title: TNF-Related Apoptosis-Inducing Ligand (TRAIL)-Armed Exosomes Deliver Proapoptotic Signals to Tumor Site.
abstract: Exosomes deliver signals to target cells and could thus be exploited as an innovative therapeutic tool. We investigated the ability of membrane TRAIL-armed exosomes to deliver proapoptotic signals to cancer cells and mediate growth inhibition in different tumor models.
  
  
  
  K562 cells, transduced with lentiviral human membrane TRAIL, were used for the production of TRAIL(+) exosomes, which were studied by nanoparticle tracking analysis, cytofluorimetry, immunoelectronmicroscopy, Western blot, and ELISA. In vitro, TRAIL(+) exosomes induced more pronounced apoptosis (detected by Annexin V/propidium iodide and activated caspase-3) in TRAIL-death receptor (DR)5(+) cells (SUDHL4 lymphoma and INT12 melanoma), with respect to the DR5(-)DR4(+)KMS11 multiple myeloma. Intratumor injection of TRAIL(+) exosomes, but not mock exosomes, induced growth inhibition of SUDHL4 (68%) and INT12 (51%), and necrosis in KMS11 tumors. After rapid blood clearance, systemically administered TRAIL(+) exosomes accumulated in the liver, lungs, and spleen and homed to the tumor site, leading to a significant reduction of tumor growth (58%) in SUDHL4-bearing mice. The treatment of INT12-bearing animals promoted tumor necrosis and a not statistically significant tumor volume reduction. In KMS11-bearing mice, despite massive perivascular necrosis, no significant tumor growth inhibition was detected.
  
  
  
  TRAIL-armed exosomes can induce apoptosis in cancer cells and control tumor progression in vivo Therapeutic efficacy was particularly evident in intratumor setting, while depended on tumor model upon systemic administration. Thanks to their ability to deliver multiple signals, exosomes thus represent a promising therapeutic tool in cancer. Clin Cancer Res; 22(14); 3499-512. ©2016 AACR.
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Licia
authors.initials: L
authors.lastname: Rivoltini
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Molecular Immunology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Chiodoni
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Squarcina
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Tortoreto
authors.affiliation: Consorzio M.I.A., Microscopy and Image Analysis, Università degli Studi di Milano Bicocca, Milan, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Villa
authors.affiliation: Consorzio M.I.A., Microscopy and Image Analysis, Università degli Studi di Milano Bicocca, Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Vergani
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Maja
authors.initials: M
authors.lastname: Bürdek
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Molecular Immunology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Botti
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Molecular Immunology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Ivano
authors.initials: I
authors.lastname: Arioli
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Agata
authors.initials: A
authors.lastname: Cova
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Molecular Immunology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Mauri
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Vergani
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bianchi
authors.affiliation: Consorzio M.I.A., Microscopy and Image Analysis, Università degli Studi di Milano Bicocca, Milan, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Della Mina
authors.affiliation: Department of Clinical Sciences and Community Health, EPIGET, Epidemiology, Epigenetics, and Toxicology Laboratory, Università degli Studi di Milano, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cantone
authors.affiliation: Department of Clinical Sciences and Community Health, EPIGET, Epidemiology, Epigenetics, and Toxicology Laboratory, Università degli Studi di Milano, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bollati
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.affiliation: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Alessandro Massimo
authors.initials: AM
authors.lastname: Gianni
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Molecular Immunology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Mario Paolo
authors.initials: MP
authors.lastname: Colombo
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. veronica.huber@istitutotumori.mi.it.
authors.forename: Veronica
authors.initials: V
authors.lastname: Huber
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D006801:Humans; D020014:K562 Cells; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009336:Necrosis / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D053148:Caspase 3