Abstract 3834
Background
MSCs are recently under intensive investigation for cell-based anti-cancer therapies and we have shown that UC-MSCs inhibit the MM cell growth in vitro. Also, UC-MSCs express chemotactic molecules that drive their migration to tumor sites and ultimately promote apoptosis by cell-to-cell cross-talk. Thus, we reasoned that UC-MSCs are suitable for gene engineering to express TRAIL in a cytotherapy approach against MM in vitro and in vivo.
Methods
UC-MSCs were transduced by a retroviral vector expressing GFP, and TRAIL under the control of IL6 promoter to induce TRAIL only in presence of IL-1α and IL-1ß secreted within the MM microenvironment. Transduced cells (92% GFP+) were assayed for TRAIL expression by q-PCR, flow cytometry, Western blot and ELISA. TRAIL+-UC-MSC apoptotic potential was tested by Annexin-V in co-cultures with MM cells or in presence of IL-1α and IL-1ß. To evaluate their in vivo anti-MM activity, we generated bone disease by intratibial injections of luminescent U266 cells in 6 week old NOD-SCID mice followed one week later by intracardiac inoculation of TRAIL+-UC-MSCs, and the tumor burden was evaluated weekly.
Results
In transduced cells, TRAIL mRNA levels were 40.000 fold higher with a concurrent 5 fold higher protein expression. TRAIL mRNA and protein levels increased when the cells were co-cultured with U266 cells, or in presence of IL-1α and IL-1ß, whereas the MM cell apoptosis after 48 hrs was 70,3 ± 3,5% compared to 20,5 ± 2,3% of control UC-MSCs. Significant reduction of MM tumor masses were detected in mice injected with TRAIL+-UC-MSCs, as compared to control mice (p
Conclusions
Our data support the TRAIL+-UC-MSCs approach to treat MM in NOD-SCID mice. Besides their migratory property to the MM microenvironment, TRAIL+-UC-MSCs reinforce their constitutive anti-MM activity by TRAIL over-expression.
Clinical trial identification
Legal entity responsible for the study
Prof. Franco Silvestris
Funding
AIRC (Associazione Italiana per la Ricerca sul Cancro)
Disclosure
All authors have declared no conflicts of interest.