Abstract
Glioblastoma is the most common and aggressive adult brain tumour, with poor median survival and limited treatment options. Following surgical resection and chemotherapy, recurrence of the disease is inevitable. Genomic studies have identified key drivers of glioblastoma development, including amplifications of receptor tyrosine kinases, which drive tumour growth. To improve treatment, it is crucial to understand survival response processes in glioblastoma that fuel cell proliferation and promote resistance to treatment. One such process is autophagy, a catabolic pathway that delivers cellular components sequestered into vesicles for lysosomal degradation. Autophagy plays an important role in maintaining cellular homeostasis and is upregulated during stress conditions, such as limited nutrient and oxygen availability, and in response to anti-cancer therapy. Autophagy can also regulate pro-growth signalling and metabolic rewiring of cancer cells in order to support tumour growth. In this review, we will discuss our current understanding of how autophagy is implicated in glioblastoma development and survival. When appropriate, we will refer to findings derived from the role of autophagy in other cancer models and predict the outcome of manipulating autophagy during glioblastoma treatment.
Highlights
Introduction to glioblastomaGlioblastoma, a grade IV astrocytoma, is the most common and aggressive type of primary brain tumour in adults
The classical subtype is distinguished by alterations causing hyperactivation of the receptor tyrosine kinases (RTKs) EGFR, with the most frequent variation being the expression of EGFRvIII, a truncated mutant that lacks the extracellular ligandbinding domain and signals constitutively in the absence of growth factors [3]
Pharmacological or genetic inhibition of autophagy in conjunction with suberoylanilide hydroxamic acid (SAHA) treatment promoted cell death in cultured glioblastoma cells [129,130]. This has been promisingly replicated in a mouse model where combining SAHA or temozolomide with the non-specific autophagy inhibitor CQ significantly reduced tumour volume of glioblastoma cells orthotopically engrafted in C57BL/6 mice [128]
Summary
Glioblastoma, a grade IV astrocytoma, is the most common and aggressive type of primary brain tumour in adults. Gene expression analyses of patient-derived tumour cells revealed three distinct glioblastoma subtypes, classical, proneural and mesenchymal, which are classified based on their molecular genotypes [1]. These molecular subtypes have been found to associate with different cellular states identified by transcriptomic analyses [2]. It is important to understand cellular survival mechanisms used by glioblastoma cells in order to develop new treatments that can effectively target the tumour. Autophagy is one such pathway that is upregulated in cancer cells in response to stress. We will first introduce the current models used to study glioblastoma and their drawbacks in order to better grasp the limitations of studying the role of autophagy in this aggressive cancer
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