title: In vitro anti-myeloma activity of TRAIL-expressing adipose-derived mesenchymal stem cells.
abstract: Recently, 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 anti-myeloma activity of TRAIL-engineered AD-MSCs and provide support for a future model of a cell-based approach against MM.
authors.affiliation: Department of Internal Medicine and Oncology, University of Bari 'A. Moro', Italy.
authors.forename: Sabino
authors.initials: S
authors.lastname: Ciavarella
authors.forename: Giulia
authors.initials: G
authors.lastname: Grisendi
authors.forename: Massimo
authors.initials: M
authors.lastname: Dominici
authors.forename: Marco
authors.initials: M
authors.lastname: Tucci
authors.forename: Oronzo
authors.initials: O
authors.lastname: Brunetti
authors.forename: Franco
authors.initials: F
authors.lastname: Dammacco
authors.forename: Franco
authors.initials: F
authors.lastname: Silvestris
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D017077:Culture Media, Conditioned; D011719:Pyrazines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D000069286:Bortezomib