TNF-Related Apoptosis-Inducing Ligand (TRAIL)–Armed Exosomes Deliver Proapoptotic Signals to Tumor Site

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 þ exosomes, which were studied by nanoparticle tracking analysis, cytofluorimetry, immunoelectronmicroscopy, Western blot, and ELISA. In vitro, TRAIL þ exosomes induced more pronounced apoptosis (detected by Annexin V/ propidium iodide and activated caspase-3) in TRAIL-death receptor (DR)5 þ cells (SUDHL4 lymphoma and INT12 melanoma), with respect to the DR5 À DR4 þ KMS11 multiple myeloma. Intratumor injection of TRAIL þ 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 þ 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.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.

Anticancer effect of icaritin inhibits cell growth of colon cancer through reactive oxygen species, Bcl-2 and cyclin D1/E signaling

“…Induction of cell apoptosis is the main type of tumor treatment (7). Regulation of the intracellular redox state determines the cell's survival fate (8).…”

Engineering Exosomes for Cancer Therapy

“…A group recently transduced k562 leukaemia cells with human TRAIL to create TRAIL+ secreted exosomes. In vitro TRAIL+ exosomes were found to induce apoptosis in melanoma and lymphoma cell lines [30]. In vivo, the exosomes homed to the site of the tumour with accumulation in the lungs, liver and spleen.…”

“…In tumour bearing mice, it was found that the engineered exosomes induced necrosis and vessel damage in the myeloma and melanoma tumour groups, but no significant reduction in tumour volume was observed. However, the lymphoma group had a significant reduction of tumour growth when compared to the control groups [30]. It was suggested by the authors that the reasoning for the results observed were that only a fraction of the administered exosomes actually homed to the site of the tumour, with large amounts becoming trapped in major organs.…”

Targeting Immune Regulatory Networks to Counteract Immune Suppression in Cancer

“…Our unit has recently tested the efficacy of antitumor activity of exosomes originating from tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-transduced cells and carrying membrane TRAIL in preclinical studies [82]. Apart from targeting tumor cells, the proapoptotic activity of TRAIL exosomes could be exploited to limit immune suppression by eliminating TRAIL death receptor-expressing MDSCs [83].…”