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.
Highlights
Glioblastoma is one of the most aggressive brain tumors and poorly responsive malignancies to treatment with among the shortest survival rates of all cancers [1]
The basic question when investigating chemokine autocrine signaling in cancer, such as presented by CCL5/CCR5 axis, is “what activates what,” whereas in paracrine signaling in heterogeneous cancers the question is “what attracts what.”
By analyzing CCL5/CCR5 mRNA and protein expression in glioma tissues in a larger cohort of 65 patients, we confirmed that both, CCL5 and CCR5 genes are increasingly expressed in advanced glioma (Figure 7)
Summary
Glioblastoma is one of the most aggressive brain tumors and poorly responsive malignancies to treatment with among the shortest survival rates of all cancers [1]. A high rate of relapse is mostly due to the resistance of glioblastoma stem cells (GSCs) and their heterogeneity and plasticity that are contributing to the resistance of recurrent tumors [3,5,6]. The brain TME is comprised of resident astrocytes, neurons, and microglial cells and infiltrating mesenchymal stem cells (MSCs), hematopoietic stem cells (HSC), and differentiated immune cells, such as macrophages [9], altogether comprising so-called tumor stroma. Understanding these selective interactions between non-cancerous so-called stromal and glioblastoma cells is crucial for the effectiveness of treatment strategies
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