The Role of Hypoxia in Glioblastoma Invasion

Abstract

Glioblastoma multiforme (GBM), a grade IV astrocytoma, is the most common and deadly type of primary malignant brain tumor, with a patient's median survival rate ranging from 15 to 17 months. The current treatment for GBM involves tumor resection surgery based on MRI image analysis, followed by radiotherapy and treatment with temozolomide. However, the gradual development of tumor resistance to temozolomide is frequent in GBM patients leading to subsequent tumor regrowth/relapse. For this reason, the development of more effective therapeutic approaches for GBM is of critical importance. Low tumor oxygenation, also known as hypoxia, constitutes a major concern for GBM patients, since it promotes cancer cell spreading (invasion) into the healthy brain tissue in order to evade this adverse microenvironment. Tumor invasion not only constitutes a major obstacle to surgery, radiotherapy, and chemotherapy, but it is also the main cause of death in GBM patients. Understanding how hypoxia triggers the GBM cells to become invasive is paramount to developing novel and more effective therapies against this devastating disease. In this review, we will present a comprehensive examination of the available literature focused on investigating how GBM hypoxia triggers an invasive cancer cell phenotype and the role of these invasive proteins in GBM progression.

Keywords: GBM; HIF; chemotherapy; hypoxia; invasion.

Figure 1

GBM distinctive pathological features. GBM is characterized by necrotic foci with surrounding cellular pseudopalisades and microvascular hyperplasia. Pseudopalisades are created by tumor cells migrating away from a central hypoxic (low oxygenated) region and forming an invasive front. Microvascular hyperplasia is an exacerbated form of angiogenesis that occurs in response to the secretion of proangiogenic factors (e.g., vascular endothelial growth factors (VEGFs), interleukin-8 (IL-8)) by the cells that form the pseudopalisades.

Figure 2

Genetic alterations that lead to HIF activation in GBM. (A) EGFR gene amplification and/or overexpression is frequent in GBM. The most common EGFR gene mutation (EGFRvIII) consists in the deletion of exons 2–7, resulting in a constitutively active and ligand independent receptor. Initiation of EGFR/EGFRvIII signaling by ligand binding, gene amplification, or mutation results in activation of the PI3K/AKT/mTOR pathway with the subsequent up-regulation of HIF-1α. PTEN gene deletion is common in GBM. PTEN protein is the main inhibitor of the PI3K/AKT signaling pathway, as such loss of PTEN function leads to increased HIF-1α via the PI3K/AKT/mTOR pathway; (B) It has been proposed that p53 may lead to inhibition of HIF activity in hypoxia by promoting MDM2-mediated ubiquitination and degradation of HIF-1α. Therefore, the loss of the p53 gene, which is common in GBM, will lead to HIF-1α stabilization.

Figure 3

Glioblastoma ZEB1-miRNA-200 feedback loop interactions. In GBM, the ZEB1-miRNA-200 feedback loop targets specific stem cell regulators, namely SOX2, OLIG2, and CD133. ZEB1 up-regulation of c-MYB by the ZEB1-miRNA-200 feedback loop leads to increased expression of the MGMT protein that repairs DNA damage caused by alkylating agents such as temozolomide. ZEB1 positively regulates the ROBO1 protein that has been shown to sever the anchorage of N-cadherin to the cytoskeleton leading to increased GBM cell motility.