Abstract
BackgroundCholangiocarcinoma is the second most common primary hepatic malignancy worldwide. The incidence of intrahepatic cholangiocarcinoma in the UK has steadily increased over the past 40 years. The main treatment is chemotherapy, and 5-year survival after radical surgery is only 25%. The carcinogenic mechanisms involved in cholangiocarcinoma remain elusive. The fibroblast growth factor-inducible 14 (Fn14)/tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) receptor-ligand system has been shown to be of importance in cellular proliferation and tumour angiogenesis in hepatocellular carcinoma. The aim of this study was to demonstrate the expression of Fn14 and TWEAK in cholangiocarcinoma and determine the functional significance of Fn14/TWEAK interaction on neoplastic cholangiocytes. MethodsHuman liver samples were obtained with consent from the Queen Elizabeth Hospital liver transplant programme. Sections were stained for Fn14 with immunohistochemical techniques. Expression of Fn14 on a cholangiocarcinoma cell line (CC-LP-1) stimulated with TNFα, interferon γ and fibroblast growth factor (FGF) basic was established quantitatively with flow cytometry. Stimulated CC-LP-1 were exposed to different concentrations of TWEAK for 24h. Apoptosis, necrosis, autophagy, and reactive oxygen species production at 24 h were determined by flow cytometry using annexin, 7AAD, dansylcadaverine, and dichlorofluorescein assays, respectively. Proliferation was determined with Ki69 nuclear staining. FindingsImmunohistochemistry revealed Fn14 on the intrahepatic malignant small bile ducts in cholangiocarcinoma. Exposure of neoplastic cholangiocytes to TWEAK for 24h induced necrosis and reduced apoptosis in FGF-activated neoplastic cholangiocytes in a dose-dependent manner. InterpretationFn14 is expressed on neoplastic cholangiocytes in intrahepatic cholangiocarcinoma. Activation of the Fn14/TWEAK receptor-ligand system induces necrosis. The role of Fn14/TWEAK in cholangiocarcinoma needs further investigation to ascertain the mechanisms involved and outcome on overall tumour viability. FundingUK Medical Research Council.
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