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      Exosomes derived from mesenchymal stem cells enhance radiotherapy-induced cell death in tumor and metastatic tumor foci

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          Abstract

          Background

          We have recently shown that radiotherapy may not only be a successful local and regional treatment but, when combined with MSCs, may also be a novel systemic cancer therapy. This study aimed to investigate the role of exosomes derived from irradiated MSCs in the delay of tumor growth and metastasis after treatment with MSC + radiotherapy (RT).

          Methods

          We have measured tumor growth and metastasis formation, of subcutaneous human melanoma A375 xenografts on NOD/SCID-gamma mice, and the response of tumors to treatment with radiotherapy (2 Gy), mesenchymal cells (MSC), mesenchymal cells plus radiotherapy, and without any treatment. Using proteomic analysis, we studied the cargo of the exosomes released by the MSC treated with 2 Gy, compared with the cargo of exosomes released by MSC without treatment.

          Results

          The tumor cell loss rates found after treatment with the combination of MSC and RT and for exclusive RT, were: 44.4% % and 12,1%, respectively. Concomitant and adjuvant use of RT and MSC, increased the mice surviving time 22,5% in this group, with regard to the group of mice treated with exclusive RT and in a 45,3% respect control group. Moreover, the number of metastatic foci found in the internal organs of the mice treated with MSC + RT was 60% less than the mice group treated with RT alone. We reasoned that the exosome secreted by the MSC, could be implicated in tumor growth delay and metastasis control after treatment.

          Conclusions

          Our results show that exosomes derived form MSCs, combined with radiotherapy, are determinant in the enhancement of radiation effects observed in the control of metastatic spread of melanoma cells and suggest that exosome-derived factors could be involved in the bystander, and abscopal effects found after treatment of the tumors with RT plus MSC. Radiotherapy itself may not be systemic, although it might contribute to a systemic effect when used in combination with mesenchymal stem cells owing the ability of irradiated MSCs-derived exosomes to increase the control of tumor growth and metastasis.

          Electronic supplementary material

          The online version of this article (10.1186/s12943-018-0867-0) contains supplementary material, which is available to authorized users.

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          Most cited references29

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          Mesenchymal stem cell exosomes.

          MSCs are an extensively used cell type in clinical trials today. The initial rationale for their clinical testing was based on their differentiation potential. However, the lack of correlation between functional improvement and cell engraftment or differentiation at the site of injury has led to the proposal that MSCs exert their effects not through their differentiation potential but through their secreted product, more specifically, exosomes, a type of extracellular vesicle. We propose here that MSC exosomes function as an extension of MSC's biological role as tissue stromal support cells. Like their cell source, MSC exosomes help maintain tissue homeostasis for optimal tissue function. They target housekeeping biological processes that operate ubiquitously in all tissues and are critical in maintaining tissue homeostasis, enabling cells to recover critical cellular functions and begin repair and regeneration. This hypothesis provides a rationale for the therapeutic efficacy of MSCs and their secreted exosomes in a wide spectrum of diseases. Here, we give a brief introduction of the biogenesis of MSC exosomes, review their physiological functions and highlight some of their biochemical potential to illustrate how MSC exosomes could restore tissue homeostasis leading to tissue recovery and repair.
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            Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha.

            We previously reported the purification, culture-expansion, and osteogenic differentiation potential of mesenchymal progenitor cells (MPCs) derived from human bone marrow. As a first step to establishing the phenotypic characteristics of MPCs, we reported on the identification of unique cell surface proteins which were detected with monoclonal antibodies. In this study, the phenotypic characterization of human marrow-derived MPCs is further established through the identification of a cytokine expression profile under standardized growth medium conditions and in the presence of regulators of the osteogenic and stromal cell lineages, dexamethasone and interleukin-1 alpha (IL-1 alpha), respectively. Constitutively expressed cytokines in this growth phase include G-CSF, SCF, LIF, M-CSF, IL-6, and IL-11, while GM-CSF, IL-3, TGF-beta 2 and OSM were not detected in the growth medium. Exposure of cells in growth medium to dexamethasone resulted in a decrease in the expression of LIF, IL-6, and IL-11. These cytokines have been reported to exert influence on the differentiation of cells derived from the bone marrow stroma through target cell receptors that utilize gp130-associated signal transduction pathways. Dexamethasone had no effect on the other cytokines expressed under growth medium conditions and was not observed to increase the expression of any of the cytokines measured in this study. In contrast, IL-1 alpha increased the expression of G-CSF, M-CSF, LIF, IL-6 and IL-11 and induced the expression of GM-CSF. IL-1 alpha had no effect on SCF expression and was not observed to decrease the production of any of the cytokines assayed. These data indicate that MPCs exhibit a distinct cytokine expression profile. We interpret this cytokine profile to suggest that MPCs serve specific supportive functions in the microenvironment of bone marrow. MPCs provide inductive and regulatory information which are consistent with the ability to support hematopoiesis, and also supply autocrine, paracrine, and juxtacrine factors that influence the cells of the marrow microenvironment itself. In addition, the cytokine profiles expressed by MPCs, in response to dexamethasone and IL-1 alpha, identify specific cytokines whose levels of expression change as MPCs differentiate or modulate their phenotype during osteogenic or stromagenic lineage entrance/progression.
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              Mesenchymal stem cells engineered for cancer therapy.

