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Mesenchymal Stem Cells Promote Metastasis of Lung Cancer Cells by Downregulating Systemic Antitumor Immune Response

Since majority of systemically administered mesenchymal stem cells (MSCs) become entrapped within the lungs, we used metastatic model of lung cancer, induced by intravenous injection of Lewis lung cancer 1 (LLC1) cells, to investigate the molecular mechanisms involved in MSC-mediated modulation of m...

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Autores principales: Gazdic, Marina, Simovic Markovic, Bojana, Jovicic, Nemanja, Misirkic-Marjanovic, Maja, Djonov, Valentin, Jakovljevic, Vladimir, Arsenijevic, Nebojsa, Lukic, Miodrag L., Volarevic, Vladislav
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534320/
https://www.ncbi.nlm.nih.gov/pubmed/28798777
http://dx.doi.org/10.1155/2017/6294717
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author Gazdic, Marina
Simovic Markovic, Bojana
Jovicic, Nemanja
Misirkic-Marjanovic, Maja
Djonov, Valentin
Jakovljevic, Vladimir
Arsenijevic, Nebojsa
Lukic, Miodrag L.
Volarevic, Vladislav
author_facet Gazdic, Marina
Simovic Markovic, Bojana
Jovicic, Nemanja
Misirkic-Marjanovic, Maja
Djonov, Valentin
Jakovljevic, Vladimir
Arsenijevic, Nebojsa
Lukic, Miodrag L.
Volarevic, Vladislav
author_sort Gazdic, Marina
collection PubMed
description Since majority of systemically administered mesenchymal stem cells (MSCs) become entrapped within the lungs, we used metastatic model of lung cancer, induced by intravenous injection of Lewis lung cancer 1 (LLC1) cells, to investigate the molecular mechanisms involved in MSC-mediated modulation of metastasis. MSCs significantly augmented lung cancer metastasis, attenuate concentrations of proinflammatory cytokines (TNF-α, IL-17), and increase levels of immunosuppressive IL-10, nitric oxide, and kynurenine in sera of LLC1-treated mice. MSCs profoundly reduced infiltration of macrophages, TNF-α-producing dendritic cells (DCs), TNF-α-, and IL-17-producing CD4+ T cells but increased IL-10-producing CD4+ T lymphocytes in the lungs of tumor-bearing animals. The total number of lung-infiltrated, cytotoxic FasL, perforin-expressing, TNF-α-, and IL-17-producing CD8+ T lymphocytes, and NKG2D-expressing natural killer (NK) cells was significantly reduced in LLC1 + MSC-treated mice. Cytotoxicity of NK cells was suppressed by MSC-conditioned medium. This phenomenon was abrogated by the inhibitors of inducible nitric oxide synthase (iNOS) and indoleamine 2,3-dioxygenase (IDO), suggesting the importance of iNOS and IDO for MSC-mediated suppression of antitumor cytotoxicity of NK cells. This study provides the evidence that MSCs promote lung cancer metastasis by suppressing antitumor immune response raising concerns regarding safety of MSC-based therapy in patients who have genetic susceptibility for malignant diseases.
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spelling pubmed-55343202017-08-10 Mesenchymal Stem Cells Promote Metastasis of Lung Cancer Cells by Downregulating Systemic Antitumor Immune Response Gazdic, Marina Simovic Markovic, Bojana Jovicic, Nemanja Misirkic-Marjanovic, Maja Djonov, Valentin Jakovljevic, Vladimir Arsenijevic, Nebojsa Lukic, Miodrag L. Volarevic, Vladislav Stem Cells Int Research Article Since majority of systemically administered mesenchymal stem cells (MSCs) become entrapped within the lungs, we used metastatic model of lung cancer, induced by intravenous injection of Lewis lung cancer 1 (LLC1) cells, to investigate the molecular mechanisms involved in MSC-mediated modulation of metastasis. MSCs significantly augmented lung cancer metastasis, attenuate concentrations of proinflammatory cytokines (TNF-α, IL-17), and increase levels of immunosuppressive IL-10, nitric oxide, and kynurenine in sera of LLC1-treated mice. MSCs profoundly reduced infiltration of macrophages, TNF-α-producing dendritic cells (DCs), TNF-α-, and IL-17-producing CD4+ T cells but increased IL-10-producing CD4+ T lymphocytes in the lungs of tumor-bearing animals. The total number of lung-infiltrated, cytotoxic FasL, perforin-expressing, TNF-α-, and IL-17-producing CD8+ T lymphocytes, and NKG2D-expressing natural killer (NK) cells was significantly reduced in LLC1 + MSC-treated mice. Cytotoxicity of NK cells was suppressed by MSC-conditioned medium. This phenomenon was abrogated by the inhibitors of inducible nitric oxide synthase (iNOS) and indoleamine 2,3-dioxygenase (IDO), suggesting the importance of iNOS and IDO for MSC-mediated suppression of antitumor cytotoxicity of NK cells. This study provides the evidence that MSCs promote lung cancer metastasis by suppressing antitumor immune response raising concerns regarding safety of MSC-based therapy in patients who have genetic susceptibility for malignant diseases. Hindawi 2017 2017-07-16 /pmc/articles/PMC5534320/ /pubmed/28798777 http://dx.doi.org/10.1155/2017/6294717 Text en Copyright © 2017 Marina Gazdic et al. http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Gazdic, Marina
Simovic Markovic, Bojana
Jovicic, Nemanja
Misirkic-Marjanovic, Maja
Djonov, Valentin
Jakovljevic, Vladimir
Arsenijevic, Nebojsa
Lukic, Miodrag L.
Volarevic, Vladislav
Mesenchymal Stem Cells Promote Metastasis of Lung Cancer Cells by Downregulating Systemic Antitumor Immune Response
title Mesenchymal Stem Cells Promote Metastasis of Lung Cancer Cells by Downregulating Systemic Antitumor Immune Response
title_full Mesenchymal Stem Cells Promote Metastasis of Lung Cancer Cells by Downregulating Systemic Antitumor Immune Response
title_fullStr Mesenchymal Stem Cells Promote Metastasis of Lung Cancer Cells by Downregulating Systemic Antitumor Immune Response
title_full_unstemmed Mesenchymal Stem Cells Promote Metastasis of Lung Cancer Cells by Downregulating Systemic Antitumor Immune Response
title_short Mesenchymal Stem Cells Promote Metastasis of Lung Cancer Cells by Downregulating Systemic Antitumor Immune Response
title_sort mesenchymal stem cells promote metastasis of lung cancer cells by downregulating systemic antitumor immune response
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534320/
https://www.ncbi.nlm.nih.gov/pubmed/28798777
http://dx.doi.org/10.1155/2017/6294717
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