No 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.

Glioblastoma is the brain tumor with the worst prognosis. This is mainly due to a cell subpopulation with an extremely aggressive potential, called glioblastoma stem-like cells (GSCs). These cells produce high levels of extracellular adenosine, which are increased even more under hypoxic conditions. Under hypoxia, adenosine signaling is related to HIF-2α expression, enhancing cell aggressiveness. Adenosine can be degraded using recombinant adenosine deaminase (ADA) to revert its pathological effects. The aim of this study was to degrade adenosine using ADA in order to decrease malignancy of GSCs. Adenosine depletion was performed using recombinant ADA. Migration and invasion were measured by transwell and matrigel-coated transwell assay, respectively. HIF-2α-dependent cell migration/invasion decreased in GSCs treated with ADA under hypoxia. MRPs-mediated chemoresistance and colony formation decreased in treatment with ADA. In conclusion, adenosine depletion using adenosine deaminase decreases GSCs aggressiveness.

Glioblastoma (GBM) is the most common and aggressive brain tumor, which causes the highest number of deaths worldwide. It is a highly vascularized tumor, infiltrative, and its tumorigenic capacity is exacerbated. All these hallmarks are therapeutic targets in GBM treatment, including surgical removal followed by radiotherapy and chemotherapy. Current therapies have not been sufficient for the effective patient's management, so the classic therapies have had to expand and incorporate new alternative treatments, including natural compounds. This review summarizes natural products and their physiological effects in in vitro and in vivo models of GBM, specifically by modulating signaling pathways involved in angiogenesis, cell migration/invasion, cell viability, apoptosis, and chemoresistance. The most important aspects of natural products and their derivatives were described in relation to its antitumoral effects. As a final result, it can be obtained that within the compounds with more evidence that supports or suggests its clinical use are the cannabinoids, terpenes, and curcumin, because many have been shown to have a significant effect in decreasing the progress of GBM through known mechanisms, such as chemo-sensitization or decrease migration and cell invasion. Natural compounds emerge as promising therapies to attack the progress of GBM.

Glioblastoma (GBM) is the most common and malignant primary brain cancer in adults. Without treatment the mean patient survival is approximately 6 months, which can be extended to 15 months with the use of multimodal therapies. The low effectiveness of GBM therapies is mainly due to the tumor infiltration into the healthy brain tissue, which depends on GBM cells’ interaction with the tumor microenvironment (TME). The interaction of GBM cells with the TME involves cellular components such as stem-like cells, glia, endothelial cells, and non-cellular components such as the extracellular matrix, enhanced hypoxia, and soluble factors such as adenosine, which promote GBM’s invasiveness. However, here we highlight the role of 3D patient-derived glioblastoma organoids cultures as a new platform for study of the modeling of TME and invasiveness. In this review, the mechanisms involved in GBM-microenvironment interaction are described and discussed, proposing potential prognosis biomarkers and new therapeutic targets.