Much like other solid tumors, GBM tumorigenesis leads to oxygen deprivation of specific regions and consequently hypoxia. This lack of oxygen tension in critical areas causes the expression of hypoxia-inducible factor 1 (HIF-1), which then causes the overexpression of VEGF. The resultant ligand binds to growth factor receptors on cancerous endothelial cells and induces angiogenesis (Vleeschouwer, 2016). This is an interesting component of cancers in general because the hypoxic areas that come from this process normally lead to cell death, but CSCs, specifically in GBM, thrive under these conditions due to the aforementioned mechanisms of angiogenesis.
There are currently two theories that aim to explain the heterogeneity of GBM solid tumors and the like: the stochastic model and the hierarchy model. The stochastic model posits that the heterogeneity of tumor cells results from both intrinsic and extrinsic factors affecting cells with the same mutations. On the other hand, the hierarchy model takes a more nuanced approach by suggesting that only a few CSCs can initiate growth of a tumor, and the heterogeneity of the GBM tumor cells arises from the related cells being at different points in development/differentiation. This model points to the small subset of CSCs being the root of cancerous growth, resistance, and recurrence (Vleeschouwer, 2016). The issue then becomes identifying the cancer stem cells
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