Glioblastoma (GB) is the most aggressive and most common malignant primary brain tumor diagnosed in adults. GB shows a poor prognosis and, unfortunately, current therapies are unable to improve its clinical outcome, imposing the need for innovative therapeutic approaches. The main reason for the poor prognosis is the great cell heterogeneity of the tumor mass and its high capacity for invading healthy tissues. Moreover, the glioblastoma microenvironment is capable of suppressing the action of the immune system through several mechanisms such as recruitment of cell modulators. Development of new therapies that avoid this immune evasion could improve the response to the current treatments for this pathology. Natural Killer (NK) cells are cellular components of the immune system more difficult to deceive by tumor cells and with greater cytotoxic activity. Their use in immunotherapy gains strength because they are a less toxic alternative to existing therapy, but the current research focuses on mimicking the NK attack strategy. Here, we summarize the most recent studies regarding molecular mechanisms involved in the GB and immune cells interaction and highlight the relevance of NK cells in the new therapeutic challenges.
Glioblastoma (GBM) is the most aggressive and common glioma subtype, with a median survival of 15 months after diagnosis. Current treatments have limited therapeutic efficacy; thus, more effective approaches are needed. The glioblastoma tumoural mass is characterised by a small cellular subpopulation – glioblastoma stem cells (GSCs) – that has been held responsible for glioblastoma initiation, cell invasion, proliferation, relapse and resistance to chemo‐ and radiotherapy. Targeted therapies against GSCs are crucial, as is understanding the molecular mechanisms that govern the GSCs. Transforming growth factor β (TGFβ) signalling and reactive oxygen species (ROS) production are known to govern and regulate cancer stem cell biology. Among the differentially expressed genes regulated by TGFβ in a transcriptomic analysis of two different patient‐derived GSCs, we found NADPH oxidase 4 (NOX4) as one of the top upregulated genes. Interestingly, when patient tissues were analysed, NOX4 expression was found to be higher in GSCs versus differentiated cells. A functional analysis of the role of NOX4 downstream of TGFβ in several patient‐derived GSCs showed that TGFβ does indeed induce NOX4 expression and increases ROS production in a NOX4‐dependent manner. NOX4 downstream of TGFβ regulates GSC proliferation, and NOX4 expression is necessary for TGFβ‐induced expression of stem cell markers and of the transcription factor nuclear factor erythroid 2‐related factor 2 (NRF2), which in turn controls the cell’s antioxidant and metabolic responses. Interestingly, overexpression of NOX4 recapitulates the effects induced by TGFβ in GSCs: enhanced proliferation, stemness and NRF2 expression. In conclusion, this work functionally establishes NOX4 as a key mediator of GSC biology.
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