Abstract
Glioblastoma multiforme is the most aggressive and malignant primary brain tumour, with a median survival rate of between 15 to 17 months. Heterogeneous regions occur in glioblastoma as a result of oxygen gradients which ranges from 0.1% to 10% in vivo. Emerging evidence suggests that tumour hypoxia leads to increased aggressiveness and chemo/radio resistance. Yet, few in vitro studies have been performed in hypoxia. Using three glioblastoma cell-lines (U87, U251, and SNB19), the adaptation of glioblastoma cells in a 1% (hypoxia) and 20% (normoxia) oxygen microenvironment on proliferation, metabolism, migration, neurosphere formation, CD133 and VEGF expression was investigated. Compared to cells maintained in normoxia (20% oxygen), glioblastoma cells adapted to 1% oxygen tension by reducing proliferation and enhancing metabolism. Both migratory tendency and neurosphere formation ability were greatly limited. In addition, hypoxic-mediated gene upregulation (CD133 and VEGF) was reversed when cells were removed from the hypoxic environment. Collectively, our results reveal that hypoxia plays a pivotal role in changing the behaviour of glioblastoma cells. We have also shown that genetic modulation can be reversed, supporting the concept of reversibility. Thus, understanding the degree of oxygen gradient in glioblastoma will be crucial in personalising treatment for glioblastoma patients.
Highlights
Glioblastoma multiforme is the most aggressive primary brain tumour classified as a grade IV astrocytoma by World Health Organization (WHO) [1,2]
To determine the effect of hypoxia on proliferation and metabolism over time, U87, U251, and SNB19 cell lines were cultured in hypoxic conditions and compared with cells maintained in normoxia for 4 days
We observed that while metabolism was enhanced in hypoxia, it was reduced in normoxia (Figure 1A–C)
Summary
Glioblastoma multiforme is the most aggressive primary brain tumour classified as a grade IV astrocytoma by World Health Organization (WHO) [1,2]. The tumour microenvironment consists of a myriad of elements [5], oxygen tension has emerged as an important microenvironmental factor in cancer treatment [6]. Glioblastoma is a heterogeneous tumour [7,8] with a subpopulation of cells at different oxygen levels [9,10,11]. Variation in oxygen concentration can be used to determine tumour heterogeneity [12]. The oxygen tension to which cells are exposed is lower than the atmospheric tension used to culture cells in the lab [13]. Determining the appropriate oxygen tension to culture cells in vitro is of utmost importance if reliable translational data can be obtained from in vitro experiments [13]
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