Advances in the Knowledge of the Molecular Biology of Glioblastoma and Its Impact in Patient Diagnosis, Stratification, and Treatment

Abstract

Gliomas are the most common primary brain tumors in adults. They arise in the glial tissue and primarily occur in the brain. Low-grade tumors of World Health Organization (WHO) grade II tend to progress to high-grade gliomas of WHO grade III and, eventually, glioblastoma of WHO grade IV, which is the most common and deadly glioma, with a median survival of 12-15 months after final diagnosis. Knowledge of the molecular biology and genetics of glioblastoma has increased significantly in the past few years, giving rise to classification methods that can help in management and stratification of glioblastoma patients. However, glioblastoma remains an incurable disease. Glioblastoma cells have acquired genetic and metabolic adaptations in order to sustain tumor growth and progression, including changes in energetic metabolism, invasive capacity, migration, and angiogenesis, that make it very difficult to find suitable therapeutic targets and to develop effective drugs. The current standard of care for glioblastoma patients is surgery followed by radiotherapy plus concomitant and adjuvant chemotherapy with temozolomide. Although progress in glioblastoma therapies in recent years has been more limited than in other tumors, numerous drugs and targets are being proposed and many clinical trials are underway to develop effective subtype-specific treatments.

Keywords: cancer therapy; diagnostics; glioblastoma; patient stratification.

Figure 1

Two models for tumor heterogeneity. In the clonal evolution model, all undifferentiated cells have similar tumorigenic capacity. In the CSC model, only CSCs (in red) can sustain tumor growth, thanks to their self‐renewal properties and enormous proliferative potential. Oncogenic events are represented by a thunderbolt.

Figure 2

Enzyme activity of IDH1/2 wildtype and IDH1/2 mutant. IDH1/2 catalyzes the oxidative decarboxylation of isocitrate to produce α‐KG, using NADP⁺ as cofactor and producing NADPH and CO₂ in the forward reaction. IDH1/2 mutations confer a gain‐of‐function activity that catalyzes the conversion of α‐KG into the oncometabolite R2HG in a NADPH‐dependent manner.

Figure 3

Metabolism and targets of oncometabolite R2HG. R2HG binds competitively to enzymes that normally use α‐KG as a cofactor, causing a decrease in the activity of these enzymes, including DNA demethylases (ten‐eleven translocation family of DNA methylcytosine dioxygenases; TET), histone lysine demethylases (KDM), DNA repair proteins (α‐KG/Fe(II)‐dependent dioxygenases; ALKBH) and HIF1α prolyl hydroxylases (egg‐laying deficiency protein nine‐like; EGLN). This leads to a hypermethylated genotype, which results in altered gene expression, and changes in the expression of HIF1α‐dependent genes through HIF1α stabilization. This figure was prepared using Servier Medical Art (https://smart.servier.com) under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/).

Figure 4

Events involved in glioma invasion. Cx43: connexin 43; NCAM: neural cell adhesion molecule; ADAM: a disintegrin and metalloproteinase; MMP: matrix metalloproteinase; PAK4: p21 activated kinase 4; ILGFBP2: insulin‐like growth factor binding protein‐2; MT‐MMP: membrane‐type matrix metalloproteinase; uPA: urokinase plasminogen activator; AKT: protein kinase B; Rac1: Ras‐related C3 botulinum toxin substrate 1; Cdc42: cell division cycle 42. This figure was prepared using Servier Medical Art (https://smart.servier.com) under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/).

Figure 5

Possible mechanism for glomeruloid bodies formation. 1) Low‐grade infiltrating glioma cells coopt pre‐existing microvessels. 2) As the tumor grows, endothelial cells try to resist cooption by releasing Ang‐2, which leads to apoptosis of these cells in the absence of VEGF. Apoptosis of endothelial cells then causes tumor cells to become hypoxic and eventually necrotic, forming initial foci of necrosis. 3) Necrotic niches become surrounded by tumor cells, forming the pattern of pseudopalisading necrosis. Pseudopalisade tumor cells upregulate the expression and secretion of VEGF, which acts on nearby endothelial cells to promote vascular proliferation, leading to the formation of glomeruloid structures.