Gliomas

Gliomas are tumours of the nervous system, which develop from glial cells; in fact they account for the majority of primary brain neoplasias. Clinically, gliomas are classified according to their malignancy (the WHO classification) into four grades: grade I covers benign tumours (e.g. pilocytic astrocytoma), groups II to IV are malignant neoplasias which differ in their aggressiveness; the most violent is glioblastoma, which belongs to group IV. Histopathologically, the gliomas are divided into astrocytomas, oligodendrocytomas and glioblastomas; although this division mostly relates to morphological similarity of tumour cell to the respective types of macroglia; the exact origin of the cancerous 'stem' cell cannot be revealed with much precision.

Biologically, the gliomas are very different from other neoplasias, as they express several systems which adapt them to malignant growth within the CNS environment. The main property of the latter is the lack of free space into which the tumour can grow, and the existence of firm boundaries (skull for the brain and vertebrae for spinal cord) which present additional restraints for neoplasia expansion. The second complication of the CNS architecture, from the point of view of cancerous growth, is a very complicated structure of parenchyma, formed by extremely narrow and low volume clefts; these prevent free dissemination of malignant cells through the tissue, which is so characteristic for tumour expansion in non-brain organs. Therefore, in order to grow gliomas must clear the space by actively eliminating the surrounding healthy cells, and actively propagate neoplasmic cells though the brain matter.

Malignant gliomas produce the room for their expansion by actively killing neurones in their vicinity. This is achieved by secretion of high amounts of glutamate, which in turn triggers excitotoxic, NMDA- and [Ca2+]i-dependent neuronal death. This glutamate-induced neuronal death also results in seizures, which often accompany malignant gliomas. The amount of glutamate synthesized and released by glioma cells is truly impressive: e.g. cultured glioma cells can increase glutamate concentration in their media from 1 ^M to 100 ^M within 5-6 hours. Release of glutamate is mediated through an electroneutral amino acid transporter

Schwann Cells
Figure 10.10 Glioma induced neuronal death. Glioma cells express high density of gluta-mate/cystine transporter; glutamate released by this transporter triggers excitotoxic neuronal death, thus clearing space for glioma invasion

which exchanges cystine for glutamate; this transporter is specifically expressed only in glioma cells (Figure 10.10). Glutamate excitotoxicity is critical for glioma expansion; inhibition of the cystine/glutamate transporter (which can be blocked by 4-carboxyphenylglycine) has been shown to significantly retard their growth. Cystine brought into the glioma cells is converted into glutathione, which increases resistance of tumour cells to oxidative stress.

The second important peculiarity of gliomas is represented by their active propagation through the nervous tissue. Glioma cells are able to travel through the brain, e.g. they easily migrate from one hemisphere to another. As a consequence, gliomas almost invariably disseminate through the whole brain. The mechanisms of glioma cell migration are several. First, they express a number of metallo-proteinases, which assist in breaking down the extracellular matrix, and produce migrating tunnels. Second, glioma cells are able to undergo substantial shrinkage, which helps them to attain an elongated shape and thus penetrate into narrow interstitial compartments. This loss of glioma cell volume is supported by several families of Cl- channels, which are activated by voltage or changes in osmolarity; in addition, glioma cells express Cl- permeable GABA receptors. Glioma cells have a high concentration of cytoplasmic Cl-, which sets the Cl- reversal potential at levels more positive than the resting potential (-40 mV); activation of Cl-channels therefore leads to Cl- efflux, which in turn drives water out of the cell, therefore reducing its volume (Figure 10.11). Inhibition of Cl- channels arrests the motility of glioma cells. Finally, glioma migration is also driven by cytosolic Ca2+ oscillations, which results from the activation of Ca2+-permeable AMPA receptors. Inhibition of Ca2+ permeability of AMPA receptors suppresses glioma dissemination and limits the tumour growth. All in all, glioma cells utilize several purely neural mechanisms to expand within the CNS; these mechanisms also render high malignancy and rapid clinical progression of glial-derived tumours.

Schwann Cell

Figure 10.11 Chloride and potassium channels assist glioma cell shrinkage; decrease in glioma cell volume greatly facilitates their invasive capabilities. To shrink, glioma cells release K+ and Cl- through ion channels, which induce water to leave the cells through aquaporins. The maintenance of K+ and Cl- concentration in glioma is accomplished by the activity of the NKCC Cl- transporter and the Na+ -K+ ATPase. (Modified from McFerrin MB, Sontheimer H (2006) A role for ion channels in glioma cell invasion. Neuron Glia Biol 2, 39-49)

Figure 10.11 Chloride and potassium channels assist glioma cell shrinkage; decrease in glioma cell volume greatly facilitates their invasive capabilities. To shrink, glioma cells release K+ and Cl- through ion channels, which induce water to leave the cells through aquaporins. The maintenance of K+ and Cl- concentration in glioma is accomplished by the activity of the NKCC Cl- transporter and the Na+ -K+ ATPase. (Modified from McFerrin MB, Sontheimer H (2006) A role for ion channels in glioma cell invasion. Neuron Glia Biol 2, 39-49)

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