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.