Abstract
BackgroundGlioblastoma multiforme (GBM) is one of the lethal malignant tumors of the central nervous system. Despite advances made in understanding this complex disease, little has been achieved in improving clinical efficacy towards it. Factors such as chemokines play important role in shaping the tumor microenvironment which in turn plays a significant role in deciding course of tumor progression. In this study, we investigated the role of chemokine IL-8 in glioblastoma progression with particular emphasis on immunomodulation, cellular proliferation, invasion and vascular mimicry.MethodsRole of IL-8 in GBM immunology was determined by correlating the expression of IL-8 by immunohistochemistry with other immune cell markers such as CD3 and CD68. Effect of high IL-8 expression on overall survival, the difference in expression level between different GBM subgroups and anatomic structures were analyzed using other databases. Two GBM cell lines –U-87MG and LN-18 were used to study the impact of targeting IL-8-CXCR1/2 signalling using neutralizing antibodies and pharmacological antagonist. Reverse transcriptase–polymerase chain reaction and immunocytochemistry were used to determine the expression of these axes. Impact on cell viability and proliferation was assessed by MTT, proliferation marker-ki-67 and clonogenic survival assays. Multicellular tumor spheroids generated from GBM cell lines were used to study invasion in matrigel.ResultsWeak Positive correlation was observed between IL-8 and CD3 as well as between IL-8 and CD68. High IL-8 expression in GBM patients was found to be associated with dismal survival. No significant difference in IL-8 expression between different molecular subgroups of GBM was observed. In vitro targeting of IL-8-CXCR1/2 signalling displayed a significant reduction in cell viability and proliferation, and spheroid invasion. Furthermore, the presence of CD34-/CXCR1+ vessels in GBM tissues showed the involvement of IL-8/CXCR1 in vascular mimicry structure formation.ConclusionThese results suggest a direct involvement of IL-8-CXCR1/2 axes in GBM progression by promoting both cell proliferation and invasion and indirectly by promoting neovascularization in the form of vascular mimicry.
Highlights
Glioblastoma multiforme (GBM) is one of the lethal malignant tumors of the central nervous system
We aimed to elucidate the role of IL-8 in GBM biology wherein we investigated its role in immune cell infiltration, GBM cell proliferation, invasion, and vascularization
Protein localization study performed on GBM and diffuse astrocytoma Formalin-fixed paraffin embedded (FFPE) sections using immunohistochemistry established expression of IL-8 in GBM cells and expression of its receptor CXCR1 primarily in tumor-associated vessels and in few cases in tumor cells as well [14]
Summary
Glioblastoma multiforme (GBM) is one of the lethal malignant tumors of the central nervous system. Recent studies have shown the role of chemokines in different aspects of tumor growth in various cancers including GBM [5] These molecules may be secreted by tumor cells or other cell types present in tumor microenvironment regulating tumor immune response, vasculogenesis and cellular proliferation [6]. One such chemokine is CXCL8 which is a known angiogenic factor and has been shown to exert a mitogenic effect in cancers such as colon cancer, prostate and ovarian cancer [7, 8]
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