymal transition induced by TGF-beta1/Snail activation is closely associated with the aggressive growth of cholangiocarcinoma, resulting in a poor prognosis.
上皮间质转化是癌症侵袭和转移起始的重要机制。本研究旨在阐明上皮间质转化在胆管癌进展中的作用。用转化生长因子-β1（TGF-β1）处理胆管癌细胞系 CCKS-1 和 TFK-1，检测其表型变化和侵袭活性。用免疫组织化学方法分析胆管癌组织切片。在体外，TGF-β1 诱导 CCKS-1 和 TFK-1 发生间质特征变化，表现为 E-钙黏蛋白和细胞角蛋白 19 表达减少，间充质标志物如波形蛋白和 S100A4 表达增加。TGF-β1 还诱导了 Snail 的核表达，两种细胞系的侵袭活性均显著增加。在小鼠异种移植模型中进行的研究表明，TGF-β1 加重了 CCKS-1 的腹膜扩散。TGF-β1 引起的所有这些变化都被同时给予可溶性 TGF-β 型 II 受体所抑制。在体内，37 例胆管癌中有 6 例（16%）表现出 Snail 核的显著免疫反应性。在这 6 例病例中，细胞角蛋白 19 的免疫表达显著减少，波形蛋白的表达显著增加。Snail 的表达与淋巴结转移和患者的不良生存率显著相关。这些结果表明，TGF-β1/Snail 激活诱导的上皮间质转化与胆管癌的侵袭性生长密切相关，导致不良预后。
