Enhanced expression of the high affinity glutamate transporter GLT-1 in C6 glioma cells delays tumour progression in rat.
High grade gliomas are known to release excitotoxic concentrations of glutamate, a process thought to contribute to their malignant phenotype through enhanced autocrine stimulation of their proliferation and destruction of the surrounding nervous tissue. A model of C6 glioma cells in which expression of the high affinity glutamate transporter GLT-1 can be manipulated both in vivo and in vitro was used in order to investigate the consequences of increasing glutamate clearance on tumour progression. These cells were grafted in the striatum of Wistar rats and doxycycline was administered after validation of tumour development by magnetic resonance imaging. Both GLT-1 expression examined by immunohistochemistry and glutamate transport activity measured on synaptosomes appeared robustly increased in samples from doxycycline-treated animals. Moreover, these rats showed extended survival times as compared to vehicle-treated animals, an effect that was consistent with volumetric data revealing delayed tumour growth. As constitutive deficiency in glutamate clearance at the vicinity of brain tumours is well established, these data illustrate the potential benefit that could be obtained by enhancing glutamate transport by glioma cells in order to reduce their invasive behaviour.
Laboratory of Experimental Pharmacology, Université catholique de Louvain, 54.10, Av. Hippocrate 54, 1200 Brussels, Belgium.
Nicolas
N
Vanhoutte
Jorge
J
Abarca-Quinones
Bénédicte F
BF
Jordan
Bernard
B
Gallez
Jean-Marie
JM
Maloteaux
Emmanuel
E
Hermans
D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D045744:Cell Line, Tumor; D003342:Corpus Striatum / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004318:Doxycycline / Q000494:pharmacology; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000235:genetics; D008279:Magnetic Resonance Imaging / Q000379:methods; D009368:Neoplasm Transplantation / Q000379:methods; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014316:Tritium / Q000378:metabolism
D027342:Excitatory Amino Acid Transporter 2; C485184:enhanced green fluorescent protein; D014316:Tritium; D049452:Green Fluorescent Proteins; D001224:Aspartic Acid; D004318:Doxycycline