Expression and Antitumor Effects of TRAIL in Human Cholangiocarcinoma

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Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)/Apo2L has been recently identified as important in promoting programmed cell death 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 receptors was determined in 13 patients with resectable intrahepatic cholangiocarcinoma. Cellular effects of TRAIL in promoting apoptosis of human cholangiocarcinoma cells were analyzed after exposure to recombinant protein, as well as following transfection with a cDNA expression construct. In vivo effects of TRAIL on tumor growth were investigated after subcutaneous injection of cholangiocarcinoma cells into nude mice. Analysis of 13 clinical and tissue samples revealed that TRAIL receptors containing the death domain were present in all cholangiocarcinomas as well as paired normal hepatic tissues derived from surgically resected margins. In contrast, 7 tumors did not express the TRAIL decoy receptors lacking the death domain; such receptors were detectable in all of the normal hepatic tissue counterparts. Recombinant 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 introduction of the generalized lymphoproliferative disease-like mutation in the TRAIL protein. Finally, in vivo administration of recombinant TRAIL substantially inhibited subcutaneous tumor growth of human cholangiocarcinoma cells. Induction of apoptosis in tumor cells is possible with a biologically active TRAIL, and suggests that this cytokine is a promising antitumor agent against human cholangiocarcinoma.