Abstract
Rapid growth of brain tumors such as glioblastoma often results in oxygen deprivation and the emergence of hypoxic zones. In consequence, the enrichment of reactive oxygen species occurs, harming nonmalignant cells and leading them toward apoptotic cell death. However, cancer cells survive such exposure and thrive in a hypoxic environment. As the mechanisms responsible for such starkly different outcomes are not sufficiently explained, we aimed to explore what transcriptome rearrangements are used by glioblastoma cells in hypoxic areas. Using metadata analysis of transcriptome in different subregions of the glioblastoma retrieved from the Ivy Glioblastoma Atlas Project, we created the reactive oxygen species-dependent map of the transcriptome. This map was then used for the analysis of differential gene expression in the histologically determined cellular tumors and hypoxic zones. The gene ontology analysis cross-referenced with the clinical data from The Cancer Genome Atlas revealed that the metabolic shift is one of the major prosurvival strategies applied by cancer cells to overcome hypoxia-related cytotoxicity.
Highlights
Oxygen levels affect various functions and processes, including cell proliferation, cell differentiation, angiogenesis, and metabolism [1,2,3]
Hypoxia is a common feature of solid tumors [32]; we claim that distinct GBM areas affected by diverse oxygen levels could serve as a good model for studying cellular adaptation to oxidative stress
hypoxia-inducible factors (HIFs)-1α is known as a master regulator of hypoxia [33], whose level/activity was shown to be upregulated in GBM, around necrotic regions [34]
Summary
Oxygen levels affect various functions and processes, including cell proliferation, cell differentiation, angiogenesis, and metabolism [1,2,3]. As a result of an imbalance between oxygen delivery capacity and consumption, referred to as hypoxia, elevated oxidative stress occurs [5,6]. Hypoxia often builds up in brain tumors, such as glioblastoma (GBM), resulting in increased necrotic death and the formation of necrotic zones surrounded by tumor cells [7,8]. This specific niche creates a favorable microenvironment for the existence of self-renewing glioblastoma stem-like cells—GSCs, which are essential for tumor initiation, resistance, and recurrence [7,8]. The emergence of perinecrotic/necrotic zones propagates the development of chemo- and radio-resistance, correlating with poor survival prognosis [9,10]
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