Abstract
Simple SummaryThe biological pathways underlying glioblastoma malignancy and radioresistance are still unclear. In this review, we describe the role of the hypoxic microenvironment and SRC proto-oncogene non-receptor tyrosine kinase in the activation of radioresistance and invasion pathways of glioblastoma. We also highlight the hypoxia- and ionizing radiation-induced infiltration, providing updated evidences on the involvement of SRC in these processes. Optimizing radiotherapy and identifying druggable molecular players are crucial steps to improve current glioblastoma therapeutic strategies.Advances in functional imaging are supporting neurosurgery and radiotherapy for glioblastoma, which still remains the most aggressive brain tumor with poor prognosis. The typical infiltration pattern of glioblastoma, which impedes a complete surgical resection, is coupled with a high rate of invasiveness and radioresistance, thus further limiting efficient therapy, leading to inevitable and fatal recurrences. Hypoxia is of crucial importance in gliomagenesis and, besides reducing radiotherapy efficacy, also induces cellular and molecular mediators that foster proliferation and invasion. In this review, we aimed at analyzing the biological mechanism of glioblastoma invasiveness and radioresistance in hypoxic niches of glioblastoma. We also discussed the link between hypoxia and radiation-induced radioresistance with activation of SRC proto-oncogene non-receptor tyrosine kinase, prospecting potential strategies to overcome the current limitation in glioblastoma treatment.
Highlights
Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor with an incidence of5/100,000 per year and a median survival of 12−15 months after diagnosis, despite aggressive multimodalCancers 2020, 12, 2860; doi:10.3390/cancers12102860 www.mdpi.com/journal/cancersCancers 2020, 12, x aggressive multimodal treatments [1]
It has been reported that induced radiation (IR)-induced invasion modulating the extracellular matrix (ECM) protein, is due to matrix metalloproteases (MMPs) action, and to high production of other components such as hyaluronic acid, which acts as an extracellular signaling molecule for the mesenchymal shift of GBM, in response to radiation; hyaluronic acid is recognized by the CD44 receptor, which is a clear marker of the mesenchymal subtype
It is well known that hypoxia is associated with increased resistance to IR, contributing to treatment failures after radiotherapy based on X-rays
Summary
Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor with an incidence of. Hypofractionated treatment of 40 Gy in 15 fractions over 3 weeks is suggested only for patients older than 70 years old and with poor performance status [7] In this context, in order to reduce GBM aggressiveness and to simultaneously increase the effect of the radiation dose, there is an urgent clinical need to develop targeted therapy and radiosensitizing agents. Strategies to reach this aim should take into account two main features of GBM: hypoxia and invasiveness. We report potential strategies to improve efficacy of radiotherapy against hypoxia, invasiveness, and SRC activation
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