Abstract
Simple SummaryGlioblastoma (GB) is the deadliest type of primary brain tumor. Following diagnosis the patient´s median survival is only 16 months. There are currently around 450 clinical trials focused on the development of more effective therapies for GB. Nevertheless, radiotherapy remains the most clinically relevant and effective treatment for this devastating disease. Unfortunately, radiotherapy resistance (radioresistance) is frequently observed in GB patients. As a consequence tumor regrowth (recurrence) occurs and eventually the patient succumbs to the disease. It is crucial to fully understand the mechanisms by which GB cells become resistant to radiation in order to improve the sensitivity of these cells to radiotherapy and develop novel strategies to overcome this issue. In this review, we examined how low tumor oxygenation (known as hypoxia) which is a main feature of GB contributes to radioresistance to better understand the implications of this tumor microenvironment in GB treatment and recurrence.Glioblastoma (GB) (grade IV astrocytoma) is the most malignant type of primary brain tumor with a 16 months median survival time following diagnosis. Despite increasing attention regarding the development of targeted therapies for GB that resulted in around 450 clinical trials currently undergoing, radiotherapy still remains the most clinically effective treatment for these patients. Nevertheless, radiotherapy resistance (radioresistance) is commonly observed in GB patients leading to tumor recurrence and eventually patient death. It is therefore essential to unravel the molecular mechanisms underpinning GB cell radioresistance in order to develop novel strategies and combinational therapies focused on enhancing tumor cell sensitivity to radiotherapy. In this review, we present a comprehensive examination of the current literature regarding the role of hypoxia (O2 partial pressure less than 10 mmHg), a main GB microenvironmental factor, in radioresistance with the ultimate goal of identifying potential molecular markers and therapeutic targets to overcome this issue in the future.
Highlights
Glioblastoma (GB) is classified by the World Health Organization (WHO) as a grade IV astrocytoma
We performed a review of the current literature, regarding the molecular mechanisms which are activated by hypoxia and that can potentially be targeted in the future to improve radiotherapy efficiency in GB patients
We revealed that several signaling pathways involved in cell cycle regulation were shown to provide radioresistance in hypoxic GB cells
Summary
Glioblastoma (GB) is classified by the World Health Organization (WHO) as a grade IV astrocytoma. 2-HG via hyper-methylation leads to the loss of differentiation of GB cells These changes caused by IDH mutation lead to reduced GB, IDH-mutant tumor growth compared to GB, IDH-WT. GB has been further sub-classified into classical, proneural, neural and mesenchymal sub-types based on specific genetic signatures [6,7] In this way, the classical sub-type is characterized by Epidermal Growth Factor Receptor (EGFR) gene amplification or mutation (leading to a constitutively active receptor) as well as by over-expression of neural stem cell genes. The classical sub-type is characterized by Epidermal Growth Factor Receptor (EGFR) gene amplification or mutation (leading to a constitutively active receptor) as well as by over-expression of neural stem cell genes These include Sonic hedgehog, Notch and NES [7]. We examined the existing literature regarding the role of hypoxia in supporting radiotherapy resistance in GB with the aim to better understand the implications of this tumor microenvironment in GB treatment and recurrence
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