In vitro anti‐myeloma activity of TRAIL‐expressing adipose‐derived mesenchymal stem cells

Abstract

SummaryRecently, genetically modified mesenchymal stem cells (MSCs) have been exploited to deliver anti-cancer bio-drugs directly within the tumour mass. Here, we explored whether adipose-derived MSCs (AD-MSCs), engineered to express the pro-apoptotic ligand TRAIL (also known as TNFSF10), kill multiple myeloma (MM) cells and migrate towards MM cells in vitro. Different MM cell lines were assessed for their sensitivity to recombinant human (rh) TRAIL alone and in combination with the proteasome inhibitor bortezomib, which was shown to enhance the effect of rhTRAIL. TRAIL + -AD-MSCs were co-cultured with bortezomib-pretreated MM cells and their killing activity was evaluated in presence or absence of caspase inhibition. AD-MSC migration towards media conditioned by both myeloma cells and myeloma bone fragments was also investigated. Despite moderate MM cell sensitivity to rhTRAIL, TRAIL + -AD-MSCs in combination with bortezomib significantly induced myeloma cell death. This effect was associated with caspase-8 activation and abrogated by capsase inhibition. On the other hand, co-culture experiments were performed to evaluate whether unmodified AD-MSCs affect myeloma cell growth in vitro. AD-MSCs appeared ineffective on myeloma cell growth and showed migratory capacity towards MM cells in vitro. These data emphasize the antimyeloma activity of TRAIL-engineered AD-MSCs and provide support for a future model of a cell-based approach against MM.

A Peculiar Molecular Profile of Umbilical Cord-Mesenchymal Stromal Cells Drives Their Inhibitory Effects on Multiple Myeloma Cell Growth and Tumor Progression

“…To date, adult MSCs ''armed'' by genetic engineering have been used to target MM cells in a few pioneering cytotherapy approaches [29]. BM-MSCs induced to overexpress Fas-L or IFN-a have been successfully applied to induce apoptosis in MM cells [13,56], while we have recently proved that AD-MSCs, engineered to stably overexpress the membrane form TRAIL, trigger a remarkable apoptosis of MM cells in vitro [14], thus improving the therapeutic efficacy of TRAIL in MM. This study, however, indicates that UC-MSCs possess a constitutive ability to control malignant plasma cell growth both in vitro and in vivo by paracrine mechanisms.…”

“…Nevertheless, a suppressive activity of MSCs on MM cell growth has also been reported, both in vitro and in animal models of the human disease [13]. We have recently demonstrated that AD-MSCs stably engineered to express the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) efficiently migrate toward MM cells and exert anti-MM cytotoxicity in vitro [14], while others showed that MM-bearing SCID-rab mice injected with placenta-derived MSCs underwent dramatic inhibition of tumor growth within the bone [15].…”

Stem Cell-Based Therapies for Cancer

“…When injected into mice, AD-MSC-TRAIL migrated to tumors and induced apoptosis in tumor cells, without significant toxicities to normal tissues (Grisendi et al, 2010). In a similar study, AD-MSCs engineered to express TRAIL were found to exhibit antimyeloma activities and significantly induce myeloma cell death in vitro (Ciavarella et al, 2012).…”

Genetically Engineered Mesenchymal Stem Cells

“…When injected into mice, AD MSC-TRAIL migrated to tumors and induced apoptosis in tumor cells, without significant toxicities to normal tissues [131]. In a similar study, AD MSC engineered to express TRAIL was found to exhibit anti-myeloma activities and significantly induce myeloma cell death in vitro [132].…”