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Rat TNF-Related Apoptosis-Inducing Ligand (rTRAIL)-Expressing Rat-Adipose-Derived Stem Cells (rADSC) Moderately Limit
Wiktor Pascal1, Mateusz Gotowiec1,2, Antoni Smoliński1
1Department of Methodology, Medical University of Warsaw, 1b Banacha Street, 02-091 Warsaw, Poland.
Background:
Adipose-derived stem cells (ADSCs) are readily harvestable, tumour-homing cells that have been engineered as vehicles for antitumour agents. TNF-related apoptosis-inducing ligand (TRAIL) selectively triggers apoptosis in many cancer cells through death receptors DR4/DR5, while sparing most healthy cells. To date, only human TRAIL has been studied in such delivery systems; a fully homologous rat model (rat TRAIL delivered by rat ADSC) has not been tested, despite being essential for future syngeneic in vivo studies.
Methods:
In this pilot, exploratory study, we lentivirally transduced rat ADSC (rADSC) to express myc-tagged rat TRAIL, characterized the expression of TRAIL-pathway components in rADSC and three rat mammary carcinoma cell lines (RBA, HH-16.cl.4, SHZ-88) at the mRNA and protein levels, and assessed the antitumour effect of rTRAIL-rADSC using recombinant TRAIL dose-response, supernatant transfer, direct co-culture, and nine-day insert co-culture assays.
Results:
rADSCs were successfully transduced and produced cell-associated rat TRAIL (66.2 pg per 50,000 cells versus 4.4-5.7 pg in controls; p < 0.05); this ELISA measures total cell-associated (intracellular plus membrane-anchored) TRAIL rather than soluble TRAIL. rADSC expressed markedly higher levels of the decoy molecule osteoprotegerin and of DR4/DR5 than the cancer cells. Two of three cancer lines (RBA, HH-16.cl.4) were susceptible to rat TRAIL, and rTRAIL-rADSC reduced their growth and increased the proportion of dead cells, with morphological features compatible with both apoptosis and necrosis, most markedly in HH-16.cl.4; the effect was separable from the empty-vector control in HH-16.cl.4 but not in RBA.
Conclusions:
In this pilot study, homologous rat TRAIL delivered by rADSC is feasible and increases cell death in TRAIL-susceptible rat mammary cancer cells, but the effect is moderate at most, contact-dependent, and in one of two susceptible lines not attributable to TRAIL itself. These findings define both the potential and the limitations of a fully translational rat model of TRAIL-based biologic brachytherapy and provide a foundation for future in vivo studies.
