Abstract
Glioblastoma (GBM) is a neoplasm characterized by an extensive blood vessel network. Hypoxic niches of GBM can induce tumorigenic properties of a small cell subpopulation called Glioblastoma stem-like cells (GSCs) and can also increase extracellular adenosine generation which activates the A3 adenosine receptor (A3AR). Moreover, GSCs potentiates the persistent neovascularization in GBM. The aim of this study was to determine if A3AR blockade can reduce the vasculogenesis mediated by the differentiation of GSCs to Endothelial Cells (ECs) under hypoxia. We evaluated the expression of endothelial cell markers (CD31, CD34, CD144, and vWF) by fluorescence-activated cell sorting (FACS), and vascular endothelial growth factor (VEGF) secretion by ELISA using MRS1220 (A3AR antagonist) under hypoxia. We validate our results using U87MG-GSCs A3AR knockout (GSCsA3-KO). The effect of MRS1220 on blood vessel formation was evaluated in vivo using a subcutaneous GSCs-tumor model. GSCs increased extracellular adenosine production and A3AR expression under hypoxia. Hypoxia also increased the percentage of GSCs positive for endothelial cell markers and VEGF secretion, which was in turn prevented when using MRS1220 and in GSCsA3-KO. Finally, in vivo treatment with MRS1220 reduced tumor size and blood vessel formation. Blockade of A3AR decreases the differentiation of GSCs to ECs under hypoxia and in vivo blood vessel formation.
Highlights
Glioblastoma (GBM) is considered the most common tumor of the central nervous system and one of the most devastating types of cancer
We found that U87MG glioblastoma stem-like cells (GSCs) had increased extracellular adenosine production (~7 fold) after 24 h of hypoxia (Figure 1A)
These results suggest that the high levels of extracellular adenosine in U87MG GSCs culture could activate the A3 adenosine receptor (A3AR) under hypoxia
Summary
Glioblastoma (GBM) is considered the most common tumor of the central nervous system and one of the most devastating types of cancer. Unlike normal vasculature where the endothelium has a low proliferation rate, tumor vasculature is highly proliferative and the formed blood vessels are often disorganized and tortuous [10]. This entails inefficient oxygen supply and as a result, extensive hypoxic areas that promote further vasculogenesis [11]. Signaling pathways modulated by adenosine are up-regulated under hypoxia and participate in various aspects of cancer, including vasculogenesis [23,24,25,26,27] This nucleoside is produced mainly by extracellular ATP hydrolysis and signals through its four Adenosine Receptors (ARs): A1 (A1AR), A2A (A2AAR), A2B (A2BAR), and A3 (A3AR) [26]. Our aim was to determine if A3AR blockade can reduce the vasculogenesis mediated by the differentiation of GSCs to ECs under hypoxia
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