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

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.

Leronlimab, a humanized monoclonal antibody to CCR5, blocks breast cancer cellular metastasis and enhances cell death induced by DNA damaging chemotherapy

“…It is likely that CCR5 plays a broader role in governing cancer metastasis as maraviroc and vicriviroc reduced prostate cancer cell metastasis to the bones, brain, and viscera in immune-competent mice [22] and reduced metastasis or cellular migration in glioblastoma [54] and a variety of other malignancies [18]. Prior studies had shown that CCR5 induces cancer cell homing to metastatic sites [12,55], augments the pro-inflammatory prometastatic immune phenotype [46], and enhances DNA repair [13], providing aberrant cell survival and resistance to DNA-damaging agents.…”

Updated Insights on EGFR Signaling Pathways in Glioma

“…Based on the expression patterns’ differences, glioblastomas are divided into three subtypes as follows: classical, proneural, and mesenchymal [ 2 ]. Because glioblastoma multiforme (GBM), a grade IV glioma [ 3 ], is one of the most aggressive primary brain tumors, recent studies and reviews have focused on deepening our understanding of the disease [ 4 , 5 , 6 , 7 , 8 , 9 ].…”

The Role of Cytokines and Chemokines in Shaping the Immune Microenvironment of Glioblastoma: Implications for Immunotherapy

“…CCL5 can act as a prognostic measure of glioblastoma patient survival, as CCL5 overexpression is associated with shorter overall survival [ 86 ]. Within the glioblastoma TME, CCL5 produced by GAMs, mesenchymal stem cells (MSCs) and tumour cells signals through CCR1, CCR5 and CD44 [ 86 , 87 , 88 , 89 ]. Similar to its ligand, CCR5 expression in glioblastoma has also been associated with poor survival [ 90 ], and this expression can be upregulated on tumour cells under hypoxic conditions as an adaptive mechanism for the adverse environment [ 91 ].…”

“…With the expression of both CCL5 and its receptor CCR5, tumour cells can use the autocrine signalling circuit to regulate their own proliferation, through activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Targeting this signalling pathway with pharmacological inhibitors such as CCR5 blocker Maraviroc, PI3K/AKT inhibitor LY294002 and PI3K inhibitor NVP-BKM120 can suppress tumour cell proliferation [ 87 , 90 , 92 , 93 ]. The link between the CCL5/CCR5 pathway and tumour growth is also evident in vivo, as knockdown of CCR5 in tumour cells can significantly reduce tumour size and expression of the proliferation marker Ki67 [ 90 ].…”