Patient-derived orthotopic xenograft models of medulloblastoma lack a functional blood-brain barrier.

Animals Blood-Brain Barrier Cell Line, Tumor Cerebellar Neoplasms Child Hedgehog Proteins Heterografts Humans Medulloblastoma Mice
blood-brain barrier magnetic resonance imaging medulloblastoma patient-derived xenograft models vasculature

Journal

Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420

Informations de publication

Date de publication:
05 05 2021
Historique:
pubmed: 2 12 2020
medline: 21 5 2021
entrez: 1 12 2020
Statut: ppublish

Résumé

Novel targeted therapies for children diagnosed with medulloblastoma (MB), the most common malignant pediatric brain tumor, are urgently required. A major hurdle in the development of effective therapies is the impaired delivery of systemic therapies to tumor cells due to a specialized endothelial blood-brain barrier (BBB). Accordingly, the integrity of the BBB is an essential consideration in any preclinical model used for assessing novel therapeutics. This study sought to assess the functional integrity of the BBB in several preclinical mouse models of MB. Dynamic contrast enhancement magnetic resonance imaging (MRI) was used to evaluate blood-brain-tumor barrier (BBTB) permeability in a murine genetically engineered mouse model (GEMM) of Sonic Hedgehog (SHH) MB, patient-derived orthotopic xenograft models of MB (SHH and Gp3), and orthotopic transplantation of GEMM tumor cells, enabling a comparison of the direct effects of transplantation on the integrity of the BBTB. Immunofluorescence analysis was performed to compare the structural and subcellular features of tumor-associated vasculature in all models. Contrast enhancement was observed in all transplantation models of MB. No contrast enhancement was observed in the GEMM despite significant tumor burden. Cellular analysis of BBTB integrity revealed aberrancies in all transplantation models, correlating to the varying levels of BBTB permeability observed by MRI in these models. These results highlight functional differences in the integrity of the BBTB and tumor vessel phenotype between commonly utilized preclinical models of MB, with important implications for the preclinical evaluation of novel therapeutic agents for MB.

Sections du résumé

BACKGROUND
Novel targeted therapies for children diagnosed with medulloblastoma (MB), the most common malignant pediatric brain tumor, are urgently required. A major hurdle in the development of effective therapies is the impaired delivery of systemic therapies to tumor cells due to a specialized endothelial blood-brain barrier (BBB). Accordingly, the integrity of the BBB is an essential consideration in any preclinical model used for assessing novel therapeutics. This study sought to assess the functional integrity of the BBB in several preclinical mouse models of MB.
METHODS
Dynamic contrast enhancement magnetic resonance imaging (MRI) was used to evaluate blood-brain-tumor barrier (BBTB) permeability in a murine genetically engineered mouse model (GEMM) of Sonic Hedgehog (SHH) MB, patient-derived orthotopic xenograft models of MB (SHH and Gp3), and orthotopic transplantation of GEMM tumor cells, enabling a comparison of the direct effects of transplantation on the integrity of the BBTB. Immunofluorescence analysis was performed to compare the structural and subcellular features of tumor-associated vasculature in all models.
RESULTS
Contrast enhancement was observed in all transplantation models of MB. No contrast enhancement was observed in the GEMM despite significant tumor burden. Cellular analysis of BBTB integrity revealed aberrancies in all transplantation models, correlating to the varying levels of BBTB permeability observed by MRI in these models.
CONCLUSIONS
These results highlight functional differences in the integrity of the BBTB and tumor vessel phenotype between commonly utilized preclinical models of MB, with important implications for the preclinical evaluation of novel therapeutic agents for MB.

Identifiants

DOI: 10.1093/neuonc/noaa266 PMID: 33258962 PMC: PMC8099473
pubmed: 33258962
pii: 6015057
doi: 10.1093/neuonc/noaa266
pmc: PMC8099473
doi:

Substances chimiques

Hedgehog Proteins 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

732-742

Commentaires et corrections

Type : CommentIn

Informations de copyright

© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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Auteurs

Laura A Genovesi (LA)

The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Queensland, Australia.
Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia.
ORCID: 0000-0001-6277-8422

Simon Puttick (S)

Probing Biosystems Future Science Platform, Commonwealth Scientific and Industrial Research Organization, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
ORCID: 0000-0003-3909-2646

Amanda Millar (A)

The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Queensland, Australia.

Marija Kojic (M)

The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Queensland, Australia.

Pengxiang Ji (P)

The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Queensland, Australia.

Anne K Lagendijk (AK)

Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia.

Caterina Brighi (C)

Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland, Australia.
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Queensland, St Lucia, Queensland, Australia.

Claudine S Bonder (CS)

Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia.
Adelaide Medical School, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia.

Christelle Adolphe (C)

The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Queensland, Australia.

Brandon J Wainwright (BJ)

The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Woolloongabba, Queensland, Australia.
Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland, Australia.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Patient-derived orthotopic xenograft models of...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Barrière hémato-encéphalique › Patient-derived orthotopic xenograft models of...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Patient-derived orthotopic xenograft models of...
questionsmedicales.fr › Maladies du système nerveux › Tumeurs du système nerveux › Tumeurs du système nerveux central › Tumeurs du cerveau › Tumeurs sous-tentorielles › Tumeurs du cervelet › Patient-derived orthotopic xenograft models of...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Patient-derived orthotopic xenograft models of...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Protéines Hedgehog › Patient-derived orthotopic xenograft models of...
questionsmedicales.fr › Régions du corps › Transplants › Hétérogreffes › Patient-derived orthotopic xenograft models of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Patient-derived orthotopic xenograft models of...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroépitheliales › Tumeurs neuroectodermiques primitives › Médulloblastome › Patient-derived orthotopic xenograft models of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Patient-derived orthotopic xenograft models of...