Tumor hypoxia: Impact on gene amplification in glioblastoma.
Gene amplification is frequently found in human glioblastoma but the mechanisms driving amplifications remain to be elucidated. Hypoxia as hallmark of glioblastoma is known to be involved in the induction of fragile sites that are central to gene amplification. We analyzed the potential of hypoxia (pO2 0%) and mini hypoxia (pO2 5%) to induce fragile sites within a homogeneously staining region (HSR) at 12q14-15 in a glioblastoma cell line (TX3868). Treatment of cells by hypoxia or by mini hypoxia induced double minutes (DMs) and caused breakage of the HSR structure at 12q14-15, suggesting a novel hypoxia inducible fragile site on 12q. Treatment with aphidicolin, a known fragile site inducer, indicates that the hypoxia inducible fragile site is a common fragile site. Reintegration of amplified sequences and occurrence of anaphase-bridge-like structures shows that mini hypoxia and hypoxia are able to initiate amplification processes in human glioblastoma cells. Hypoxia as known tumor microenvironment factor is crucial for the development of amplifications in glioblastoma. The identification and characterization of novel common fragile sites induced by hypoxia will improve the understanding of mechanisms underlying amplifications in glioblastoma.
Fischer
Ulrike
U
Institut für Humangenetik, Universitätskliniken des Saarlandes, D-66421 Homburg/Saar, Germany. hgufis@uniklinikum-saarland.de.
Radermacher
Jens
J
Mayer
Jens
J
Mehraein
Yasmin
Y
Meese
Eckart
E
D000818:Animals; D016590:Aphidicolin / Q000494:pharmacology; D001483:Base Sequence; D015687:Cell Hypoxia / Q000235:genetics; D043283:Chromosome Fragile Sites / Q000187:drug effects / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005784:Gene Amplification / Q000187:drug effects / Q000502:physiology*; D005909:Glioblastoma / Q000098:blood supply* / Q000235:genetics*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data
D004791:Enzyme Inhibitors; D016590:Aphidicolin