TNF-related apoptosis-inducing ligand (trail)-armed exosomes deliver proapoptotic signals to tumor site

Licia Rivoltini, Claudia Chiodoni, Paola Squarcina, Monica Livia Tortoreto, Antonello Villa, Barbara Vergani, Maja Bürdek, Laura Botti, Ivano Arioli, Agata Cova, Giorgio Mauri, Elisabetta Vergani, Beatrice Bianchi, Pamela Della Mina, Laura Cantone, Valentina Bollati, Nadia Zaffaroni, Alessandro Massimo Gianni, Mario Paolo Colombo, Veronica Huber

Research output: Contribution to journalArticle

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Abstract

Purpose: 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. Experimental Methods and Results: 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 accumulatedintheliver,lungs,andspleenandhomedtothetumor 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)3499-3512
Number of pages14
JournalClinical Cancer Research
Volume22
Issue number14
DOIs
Publication statusPublished - Jul 15 2016

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TNF-Related Apoptosis-Inducing Ligand
Exosomes
Neoplasms
TNF-Related Apoptosis-Inducing Ligand Receptors
Necrosis
Growth
Apoptosis
Membranes
K562 Cells
Propidium
Annexin A5
Therapeutics
Tumor Burden
Multiple Myeloma
Caspase 3
Nanoparticles
Melanoma
Lymphoma
Western Blotting
Enzyme-Linked Immunosorbent Assay

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

TNF-related apoptosis-inducing ligand (trail)-armed exosomes deliver proapoptotic signals to tumor site. / Rivoltini, Licia; Chiodoni, Claudia; Squarcina, Paola; Tortoreto, Monica Livia; Villa, Antonello; Vergani, Barbara; Bürdek, Maja; Botti, Laura; Arioli, Ivano; Cova, Agata; Mauri, Giorgio; Vergani, Elisabetta; Bianchi, Beatrice; Mina, Pamela Della; Cantone, Laura; Bollati, Valentina; Zaffaroni, Nadia; Gianni, Alessandro Massimo; Colombo, Mario Paolo; Huber, Veronica.

In: Clinical Cancer Research, Vol. 22, No. 14, 15.07.2016, p. 3499-3512.

Research output: Contribution to journalArticle

Rivoltini, Licia ; Chiodoni, Claudia ; Squarcina, Paola ; Tortoreto, Monica Livia ; Villa, Antonello ; Vergani, Barbara ; Bürdek, Maja ; Botti, Laura ; Arioli, Ivano ; Cova, Agata ; Mauri, Giorgio ; Vergani, Elisabetta ; Bianchi, Beatrice ; Mina, Pamela Della ; Cantone, Laura ; Bollati, Valentina ; Zaffaroni, Nadia ; Gianni, Alessandro Massimo ; Colombo, Mario Paolo ; Huber, Veronica. / TNF-related apoptosis-inducing ligand (trail)-armed exosomes deliver proapoptotic signals to tumor site. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 14. pp. 3499-3512.
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abstract = "Purpose: 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. Experimental Methods and Results: 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 accumulatedintheliver,lungs,andspleenandhomedtothetumor 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. Conclusions: 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.",
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AU - Rivoltini, Licia

AU - Chiodoni, Claudia

AU - Squarcina, Paola

AU - Tortoreto, Monica Livia

AU - Villa, Antonello

AU - Vergani, Barbara

AU - Bürdek, Maja

AU - Botti, Laura

AU - Arioli, Ivano

AU - Cova, Agata

AU - Mauri, Giorgio

AU - Vergani, Elisabetta

AU - Bianchi, Beatrice

AU - Mina, Pamela Della

AU - Cantone, Laura

AU - Bollati, Valentina

AU - Zaffaroni, Nadia

AU - Gianni, Alessandro Massimo

AU - Colombo, Mario Paolo

AU - Huber, Veronica

PY - 2016/7/15

Y1 - 2016/7/15

N2 - Purpose: 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. Experimental Methods and Results: 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 accumulatedintheliver,lungs,andspleenandhomedtothetumor 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. Conclusions: 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.

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