Perinecrotic glioma proliferation and metabolic profile within an intracerebral tumor xenograft.
Intracerebral C6 glioma xenografts spontaneously develop centrally located necrotic regions that are bordered by densely packed neoplastic cells. Proliferative and metabolic heterogeneity in these perinecrotic regions were assessed by bromodeoxyuridine (BrdU) incorporation, by immunocytological and by histochemical analyses. The borders of necrotic regions are comprised of glioma cells that express increased levels of the type 1 glucose transporter (GLUT-1) with rare cells having incorporated BrdU. By contrast, BrdU-positive glioma cells are located immediately adjacent to GLUT-1-positive cells bordering areas of necrosis. BrdU-positive glioma cells are also scattered throughout poorly vascularized, central regions of the tumor and are present at the highly vascularized tumor periphery. GLUT-1 expression increased considerably when C6 glioma cells were grown for 48 h under either the acidotic conditions of pH 6.8 or under hypoxic conditions. The perinecrotic GLUT-1-positive glioma cells in poorly vascularized, centrally located tumor regions demonstrated a 75% reduction in glycogen content and negligible glycogenolytic capacity, when compared with normal brain white matter. Cytochrome c oxidase (COX) and lactate dehydrogenase (LDH) maintained 50% enzymatic activity compared to controls, while succinate dehydrogenase (SDH) activity was 25% of control values. Based upon these findings, a metabolic model is proposed in which GLUT-1-positive perinecrotic cells are growth arrested and predominantly rely upon non-oxidative glycolysis. It is further postulated that BrdU-positive, GLUT-1-negative glioma cells within the poorly vascularized, central tumor region convert glucose-6-phosphate to nucleotide precursors for DNA replication.
Gorin
Fredric
F
Department of Neurology, University of California Davis School of Medicine, 1515 Newton Court, Room 510, Davis, CA 95616, USA. fagorin@ucdavis.edu
Harley
William
W
Schnier
Joachim
J
Lyeth
Bruce
B
Jue
Thomas
T
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D003576:Electron Transport Complex IV / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005910:Glioma; D024981:Glycogen Phosphorylase / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry / Q000379:methods; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D009368:Neoplasm Transplantation / Q000379:methods; D009389:Neovascularization, Pathologic / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D013194:Staining and Labeling; D019802:Succinic Acid / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014183:Transplantation, Heterologous / Q000379:methods; D014407:Tumor Cells, Cultured
D027342:Excitatory Amino Acid Transporter 2; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D019802:Succinic Acid; D007770:L-Lactate Dehydrogenase; D003576:Electron Transport Complex IV; D024981:Glycogen Phosphorylase; D001973:Bromodeoxyuridine