              Recent pre-clinical and clinical studies have shown that stem cell-based therapies hold tremendous promise for the treatment of human disease. Mesenchymal stem cells (MSC) are emerging as promising anti-cancer agents which have an enormous potential to be utilized to treat a number of different cancer types. MSC have inherent tumor-trophic migratory properties, which allows them to serve as vehicles for delivering effective, targeted therapy to isolated tumors and metastatic disease. MSC have been readily engineered to express anti-proliferative, pro-apoptotic, anti-angiogenic agents that specifically target different cancer types. Many of these strategies have been validated in a wide range of studies evaluating treatment feasibility or efficacy, as well as establishing methods for real-time monitoring of stem cell migration in vivo for optimal therapy surveillance and accelerated development. This review aims to provide an in depth status of current MSC-based cancer therapies, as well as the prospects for their clinical translation. Copyright © 2011 Elsevier B.V. All rights reserved.
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                Author and article information

                Contributors
                vafarias@ugr.es
                fovalle@ugr.es
                s.serrano@ipb.csic.es
                per.anderson@genyo.es
                eandres@ipb.csic.es
                jjpenalver@ugr.es
                aris.tovar@gmail.com
                anieto@ugr.es
                asantos@ugr.es
                francisco.martin@genyo.es
                jose.exposito.sspa@juntadeandalucia.es
                joliver@ipb.csic.es
                jmrdar@ugr.es
                Journal
                Mol Cancer
                Mol. Cancer
                Molecular Cancer
                BioMed Central (London )
                1476-4598
                15 August 2018
                15 August 2018
                2018
                : 17
                : 122
                Affiliations
                [1 ]ISNI 0000 0004 0500 8423, GRID grid.418805.0, Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, , PTS Granada and CIBERONC (Instituto de Salud Carlos III), ; 18016 Granada, Spain
                [2 ]ISNI 0000 0004 0500 8423, GRID grid.418805.0, Instituto de Parasitología y Biomedicina “López Neyra”, Consejo Superior de Investigaciones Científicas, , PTS Granada, 18016 and CIBERONC (Instituto de Salud Carlos III), ; Granada, Spain
                [3 ]ISNI 0000000121678994, GRID grid.4489.1, Departamento de Anatomía Patológica, Facultad de Medicina, , Universidad de Granada, ; PTS Granada, 18016 Granada, Spain
                [4 ]ISNI 0000000121678994, GRID grid.4489.1, GENYO, Centre for Genomics and Oncological Research, , Pfizer/Universidad de Granada/Junta de Andalucía, PTS Granada, ; 18016 Granada, Spain
                [5 ]ISNI 0000000121678994, GRID grid.4489.1, Unidad de radiología experimental, Centro de Instrumentación Científica, Centro de Investigación Biomédica, , Universidad de Granada, ; PTS Granada, 18016 Granada, Spain
                [6 ]GRID grid.418355.e, Complejo Hospitalario de Granada, , Servicio Andaluz de Salud, PTS Granada, ; 18016 Granada, Spain
                [7 ]ISNI 0000000121678994, GRID grid.4489.1, Unidad de experimentación animal, Centro de Instrumentación Científica, Centro de Investigación Biomédica, , Universidad de Granada, ; PTS Granada, 18016 Granada, Spain
                [8 ]ISNI 0000000121678994, GRID grid.4489.1, Unidad de microscopia, Centro de Instrumentación Científica, Centro de Investigación Biomédica, , Universidad de Granada, PTS Granada, ; 18016 Granada, Spain
                Article
                867
                10.1186/s12943-018-0867-0
                6094906
                30111323
                89aa1b4f-2b03-4afc-a827-1aa6848aef46
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 16 November 2017
                : 31 July 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100007136, Secretaría de Estado de Investigación, Desarrollo e Innovación;
                Award ID: SAF2012-40011-C02-02 to JMRdA
                Award ID: SAF2012-40011-C02-01
                Award ID: SAF2015-70520- R
                Funded by: FundRef http://dx.doi.org/10.13039/501100003593, Conselho Nacional de Desenvolvimento Científico e Tecnológico;
                Funded by: FundRef http://dx.doi.org/10.13039/501100006461, Agencia de Innovación y Desarrollo de Andalucía;
                Award ID: P12-CTS-383
                Funded by: FundRef http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III;
                Award ID: RD12/0036/0026
                Award ID: CB16/12/00421
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Oncology & Radiotherapy
                experimental radiotherapy,bystander effect,abscopal effect,mesenchymal stem cells,cell therapy,metastasis spread,proteomic analysis,annexin a1,melanoma xenograft

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