Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype.
Elsevier (Cell Press)
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Phoenix, T., Patmore, D., Boop, S., Boulos, N., Jacus, M., Patel, Y., Roussel, M., et al. (2016). Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype.. Cancer Cell, 29 (4), 508-522. https://doi.org/10.1016/j.ccell.2016.03.002
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.
Animals, Antineoplastic Agents, Blood-Brain Barrier, Carrier Proteins, Cerebellar Neoplasms, Culture Media, Conditioned, Disease Models, Animal, Drug Resistance, Neoplasm, Endothelium, Vascular, Genetic Association Studies, Genetic Vectors, Genotype, Glucose Transporter Type 1, Humans, Medulloblastoma, Membrane Proteins, Mice, Mice, Transgenic, Neoplasm Proteins, Paracrine Communication, Pericytes, Recombinant Fusion Proteins, Tight Junctions, Transduction, Genetic, Vincristine, Wnt Proteins, Wnt Signaling Pathway
This work was supported by grants from the NIH (R.J.G., P01CA96832 and P30CA021765), the American Lebanese Syrian Associated Charities and Cancer Research UK.
National Cancer Institute (NCI) (R01CA129541)
National Cancer Institute (NCI) (P01CA096832)
External DOI: https://doi.org/10.1016/j.ccell.2016.03.002
This record's URL: https://www.repository.cam.ac.uk/handle/1810/254416
Attribution-NonCommercial-NoDerivs 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by-nc-nd/2.0/uk/
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