Tumor location, but not H3.3K27M, significantly influences the blood–brain-barrier permeability in a genetic mouse model of pediatric high-grade glioma

Ergys Subashi, Francisco J. Cordero, Kyle G. Halvorson, Yi Qi, John C. Nouls, Oren J. Becher*, G. Allan Johnson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Pediatric high-grade gliomas (pHGGs) occur with strikingly different frequencies in infratentorial and supratentorial regions. Although histologically these malignancies appear similar, they represent distinct diseases. Recent genomic studies have identified histone K27M H3.3/H3.1 mutations in the majority of brainstem pHGGs; these mutations are rarely encountered in pHGGs that arise in the cerebral cortex. Previous research in brainstem pHGGs suggests a restricted permeability of the blood–brain-barrier (BBB). In this work, we use dynamic contrast-enhanced (DCE) MRI to evaluate BBB permeability in a genetic mouse model of pHGG as a function of location (cortex vs. brainstem, n = 8 mice/group) and histone mutation (mutant H3.3K27M vs. wild-type H3.3, n = 8 mice/group). The pHGG models are induced either in the brainstem or the cerebral cortex and are driven by PDGF signaling and p53 loss with either H3.3K27M or wild-type H3.3. T2-weighted MRI was used to determine tumor location/extent followed by 4D DCE-MRI for estimating the rate constant (Ktrans) for tracer exchange across the barrier. BBB permeability was 67% higher in cortical pHGGs relative to brainstem pHGGs (t test, p = 0.012) but was not significantly affected by the expression of mutant H3.3K27M versus wild-type H3.3 (t-test, p = 0.78). Although mice became symptomatic at approximately the same time, the mean volume of cortical tumors was 3.6 times higher than the mean volume of brainstem tumors. The difference between the mean volume of gliomas with wild-type and mutant H3.3 was insignificant. Mean Ktrans was significantly correlated to glioma volume. These results present a possible explanation for the poor response of brainstem pHGGs to systemic therapy. Our findings illustrate a potential role played by the microenvironment in shaping tumor growth and BBB permeability.

Original languageEnglish (US)
Pages (from-to)243-251
Number of pages9
JournalJournal of Neuro-Oncology
Volume126
Issue number2
DOIs
StatePublished - 2016

Keywords

  • Blood–brain-barrier
  • DIPG
  • High-grade glioma
  • K27M
  • MRI
  • Perfusion
  • Permeability

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

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