Expression and antitumor effects of TRAIL in human cholangiocarcinoma

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)/Apo2L has been recently identified as important in promoting programmed cell dea th in breast and colon adenocarcinomas. In this study, we investigated the expression and therapeutic potential of TRAIL in cholangiocarcinoma, one of the most devastating human hepatic malignancies. Expression of TRAIL recep tors was determined in 13 patients with resectable intrahepatic cholangioca rcinoma. Cellular effects of TRAIL in promoting apoptosis of human cholangi ocarcinoma cells were analyzed after exposure to recombinant protein, as we ll as following transfection with a cDNA expression construct. In vivo effe cts of TRAIL on tumor growth were investigated after subcutaneous injection of cholangiocarcinoma cells into nude mice. Analysis of 13 clinical and ti ssue samples revealed that TRAIL receptors containing the death domain were present in all cholangiocarcinomas as well as paired normal hepatic tissue s derived from surgically resected margins. In contrast, 7 tumors did not e xpress the TRAIL decoy receptors lacking the death domain; such receptors w ere detectable in all of the normal hepatic tissue counterparts. Recombinan t TRAIL induced extensive programmed cell death in cholangiocarcinoma cell lines lacking decoy receptor expression. Transfection of the ectodomain of TRAIL also induced cellular apoptosis; this effect was abolished by introdu ction of the generalized lymphoproliferative disease-like mutation in the T RAIL protein. Finally, in vivo administration of recombinant TRAIL substant ially inhibited subcutaneous tumor growth of human cholangiocarcinoma cells . Induction of apoptosis in tumor cells is possible with a biologically act ive TRAIL, and suggests that this cytokine is a promising antitumor agent a gainst human cholangiocarcinoma.