Cytokine CCL5 and receptor CCR5 axis in glioblastoma multiformae
BACKGROUND. Glioblastoma is the most frequent and aggressive brain tumour in humans with median survival from 12 to 15 months after the diagnosis. This is mostly due to therapy resistant glioblastoma stem cells in addition to inter-tumour heterogeneity that is due to infiltration of a plethora of host cells. Besides endothelial cells, mesenchymal stem cells and their differentiated progenies, immune cells of various differentiation states, including monocytes, comprise resident, brain tumour microenvironment.
CONCLUSIONS. Recent studies have provided compelling evidence for CCL5/CCR5 in the invasive and metastatic behaviour of many cancer types. CCR5, a G-protein coupled receptor, known to function as an essential co-receptor for HIV entry, is now known to participate in driving tumour heterogeneity, the formation of cancer stem cells and the promotion of cancer invasion and metastasis. Clinical trials have recently opened targeting CCR5 using a humanized monoclonal antibody (leronlimab) for metastatic triple negative breast cancer (TNBC) or a small molecule inhibitor (Maraviroc) for metastatic colon cancer. In this review, the CCL5 and CCR5 structure and signalling mechanisms in glioblastoma are discussed. In addition, the CCL5/CCR5 axis directs infiltration and interactions with of monocytes/macrophages and mesenchymal stem cells, comprising glioblastoma stem cell niches.
PERSPECTIVES. Ass CCR5 is highly expressed in glioblastoma and is associated with poor prognosis of patients, CCL5/CCR5 may be an excellent new target for cancer glioblastoma therapy is suggested. The molecular mechanisms by which chemoattractant and receptor respond within the complex tissue microenvironment to promote cancer stem cells and tumour heterogeneity, are discussed herein.
Key words: cytokines, CCL5-RANTES; glioblastoma, tumour microenvironment, mesenchymal stem cells, signalling.