Ion Channels and Amino Acid Transporters Support the Growth and Invasion of Primary Brain Tumors

Abstract

The malignant growth of glial support cells causes gliomas, highly invasive, primary brain tumors that are largely resistant to therapy. Individual tumor cells spread by active cell migration, invading diffusely into the normal brain. This process is facilitated by Cl -channels that endow glioma cells with an enhanced ability to quickly adjust their shape and cell volume to fit the narrow and tortuous extracellular brain spaces. Once satellite tumors enlarge, their growth is limited by the spatial constraints imposed by the bony cavity of the skull and spinal column. Glioma cells circumvent this limitation by active destruction of peritumoral neural tissue through the release of glutamate, inducing peritumoral seizures and ultimately excitotoxic neuronal cell death. Hence, primary brain tumors support their unusual biology by taking advantage of ion channels and transporters that are designed to support ion homeostatic functions in normal brain.

Extracellular thiol-assisted selenium uptake dependent on the x c − cystine transporter explains the cancer-specific cytotoxicity of selenite

“…Selenium was enriched 10-to 13-fold compared with normal brain tissue, and positive scans were achieved as early as 4 h after injection, suggesting a high-affinity uptake. The x c Ϫ antiporter has been particularly associated with brain tumors, in which glutamate release also might be involved in destruction of neuronal tissue during tumor invasion (18); for example, the x c Ϫ antiporter was prominently expressed in all samples derived from 5 glioma patients (19). Furthermore, sodium selenite has been shown to induce superoxide-mediated mitochondrial damage and subsequent autophagic cell death in 3 malignant glioma cell lines (20).…”

Haploinsufficiency of Atp2a2, Encoding the Sarco(endo)plasmic Reticulum Ca2+-ATPase Isoform 2 Ca2+ Pump, Predisposes Mice to Squamous Cell Tumors via a Novel Mode of Cancer Susceptibility

“…The contribution of transport proteins to tumor growth and invasion is only beginning to be elucidated (22). Analyses of the Atp2a2 +/À mouse, which lacks one copy of the gene encoding the ubiquitous ER Ca 2+ pump, is important as it is the first animal model to establish a direct link between altered Ca 2+ handling and cancer.…”

914 Blood Glutamate Scavengers Prolong the Survival of Rats and Mice With Brain-implanted Gliomas

“…This ability stems from the fact that excess Glu in the peritumoral space of gliomas plays a crucial role in glioma invasiveness. Glu released via the Glu-Cystine exchanger kills neighboring neurons and allows the tumor to occupy an ever increasing space within the brain [2][3][4]. Our results demonstrate that treatment with blood Glu scavengers clearly contributes to the inhibition of the glioma invasiveness as well as to the survival of the treated animals.…”

“…In the last few years, an ever increasing body of data have suggested that L-Glutamate (Glu) plays a crucial role in the growth of malignant gliomas, their invasiveness and ability to destroy neighboring brain tissue while being also the possible cause of the tumor-associated seizures that often occur in conjunction with gliomas [1][2][3][4].…”