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

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          Abstract

          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.

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          Most cited references52

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          Multidimensional communication in the microenvirons of glioblastoma

          Glioblastomas are heterogeneous and invariably lethal tumours. They are characterized by genetic and epigenetic variations among tumour cells, which makes the development of therapies that eradicate all tumour cells challenging and currently impossible. An important component of glioblastoma growth is communication with and manipulation of other cells in the brain environs, which supports tumour progression and resistance to therapy. Glioblastoma cells recruit innate immune cells and change their phenotype to support tumour growth. Tumour cells also suppress adaptive immune responses, and our increasing understanding of how T cells access the brain and how the tumour thwarts the immune response offers new strategies for mobilizing an antitumour response. Tumours also subvert normal brain cells — including endothelial cells, neurons and astrocytes — to create a microenviron that favours tumour success. Overall, after glioblastoma-induced phenotypic modifications, normal cells cooperate with tumour cells to promote tumour proliferation, invasion of the brain, immune suppression and angiogenesis. This glioblastoma takeover of the brain involves multiple modes of communication, including soluble factors such as chemokines and cytokines, direct cell–cell contact, extracellular vesicles (including exosomes and microvesicles) and connecting nanotubes and microtubes. Understanding these multidimensional communications between the tumour and the cells in its environs could open new avenues for therapy.
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            Overcoming therapeutic resistance in glioblastoma: the way forward

            Glioblastoma is the most common and lethal primary malignant brain tumor in adults. Patients die from recurrent tumors that have become resistant to therapy. New strategies are needed to design future therapies that target resistant cells. Recent genomic studies have unveiled the complexity of tumor heterogeneity in glioblastoma and provide new insights into the genomic landscape of tumor cells that survive and initiate tumor recurrence. Resistant cells also co-opt developmental pathways and display stem-like properties; hence we propose to name them recurrence-initiating stem-like cancer (RISC) cells. Genetic alterations and genomic reprogramming underlie the innate and adaptive resistance of RISC cells, and both need to be targeted to prevent glioblastoma recurrence.
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              Chemokines in tumor progression and metastasis

              Chemokines play a vital role in tumor progression and metastasis. Chemokines are involved in the growth of many cancers including breast cancer, ovarian cancer, pancreatic cancer, melanoma, lung cancer, gastric cancer, acute lymphoblastic leukemia, colon cancer, non-small lung cancer and non-hodgkin's lymphoma among many others. The expression of chemokines and their receptors is altered in many malignancies and leads to aberrant chemokine receptor signaling. This review focuses on the role of chemokines in key processes that facilitate tumor progression including proliferation, senescence, angiogenesis, epithelial mesenchymal transition, immune evasion and metastasis.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                12 June 2020
                June 2020
                : 21
                : 12
                : 4199
                Affiliations
                [1 ]Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, 1000 Ljubljana, Slovenia; metka.novak@ 123456nib.si (M.N.); mkoprivnikarkrajnc@ 123456gmail.com (M.K.K.); barbara.hrastar@ 123456gmail.com (B.H.); barbara.breznik@ 123456nib.si (B.B.); bernarda.majc@ 123456nib.si (B.M.); mateja.mlinar@ 123456nib.si (M.M.); ana.rotter@ 123456nib.si (A.R.)
                [2 ]Jožef Stefan International Postgraduate School, 1000 Ljubljana, Slovenia
                [3 ]Department of Neurosurgery, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; andrej.porcnik@ 123456ukclj.si
                [4 ]Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; Jernej.MLAKAR@ 123456mf.uni-lj.si
                [5 ]Department of Biotechnology and Systems Biology, National Institute of Biology, 1000 Ljubljana, Slovenia; katja.stare@ 123456nib.si
                [6 ]Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Pennsylvania Biotechnology Center, Wynnewood, PA 19096, USA
                [7 ]Faculty of Chemistry and Chemical Technology, University of Ljubljana, 1000 Ljubljana, Slovenia
                Author notes
                [* ]Correspondence: richard.pestell@ 123456gmail.com (R.G.P.); tamara.lah@ 123456nib.si (T.L.T.); Tel.: +0386-5-9232-703 (T.L.T.)
                Author information
                https://orcid.org/0000-0003-0247-5811
                https://orcid.org/0000-0002-6879-0980
                https://orcid.org/0000-0002-3999-9400
                https://orcid.org/0000-0003-3244-8777
                Article
                ijms-21-04199
                10.3390/ijms21124199
                7352708
                32545571
                563b2923-575c-49b3-a55e-ee91637ce8cb
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 15 May 2020
                : 08 June 2020
                Categories
                Article

                Molecular biology
                ccl5,ccr5,chemokines,glioblastoma,invasion,maraviroc,mesenchymal stem cells
                Molecular biology
                ccl5, ccr5, chemokines, glioblastoma, invasion, maraviroc, mesenchymal stem cells

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