Newly established tumourigenic primary human colon cancer cell lines are sensitive to TRAIL-induced apoptosis in vitro and in vivo.
Most data on the therapeutic potential of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) as well as resistance to FAS ligand (FASL) in colorectal cancer have come from in vitro studies using cell lines. To gain a clearer understanding about the susceptibility of patient tumours to TRAIL and FASL, we derived primary human cancer epithelial cells from colon cancer patients. Characterisation of primary cultures PAP60 and MIH55 determined their highly proliferating advantage, transforming capability and tumorigenicity in vitro and in vivo. Although FASL treatment appeared to cause little apoptosis only in the PAP60 primary culture, increased apoptosis independent of p53 was observed in both primary PAP60 and MIH55 and control cell lines Caco-2, HT29 and DLD-1 after treatment with SuperKiller TRAIL. Expression analysis of death receptors (DR) in the original parental tumours, the primary cultures before and after engraftment as well as the mouse xenografts, revealed a significant upregulation of both DR4 and DR5, which correlated to differences in sensitivity of the cells to TRAIL-induced apoptosis. Treating patient tumour xenograft/SCID mouse models with Killer TRAIL in vivo suppressed tumour growth. This is the first demonstration of TRAIL-induced apoptosis in characterised tumorigenic primary human cultures (in vitro) and antitumour activity in xenograft models (in vivo).
Oikonomou
E
E
Laboratory of Signal Mediated Gene Expression, Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Vasileos Konstantinou Avenue 48, 11635, Athens, Greece.
Kothonidis
K
K
Taoufik
E
E
Probert
E
E
Zografos
G
G
Nasioulas
G
G
Andera
L
L
Pintzas
A
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D053222:Fas Ligand Protein / Q000494:pharmacology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
D053222:Fas Ligand Protein; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human