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.
Highlights
Glioblastoma multiforme (GBM) is the most common type of primary malignant brain tumor, classified by the World Health Organization (WHO) as a grade IV astrocytoma
The treatment protocol for GBM patients has not changed since 2005, and temozolomide treatment in particular has been shown to be primarily limited to tumors with methylguanine DNA methyltransferase (MGMT) promoter methylation [5]
We have compiled, to the best of our knowledge, the progress made in identifying hypoxia responsive invasive proteins in GBM, the molecular mechanisms by which these proteins contribute to GBM migration and invasion, and the advancements made regarding the development of pharmacological drugs against these proteins
Summary
Glioblastoma multiforme (GBM) is the most common type of primary malignant brain tumor, classified by the World Health Organization (WHO) as a grade IV astrocytoma. The proneural signature further contains high expression of several proneural developmental genes, such as SOX, DCX, DLL3, ASCL1, and TCF4 [9] Within this subtype isocitrate dehydrogenase (IDH) gene mutations associated with improved patient outcome are observed [8]. Microvascular hyperplasia is characterized by a large number of enlarged and rapidly dividing endothelial cells, pericytes, and smooth muscle cells that form tuft micro-aggregates at the leading edge of sprouting blood vessels [20] It can take the shape of ‘glomeruloid bodies’ that constitute a characteristic feature of GBM. Tumor invasion constitutes a major obstacle to therapy, but it is the main cause of death in GBM patients For this reason, an increasing amount of research has been focused on characterizing the molecular and cellular mechanisms that regulate GBM cell invasiveness.
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