Chemokine CCL5 and Its Receptor CCR5 As a Potential Therapeutic Targets in Glioblastoma

Chemokine CCL5 and its receptor CCR5 as a potential therapeutic targets in glioblastoma

P­08.2­14

M. NovakI, M. Koprivnikar KrajncI, B. HrastarI, B. BreznikI, B. MajcI,II, A. RotterI, A. PorčnikIII, J. MlakarIV , R.G. PestellV, T. Lah TurnšekI,VI

INational Institute of Biology, Ljubljana, Slovenia, IIThe Jožef Stefan International Postgraduate School, Ljubljana, Slovenia, IIIDepartment of Neurosurgery, University Medical Centre, Ljubljana, Slovenia, IV Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia, VPennsylvania Cancer and Regenerative Medicine Research Center, Baruch S.Blumberg Institute, Pennsylvania Biotechnology Center, Pennsylvania, United States of America, VI Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia

The chemokine CCL5 has a role in inflammatory diseases and in cancer progression. CCL5 interacts mostly, but not exclusively with the receptor CCR5, promoting intra­ and inter­cellular interactions of tumor cells within the tumor microenvironment. In this study we explored CCL5/CCR5 as possible therapeutic targets in treatment of glioblastoma (GB). We analysed CCL5/CCR5 mRNA and protein expression in glioma tissues, GB cells and GB stem cells (GSCs), derived from patients. Higher mRNA expression of CCL5/CCR5 was detected in recurrent GBs as compared to primary GBs and less­malignant low­grade gliomas. Low grade gliomas rely on stromal chemokine stimulation, whereas high grade GB, establish an autocrine chemokine stimulation, becoming independent of stroma, leading to higher tumor malignancy and lower survival rate of GB patients. CCL5 and CCR5 proteins were heterogeneously expressed among GB tissues and GB cells, present in some samples, but absent in others. Interestingly, only CCR5 was detected in GSCs. Both were expressed in stromal cells, such as mesenchymal stem cells (MSCs) and macrophages.There are four genetically defined GB subtypes: the proneural (PN), mesenchymal (MES), neural (N), and classical (CL), which differ significantly in survival rate, being the shortest in MES subtype. We have found Cl subtype exhibited the highest levels of both CCL5 and CCR5 expressions, while MES expressed the lowest. We demonstrated the invasion of patients­derived GB cells was highly dependent on CCL5/CCR5 signaling, as it was strongly inhibited by the synthetic CCR5 antagonist maraviroc. The invasion of GB cells when co­cultured with MSCs was also inhibited by maraviroc, suggesting the release of CCR5 antagonists, e.g. CCL5 from MSCs upon co­culturing. In conclusion, as GB and stromal cells in the tumor microenvironment induce expression of CCR5 and CCL5, functionally governing invasion, the CCR5/CCL5 axis may be a potential therapeutic target for this deadly disease.