Book of abstract 2008

Human colon cancer xenografts are sensitive to TRAIL induced
apoptosis in vivo via death receptor upregulation
Eftychia Oikonomou1, Georgios Zografos2, Ladislav Andera3, Alexandros Pintzas1
1Laboratory of Signal Mediated Gene Expression, Institute of Biological Research and Biotechnology,
National Hellenic Research Foundation, Vasileos Konstantinou Ave. 48, 11635, Athens, Greece; 23 rd
Dept. of Surgery, G. Genimatas General Hospital of Athens, Mesogion Ave. 154, 15669, Athens, Greece;
3Laboratory of Cell Signaling and Apoptosis, Institute of Molecular Genetics, Czech Academy of Sciences,
Videnska 1083, CZ-14220 Prague 4, Czech Republic
The tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a
member of TNF family, is particularly interesting for its unique properties to induce death
of cancer cells (including colon) while sparing most normal cells. Controversial results
exist about the sensitive of primary cells to TRAIL, therefore a better insight is required.
Primary human cancer epithelial cells were derived from patients with colon cancer at
different stages and characterised in vitro and in vivo. Both primary cell lines, PAP60 and
MIH55, were found to be highly proliferative with increased transforming capability and
tumourigenicity as concluded by their ability to form tumour in SCID mice. Increased
apoptosis independent of p53 was observed in both primary PAP60 and MIH55 cell lines
after treatment with SuperKiller TRAIL as detected by an increase in PARP cleavage and
activation of caspase-3. Expression analysis of death receptors (DR) by means of RT-PCR
and flow cytometry performed 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, with the latter being the most differentially expressed. DR
expression pattern analysis correlated to differences in sensitivity of the cells to TRAIL
induced apoptosis. Treating patient tumour xenograft/ SCID mouse models with Killer
TRAIL in vivo for 5 consecutive days suppressed tumour growth and upregulation of DR4
and DR5 that directly correlated to its antitumour activity. This is the first demonstration
of TRAIL induced apoptosis in characterised tumourigenic primary human cultures (in
vitro) followed by the antitumour activity in xenograft models (in vivo).
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