Abstract
Glioblastoma (GBM) is the most common and malignant type of primary brain tumor, showing rapid development and resistance to therapies. On average, patients survive 14.6 months after diagnosis and less than 5% survive five years or more. Several pieces of evidence have suggested that the DNA damage signaling and repair activities are directly correlated with GBM phenotype and exhibit opposite functions in cancer establishment and progression. The functions of these pathways appear to present a dual role in tumorigenesis and cancer progression. Activation and/or overexpression of ATRX, ATM and RAD51 genes were extensively characterized as barriers for GBM initiation, but paradoxically the exacerbated activity of these genes was further associated with cancer progression to more aggressive stages. Excessive amounts of other DNA repair proteins, namely HJURP, EXO1, NEIL3, BRCA2, and BRIP, have also been connected to proliferative competence, resistance and poor prognosis. This scenario suggests that these networks help tumor cells to manage replicative stress and treatment-induced damage, diminishing genome instability and conferring therapy resistance. Finally, in this review we address promising new drugs and therapeutic approaches with potential to improve patient survival. However, despite all technological advances, the prognosis is still dismal and further research is needed to dissect such complex mechanisms.
Highlights
Gliomas are brain cancers that present glial differentiation and represent a group of highly heterogeneous tumors with diverse histological, immunohistochemical and molecular characteristics (Louis et al, 2016; Wirsching and Weller, 2016)
We focused on alterations of DNA damage response (DDR) and DNA repair genes encountered in astrocytomas from different grades, aiming to draw an integrated view of how dysfunctions in these pieces of machinery are orchestrated to allow tumorigenesis, cancer progression, resistance to therapy, as well as its potential involvement in controlling the marked genomic instability of GBM cells
Silencing of EXO1 in T98G cells led to faster restoration of DNA injury induced by ionizing radiation (IR), suggesting that the absence of EXO1 possibly directs the double-strand breaks (DSB) repair to the faster and error-prone non-homologous end joining (NHEJ) pathway. These results indicate a potential role of EXO1 to facilitate DNA repair during astrocytoma progression
Summary
Gliomas are brain cancers that present glial differentiation and represent a group of highly heterogeneous tumors with diverse histological, immunohistochemical and molecular characteristics (Louis et al, 2016; Wirsching and Weller, 2016). They correspond to only 2% of the overall cases of cancer. Dedifferentiation, diffuse infiltration, exacerbated proliferation, presence of necrosis and angiogenesis, resistance to apoptosis and conspicuous genomic instability These tumors are seriously aggressive and resistant to available treatments, which involve surgical resection, radiotherapy, and chemotherapy with temozolomide (TMZ) (Louis et al, 2016).
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