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Open AccessArticle

CCR5-Mediated Signaling is Involved in Invasion of Glioblastoma Cells in Its Microenvironment

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Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia
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Jožef Stefan International Postgraduate School, 1000 Ljubljana, Slovenia
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Department of Neurosurgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
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Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
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Department of Biotechnology and Systems Biology, National Institute of Biology, 1000 Ljubljana, Slovenia
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Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, PA 19096, USA
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Faculty of Chemistry and Chemical Technology, University of Ljubljana, 1000 Ljubljana, Slovenia
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(12), 4199; https://doi.org/10.3390/ijms21124199
Received: 15 May 2020 / Revised: 1 June 2020 / Accepted: 8 June 2020 / Published: 12 June 2020
(This article belongs to the Special Issue Molecular Biology of Brain Tumors)
The chemokine CCL5/RANTES is a versatile inflammatory mediator, which interacts with the receptor CCR5, promoting cancer cell interactions within the tumor microenvironment. Glioblastoma is a highly invasive tumor, in which CCL5 expression correlates with shorter patient survival. Using immunohistochemistry, we identified CCL5 and CCR5 in a series of glioblastoma samples and cells, including glioblastoma stem cells. CCL5 and CCR5 gene expression were significantly higher in a cohort of 38 glioblastoma samples, compared to low-grade glioma and non-cancerous tissues. The in vitro invasion of patients-derived primary glioblastoma cells and glioblastoma stem cells was dependent on CCL5-induced CCR5 signaling and is strongly inhibited by the small molecule CCR5 antagonist maraviroc. Invasion of these cells, which was enhanced when co-cultured with mesenchymal stem cells (MSCs), was inhibited by maraviroc, suggesting that MSCs release CCR5 ligands. In support of this model, we detected CCL5 and CCR5 in MSC monocultures and glioblastoma-associated MSC in tissue sections. We also found CCR5 expressing macrophages were in close proximity to glioblastoma cells. In conclusion, autocrine and paracrine cross-talk in glioblastoma and, in particular, glioblastoma stem cells with its stromal microenvironment, involves CCR5 and CCL5, contributing to glioblastoma invasion, suggesting the CCL5/CCR5 axis as a potential therapeutic target that can be targeted with repositioned drug maraviroc. View Full-Text
Keywords: CCL5; CCR5; chemokines; glioblastoma; invasion; maraviroc; mesenchymal stem cells CCL5; CCR5; chemokines; glioblastoma; invasion; maraviroc; mesenchymal stem cells
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Novak, M.; Koprivnikar Krajnc, M.; Hrastar, B.; Breznik, B.; Majc, B.; Mlinar, M.; Rotter, A.; Porčnik, A.; Mlakar, J.; Stare, K.; Pestell, R.G.; Lah Turnšek, T. CCR5-Mediated Signaling is Involved in Invasion of Glioblastoma Cells in Its Microenvironment. Int. J. Mol. Sci. 2020, 21, 4199.

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