title: Glutamate as chemotactic fuel for diffuse glioma cells: are they glutamate suckers?
abstract: Diffuse gliomas comprise a group of primary brain tumors that originate from glial (precursor) cells and present as a variety of malignancy grades which have in common that they grow by diffuse infiltration. This phenotype complicates treatment enormously as it precludes curative surgery and radiotherapy. Furthermore, diffusely infiltrating glioma cells often hide behind a functional blood-brain barrier, hampering delivery of systemically administered therapeutic and diagnostic compounds to the tumor cells. The present review addresses the biological mechanisms that underlie the diffuse infiltrative phenotype, knowledge of which may improve treatment strategies for this disastrous tumor type. The invasive phenotype is specific for glioma: most other brain tumor types, both primary and metastatic, grow as delineated lesions. Differences between the genetic make-up of glioma and that of other tumor types may therefore help to unravel molecular pathways, involved in diffuse infiltrative growth. One such difference concerns mutations in the NADP(+)-dependent isocitrate dehydrogenase (IDH1 and IDH2) genes, which occur in >80% of cases of low grade glioma and secondary glioblastoma. In this review we present a novel hypothesis which links IDH1 and IDH2 mutations to glutamate metabolism, possibly explaining the specific biological behavior of diffuse glioma.
authors.affiliation: Radboud University Medical Centre, Department of Pathology, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Sanne A M
authors.initials: SA
authors.lastname: van Lith
authors.affiliation: Radboud University Medical Centre, Department of Pathology, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Navis
authors.affiliation: Radboud University Medical Centre, Department of Pathology, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Kiek
authors.initials: K
authors.lastname: Verrijp
authors.affiliation: Norlux Neuro-Oncology Laboratory, CRP-Santé Luxembourg, 84 Val Fleuri, L-1526, Luxembourg.
authors.forename: Simone P
authors.initials: SP
authors.lastname: Niclou
authors.affiliation: NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, N-5019 Bergen, Norway.
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
authors.affiliation: Radboud University Medical Centre, Department of Pathology, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; Department of Pathology, VU Medical Centre, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
authors.affiliation: Radboud University Medical Centre, Department of Pathology, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Tops
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Centre, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Remco
authors.initials: R
authors.lastname: Molenaar
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Centre, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Cornelis J F
authors.initials: CJ
authors.lastname: van Noorden
authors.affiliation: Radboud University Medical Centre, Department of Pathology, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: william.leenders@radboudumc.nl.
authors.forename: William P J
authors.initials: WP
authors.lastname: Leenders
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002633:Chemotaxis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D018698:Glutamic Acid / Q000494:pharmacology / Q000502:physiology*; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D005973:Glutamine; D018698:Glutamic Acid; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: 2-Hydroxyglutarate; Diffuse infiltration; Glioma; Glutamate; Isocitrate dehydrogenase; Metabolism