The Significance of Epithelial-Mesenchymal Transition (EMT) in Extrahepatic Bile Duct Carcinoma: A Clinicopathologic Study of 122 Cases
Takeo Nitta, Tomoko Mitsuhashi, Yutaka Hatanaka, Kanako C Hatanaka, Satoshi Hirano, Yoshihiro Matsuno. Hokkaido University Hospital, Sapporo, Hokkaido, Japan; Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan
Background: EMT is characterized by a loss of cell adhesion and increased cell mobility due to cells gaining a mesenchymal phenotype, and is an important mechanism behind initiation of cancer invasion and metastasis. Although EMT has been documented in a large number of cancers, most studies have used in vitro systems that employ cell lines and focused on the detailed mechanism of EMT, identifying a number of transcription factors (TFs) and signaling pathways involved. Therefore, little is known about the exact pattern of EMT in patient cancer tissues or the clinical importance of EMT itself in extrahepatic bile duct carcinoma (EHBDC). This study was performed to clarify the involvement of EMT in the progression of EHBDC.
Design: A total of 122 cases of surgically resected EHBDC were examined. Immunohistochemical studies of the proteins known to be involved in EMT in various cancers (E-cadherin, CK19, S100A4, vimentin, fibronection, N-cadherin, snail, slug, twist, zeb1 and zeb2) were performed using tissue microarray (TMA) (each consisted of a tumor center, an invasive front, and non-neoplastic bile ducts). Selected markers (E-cadherin, S100A4, zeb1 and zeb2) were studied also in 10 representative cases using whole sections to evaluate the tumor heterogeneity. The antibodies against TFs were validated using several cancer cell lines as positive controls. Survival curves were calculated by the Kaplan-Meier method and evaluated using log-rank test.
Results: The EMT-related proteins were expressed in the stroma and epithelium of a subset of EHBDC. The expression of these markers in the epithelium was not related to the tumor differentiation. The differences between the tumor center and the invasive front were not so evident. High EMT evaluated by the loss of epithelial E-cadherin was associated with reduced overall survival (ROS) in both the tumor center and the invasive front (p=0.0337 and p=0.025, respectively). Other markers such as S100A4, zeb1 and zeb2 were not significantly associated with ROS.
Conclusions: This is the first comprehensive study of EMT in tissues from patients with EHBDCs. A subset of EHBDCs is expected to lose their epithelial phenotype and sequentially acquire a mesenchymal phenotype. Although little has been known about the clinical significance of the different phenotypes of EMT in EHBDCs, the loss of epithelial E-cadherin might be a significant EMT-related event to predict a poor prognosis of EHBDC.
Wednesday, March 6, 2013 9:30 AM
Poster Session V # 107, Wednesday Morning