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

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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 (K trans) 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 K trans 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.

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Acknowledgments

This work was performed at the Duke Center for In Vivo Microscopy, an NIH/NIBIB National Biomedical Technology Resource Center (P41 EB015897 and 1S10OD010683-01). The authors wish to thank Ms. Sally Zimney for the careful editorial assistance. KGH is supported by NINDS R25 NS065731 (PI John Sampson). OJB is a Rory David Deutsch scholar, is supported by the Damon Runyon Cancer Research Foundation, and K02NS086917.

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    Authors and Affiliations

    1. Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA

      Ergys Subashi

    2. Center for In Vivo Microscopy, Duke University Medical Center, Box 3302, Durham, NC, 27710, USA

      Ergys Subashi, Yi Qi, John C. Nouls & G. Allan Johnson

    3. Division of Hematology-Oncology, Department of Pediatrics, Duke University Medical Center, Box 91001, Durham, NC, 27710, USA

      Francisco J. Cordero, Kyle G. Halvorson & Oren J. Becher

    4. Department of Pathology, Duke University Medical Center, Durham, NC, USA

      Francisco J. Cordero, Kyle G. Halvorson & Oren J. Becher

    5. Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA

      Francisco J. Cordero, Kyle G. Halvorson & Oren J. Becher

    6. Department of Radiology, Duke University Medical Center, Durham, NC, USA

      Yi Qi, John C. Nouls & G. Allan Johnson

    7. Department of Biomedical Engineering, Duke University Medical Center, Durham, NC, USA

      G. Allan Johnson

    8. Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA

      Kyle G. Halvorson

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    Ergys Subashi and Francisco J. Cordero have contributed equally to this work.

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    Subashi, E., Cordero, F.J., Halvorson, K.G. et al. Tumor location, but not H3.3K27M, significantly influences the blood–brain-barrier permeability in a genetic mouse model of pediatric high-grade glioma. J Neurooncol 126, 243–251 (2016). https://doi.org/10.1007/s11060-015-1969-9

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