title: Adipose-derived mesenchymal stem cells as stable source of tumor necrosis factor-related apoptosis-inducing ligand delivery for cancer therapy.
abstract: Adipose-derived mesenchymal stromal/stem cells (AD-MSC) may offer efficient tools for cell-based gene therapy approaches. In this study, we evaluated whether AD-MSC could deliver proapoptotic molecules for cancer treatment. Human AD-MSCs were isolated and transduced with a retroviral vector encoding full-length human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a proapoptotic ligand that induces apoptosis in a variety of human cancers but not normal tissues. Although several studies have documented the antitumor activity of recombinant human TRAIL, its use in vivo is limited by a short half-life in plasma due to a rapid clearance by the kidney. We found that these limitations can be overcome using stably transduced AD-MSC, which could serve as a constant source of TRAIL production. AD-MSC armed with TRAIL targeted a variety of tumor cell lines in vitro, including human cervical carcinoma, pancreatic cancer, colon cancer, and, in combination with bortezomib, TRAIL-resistant breast cancer cells. Killing activity was associated with activation of caspase-8 as expected. When injected i.v. or s.c. into mice, AD-MSC armed with TRAIL localized into tumors and mediated apoptosis without significant apparent toxicities to normal tissues. Collectively, our results provide preclinical support for a model of TRAIL-based cancer therapy relying on the use of adipose-derived mesenchymal progenitors as cellular vectors.
authors.affiliation: Department of Oncology, Hematology and Respiratory Diseases, Plastic Surgery Unit, University-Hospital of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Grisendi
authors.forename: Rita
authors.initials: R
authors.lastname: Bussolari
authors.forename: Luigi
authors.initials: L
authors.lastname: Cafarelli
authors.forename: Istvan
authors.initials: I
authors.lastname: Petak
authors.forename: Valeria
authors.initials: V
authors.lastname: Rasini
authors.forename: Elena
authors.initials: E
authors.lastname: Veronesi
authors.forename: Giorgio
authors.initials: G
authors.lastname: De Santis
authors.forename: Carlotta
authors.initials: C
authors.lastname: Spano
authors.forename: Mara
authors.initials: M
authors.lastname: Tagliazzucchi
authors.forename: Helga
authors.initials: H
authors.lastname: Barti-Juhasz
authors.forename: Laura
authors.initials: L
authors.lastname: Scarabelli
authors.forename: Franco
authors.initials: F
authors.lastname: Bambi
authors.forename: Antonio
authors.initials: A
authors.lastname: Frassoldati
authors.forename: Giulio
authors.initials: G
authors.lastname: Rossi
authors.forename: Christian
authors.initials: C
authors.lastname: Casali
authors.forename: Uliano
authors.initials: U
authors.lastname: Morandi
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Horwitz
authors.forename: Paolo
authors.initials: P
authors.lastname: Paolucci
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Conte
authors.forename: Massimo
authors.initials: M
authors.lastname: Dominici
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D053181:Caspase 8 / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology; D018920:Coculture Techniques; D004789:Enzyme Activation; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D011719:Pyrazines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D014161:Transduction, Genetic; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D000069286:Bortezomib; D053181:Caspase 8