1. Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype.
- Author
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Phoenix TN, Patmore DM, Boop S, Boulos N, Jacus MO, Patel YT, Roussel MF, Finkelstein D, Goumnerova L, Perreault S, Wadhwa E, Cho YJ, Stewart CF, and Gilbertson RJ
- Subjects
- Animals, Antineoplastic Agents pharmacokinetics, Carrier Proteins physiology, Cerebellar Neoplasms blood supply, Cerebellar Neoplasms classification, Cerebellar Neoplasms drug therapy, Cerebellar Neoplasms metabolism, Culture Media, Conditioned pharmacology, Disease Models, Animal, Drug Resistance, Neoplasm physiology, Endothelium, Vascular metabolism, Endothelium, Vascular ultrastructure, Genetic Association Studies, Genetic Vectors therapeutic use, Genotype, Glucose Transporter Type 1 physiology, Humans, Medulloblastoma blood supply, Medulloblastoma classification, Medulloblastoma drug therapy, Medulloblastoma metabolism, Membrane Proteins physiology, Mice, Mice, Transgenic, Neoplasm Proteins physiology, Paracrine Communication drug effects, Pericytes pathology, Recombinant Fusion Proteins metabolism, Tight Junctions ultrastructure, Transduction, Genetic, Vincristine pharmacokinetics, Vincristine therapeutic use, Wnt Proteins genetics, Wnt Proteins physiology, Wnt Signaling Pathway drug effects, Blood-Brain Barrier, Cerebellar Neoplasms genetics, Medulloblastoma genetics
- 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.)
- Published
- 2016
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