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Cancer Cell. 2016 Apr 11;29(4):508-22. doi: 10.1016/j.ccell.2016.03.002. Epub 2016 Mar 31.

Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype.

Author information

1
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
2
Li Ka Shing Centre, CRUK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, England.
3
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
4
Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
5
Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
6
Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
7
Department of Neurology and Neurological Sciences, Stanford University Medical Center, 1201 Welch Road, Stanford, CA 94305, USA.
8
Department of Neurology and Neurological Sciences, Stanford University Medical Center, 1201 Welch Road, Stanford, CA 94305, USA; Department of Neurosurgery, Stanford University Medical Center, 1201 Welch Road, Stanford, CA 94305, USA.
9
Li Ka Shing Centre, CRUK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, England. Electronic address: richard.gilbertson@cruk.cam.ac.uk.

Abstract

The childhood brain tumor, medulloblastoma, includes four subtypes with very different prognoses. Here, we show that paracrine signals driven by mutant β-catenin in WNT-medulloblastoma, an essentially curable form of the disease, induce an aberrant fenestrated vasculature that permits the accumulation of high levels of intra-tumoral chemotherapy and a robust therapeutic response. In contrast, SHH-medulloblastoma, a less curable disease subtype, contains an intact blood brain barrier, rendering this tumor impermeable and resistant to chemotherapy. The medulloblastoma-endothelial cell paracrine axis can be manipulated in vivo, altering chemotherapy permeability and clinical response. Thus, medulloblastoma genotype dictates tumor vessel phenotype, explaining in part the disparate prognoses among medulloblastoma subtypes and suggesting an approach to enhance the chemoresponsiveness of other brain tumors.

PMID:
27050100
PMCID:
PMC4829447
[Available on 2017-04-11]
DOI:
10.1016/j.ccell.2016.03.002
[Indexed for MEDLINE]

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