Abstract
Malignancy of glioblastoma multiforme (GBM), the most common and aggressive form of human brain tumor, strongly depends on its enhanced cell invasion and death evasion which make surgery and accompanying therapies highly ineffective. Several ion channels that regulate membrane potential, cytosolic Ca2+ concentration and cell volume in GBM cells play significant roles in sustaining these processes. Among them, the volume-regulated anion channel (VRAC), which mediates the swelling-activated chloride current (IClswell) and is highly expressed in GBM cells, arguably plays a major role. VRAC is primarily involved in reestablishing the original cell volume that may be lost under several physiopathological conditions, but also in sustaining the shape and cell volume changes needed for cell migration and proliferation. While experimentally VRAC is activated by exposing cells to hypotonic solutions that cause the increase of cell volume, in vivo it is thought to be controlled by several different stimuli and modulators. In this review we focus on our recent work showing that two conditions normally occurring in pathological GBM tissues, namely high serum levels and severe hypoxia, were both able to activate VRAC, and their activation was found to promote cell migration and resistance to cell death, both features enhancing GBM malignancy. Also, the fact that the signal transduction pathway leading to VRAC activation appears to involve GBM specific intracellular components, such as diacylglicerol kinase and phosphatidic acid, reportedly not involved in the activation of VRAC in healthy tissues, is a relevant finding. Based on these observations and the impact of VRAC in the physiopathology of GBM, targeting this channel or its intracellular regulators may represent an effective strategy to contrast this lethal tumor.
Highlights
Malignancy of glioblastoma multiforme (GBM), the most common and aggressive form of human brain tumor, strongly depends on its enhanced cell invasion and death evasion which make surgery and accompanying therapies highly ineffective
Given that zero fetal calf serum (FCS)/bFGF+EGF medium is known to enrich for GBM stem cells while FCS promotes cell differentiation, these results suggest that GBM stem cells behave as the neural stem cells residing in the subventricular area, which remain in situ, while neuroblasts move towards the olfactory bulb
Knowing that sustained hypoxia-induced cell swelling is usually regarded as a death insult, we guessed that the hypoxia-activated volume-regulated anion channel (VRAC) in GBM cells would represent a survival reaction to limit cell swelling and prevent necrotic death, which often occur under hypoxic conditions (Figure 5b)
Summary
Glioblastoma (GBM) is the most common and aggressive primary brain tumor [1,2]. It normally results in the patient death within 15 months, despite modern diagnostics and treatments [3,4]. Recent advances in molecular genetics have shown that the previous categories into which gliomas were grouped, based on their histological features, correlate surprisingly well with only a small number of frequently occurring molecular traits In accordance with these observations and the 2016 revised criteria of the World Health Organization, gliomas can be subdivided into three major groups based on only two parameters: the mutation status of isocitrate dehydrogenase 1 (IDH1, a protein mutated in most low-grade infiltrating gliomas, and detected by immunohistochemical staining) and the deletion status of chromosome arms. The PI3Ks family is involved in the control of cell adhesion and actin reorganization during cell migration [20,21], and its aberrant activation in GBM is associated with increasing tumor grade and with high motility and invasion rates [22,23]
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