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.
Copyright © 2016 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacokinetics
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Blood-Brain Barrier*
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Carrier Proteins / physiology
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Cerebellar Neoplasms / blood supply
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Cerebellar Neoplasms / classification
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Cerebellar Neoplasms / drug therapy
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Cerebellar Neoplasms / genetics*
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Cerebellar Neoplasms / metabolism
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Culture Media, Conditioned / pharmacology
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Disease Models, Animal
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Drug Resistance, Neoplasm / physiology
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Endothelium, Vascular / metabolism
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Endothelium, Vascular / ultrastructure
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Genetic Association Studies
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Genetic Vectors / therapeutic use
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Genotype
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Glucose Transporter Type 1 / physiology
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Humans
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Medulloblastoma / blood supply
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Medulloblastoma / classification
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Medulloblastoma / drug therapy
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Medulloblastoma / genetics*
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Medulloblastoma / metabolism
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Membrane Proteins / physiology
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Mice
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Mice, Transgenic
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Neoplasm Proteins / physiology
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Paracrine Communication / drug effects
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Pericytes / pathology
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Recombinant Fusion Proteins / metabolism
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Tight Junctions / ultrastructure
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Transduction, Genetic
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Vincristine / pharmacokinetics
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Vincristine / therapeutic use
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Wnt Proteins / genetics
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Wnt Proteins / physiology
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Wnt Signaling Pathway / drug effects
Substances
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Antineoplastic Agents
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Carrier Proteins
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Culture Media, Conditioned
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Glucose Transporter Type 1
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Membrane Proteins
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Neoplasm Proteins
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PLVAP protein, human
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Recombinant Fusion Proteins
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SLC2A1 protein, human
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WNT7A protein, human
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Wnt Proteins
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Vincristine