Ion Channels in GBM Cell Migration and Death

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This entry is adapted from the peer-reviewed paper 10.3390/biom13121742

Ca²⁺-activated K⁺ channels of large- and intermediate-conductance (BK and IK, respectively) and the volume-regulated anion channel (VRAC), are the main K⁺ and Cl^- channels highly-expressed in glioblastoma (GBM) cells, where they play an essential role in the control of cell volume and, in turn, migration, invasion, and apoptotic cell death, the three main features underlying GBM malignancy and lethality.

cell death glioblastoma hypoxia

1. Glioblastoma

Glioblastoma (GBM) is the most common and aggressive type of brain tumor. It has been classified by the World Health Organization (WHO) as a grade IV astrocytoma among the four grades (I–IV) of greater progressive malignancy, defined according to clinical and histopathological criteria, such as excessive hypercellularity, endothelial cell hypertrophy, microvascular hyperplasia and necrotic areas. GBM is not curable and patients’ median survival, applying the best standard care possible, is around 15 months from diagnosis ^[1]^[2]. The current standard treatment includes surgical tumor resection based on pre-operative magnetic resonance images (if available), followed by radiotherapy and chemotherapy (with temozolomide) ^[3]^[4]^[5]. Full surgical resection of the tumor, on which most hopes for solid tumors are focused, is never feasible or complete for GBM due to its high invasiveness. As result, although surgery can significantly increase patient survival, it is never resolving and eventually tumor progression continues and patient death occurs. The high migratory and invasive potential, which is responsible for the widespread infiltration of tumor cells into the healthy brain parenchyma, and the formation of new foci are therefore the main problems in GBM tumors.

GBM cells invade following different routes, mainly through the brain parenchyma, white matter tracts and blood vessels ^[6]. Using the magnetic resonance imaging of GBM patients, Esmaeili and coworkers found a preferential direction of GBM cell migration along the white matter fibers ^[7], confirming earlier studies from Sontheimer’s laboratory ^[8].

2. Ion Channels in GBM Cell Migration and Death

The basic mechanism underlying the migration of GBM cells, indeed of cells in general, can be described as the cyclic succession of two distinct processes: the protrusion of the cell front, due to actin polymerization with the formation of pseudopods, and the retraction of the rear cell body, due to forces produced by actomyosin contraction. Both processes, to develop properly, must be accompanied by the local remodeling of the cell volume and shape ^[9]^[10]^[11], a notion confirmed by live imaging studies in glioma cells ^[8]. These major remodeling of the cell shape and volume are made possible by the complex interplay of ion channels and transporters outlined below ^[11]^[12]^[13]^[14]^[15].

At the leading edge of GBM cells, the activation of the Na⁺/K⁺/2Cl⁻ cotransporter (NKCC1), which brings one Na⁺, one K⁺ and two Cl^– ions inside the cell, accompanied by the iso-osmotic influx of water, leads to an increase in cell volume ^[16]. For the cell to move forward, the protrusion of the cell front must be followed by the retraction of the rear end, which, as shown in Figure 1, results in a significant decrease in cell volume by the extrusion of ions (i.e., K⁺ and Cl⁻) and osmotic water ^[9]^[10]^[11]. More precisely, the retraction of the trailing edge begins with the activation of MSCs and VRAC, which occurs in response to the stretching of the membrane caused by the NKCC1-dependent increase in cell volume. The activation of the MSCs and the consequent Ca²⁺ influx activate the K_Ca channels and the efflux of K⁺ ions that, in combination with the efflux of Cl⁻ through the VRAC and osmotic water, results in the reduction of cell volume required for the retraction of the rear end (Figure 1).

Figure 1. The basic hydrodynamic model of GBM cell migration. GBM cells express ion channels and transporters that underlie shape and volume changes, steps required for cell migration. These include, in the leading edge, NKCC1, and, in the trailing edge, VRAC, K_Ca and the MSC channels. The migration cycle includes the uptake of Na⁺, K⁺ and Cl⁻ ions al the leading edge, which attracts osmotic water, resulting in a volume increase and leading edge protrusion. This stretches the membrane and activates both MSC and VRAC at the trailing edge. The resulting Ca²⁺ influx activates the K_Ca channels, determining in this way the efflux of K⁺ and Cl⁻ ions, followed by osmotic water, and a decrease in volume at the trailing edge, promoting its retraction.

These hydrodynamic events, involving the concerted transmembrane flow of ions and osmotic water and consequent changes in shape and volume, help GBM cells to invade the brain parenchyma. It is important to emphasize, however, that they only have a permissive or facilitatory role in the process, with no implications for tumor initiation ^[9].

Volume changes induced by ion channels are also crucial for cell death. In GBM, K_Ca channels have been implicated in the so-called apoptotic volume decrease (AVD), a mechanism whereby the cell reduces its volume before apoptosis (Figure 2, left branch). Using a grade IV human GBM cell line, Sontheimer and coworkers examined the contribution of K_Ca channels to AVD after the addition of either staurosporine or TRAIL to activate the intrinsic or extrinsic pathway of apoptosis, respectively ^[17]. The use of specific K_Ca channel inhibitors revealed that staurosporine-induced AVD was dependent on K⁺ efflux through IK channels, while TRAIL-induced AVD was mediated by BK channels. Conversely, an increase in cell volume, called necrotic volume increase (NVI), is observed during necrosis (Figure 2, right branch). This is mainly caused by the influx of NaCl, due to the reduced energy supply and activity of the Na⁺/K⁺ pump, followed by the osmotically driven entry of water. This second type of death is particularly interesting in this context, since GBM cells need to develop strategies to resist hypoxic-induced necrosis.

Figure 2. Schematic representation of the role of ion channels in the regulation of cell volume during cell death. Upon persistent death insult, cell shrinkage and cell swelling are hallmarks of the early phases of apoptotic and necrotic cell death, respectively. The early-phase shrinkage of apoptotic cells is termed apoptotic volume decrease (AVD) and is mediated by Cl⁻ and K⁺ channels and the net efflux of KCl, which promotes the osmotic loss of water from the cell. The early-phase swelling of necrotic cells is termed necrotic volume increase (NVI) and is mainly mediated by the transport of Na⁺ and Cl⁻ ions inside the cell, with the resulting influx of water from the extracellular environment. Inspired by ^[18].

References

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Antonio Michelucci

Luigi Sforna

Fabio Franciolini

Luigi Catacuzzeno

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Update Date: 14 Dec 2023

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1. Glioblastoma

2. Ion Channels in GBM Cell Migration and Death

References