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

The chemokineCCL5/RANTES is a versatile inflammatory mediator, which interacts with the receptorCCR5, promoting cancer cell interactions within the tumor microenvironment. Glioblastoma is a highly invasive tumor, in whichCCL5expression correlates with shorter patient survival. Using immunohistochemistry, we identifiedCCL5andCCR5in a series of glioblastoma samples and cells, including glioblastoma stem cells.CCL5andCCR5gene 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 onCCL5-inducedCCR5signaling and is strongly inhibited by the small moleculeCCR5antagonist maraviroc. Invasion of these cells, which was enhanced when co-cultured with mesenchymal stem cells (MSCs), was inhibited by maraviroc, suggesting that MSCs releaseCCR5ligands. In support of this model, we detectedCCL5andCCR5in MSC monocultures and glioblastoma-associated MSC in tissue sections. We also foundCCR5expressing 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, involvesCCR5andCCL5, contributing to glioblastoma invasion, suggesting theCCL5/CCR5axis as a potential therapeutic target that can be targeted with repositioned drug maraviroc.