TRAIL inhibits tumor growth but is nontoxic to human hepatocytes in chimeric mice.
Tumor necrosis factor (TNF) family ligand TNF-alpha and Fas ligand (FasL) can trigger apoptosis in solid tumors, but their clinical usage has been limited by hepatotoxicity. TNF-related apoptosis-inducing ligand (TRAIL) is a newly identified member of the TNF family, and its clinical application currently is under a similar debate. Here, we report a recombinant soluble form of human TRAIL (114 to 281 amino acids) that induces apoptosis in tumor cells but not human hepatocytes. We first isolated human hepatocytes from patients and showed that the human hepatocytes expressed Fas but no TRAIL death receptor DR4 and little DR5 on the cell surface. Antibody cross-linked FasL, but not TRAIL, triggered apoptosis of the human hepatocytes through cleavage of caspases. We then examined TRAIL hepatotoxicity in severe combined immunodeficient/Alb-uPA chimeric mice harboring human hepatocytes. Intravenous injection of FasL, but not TRAIL, caused apoptotic death of human hepatocytes within the chimeric liver, thus killing the mice. Finally, we showed that repeated intraperitoneal injections of TRAIL inhibited intraperitoneal and subcutaneous tumor growth without inducing apoptosis in human hepatocytes in these chimeric mice. The results indicate that the recombinant soluble human TRAIL has a profound apoptotic effect on tumor cells but is nontoxic to human hepatocytes in vitro and in vivo.
Hao
Chunhai
C
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada. chao@emory.edu
Song
Jin H
JH
Hsi
Belinda
B
Lewis
Jamie
J
Song
Doyoun K
DK
Petruk
Kenneth C
KC
Tyrrell
David L J
DL
Kneteman
Norman M
NM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D048708:Cell Growth Processes / Q000187:drug effects; D017690:Cell Transplantation; D002678:Chimera; D053222:Fas Ligand Protein; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000637:transplantation; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000494:pharmacology / Q000633:toxicity; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000633:toxicity
D051017:Apoptosis Regulatory Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha