Blockade of a Laminin-411-Notch Axis with CRISPR/Cas9 or a Nanobioconjugate Inhibits Glioblastoma Growth through Tumor-Microenvironment Cross-talk.
Animals
Apoptosis
Biomarkers, Tumor
/ genetics
Brain
/ metabolism
CRISPR-Cas Systems
Cell Proliferation
Gene Expression Regulation, Neoplastic
Glioblastoma
/ genetics
Humans
Laminin
/ antagonists & inhibitors
Mice
Mice, Nude
Nanoparticles
/ chemistry
Neoplastic Stem Cells
/ metabolism
Prognosis
Receptors, Notch
/ genetics
Signal Transduction
Survival Rate
Tumor Cells, Cultured
Tumor Microenvironment
Xenograft Model Antitumor Assays
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
15 03 2019
15 03 2019
Historique:
received:
31
08
2018
revised:
07
11
2018
accepted:
15
01
2019
pubmed:
20
1
2019
medline:
19
12
2019
entrez:
20
1
2019
Statut:
ppublish
Résumé
There is an unmet need for the treatment of glioblastoma multiforme (GBM). The extracellular matrix, including laminins, in the tumor microenvironment is important for tumor invasion and progression. In a panel of 226 patient brain glioma samples, we found a clinical correlation between the expression of tumor vascular laminin-411 (α4β1γ1) with higher tumor grade and with expression of cancer stem cell (CSC) markers, including Notch pathway members, CD133, Nestin, and c-Myc. Laminin-411 overexpression also correlated with higher recurrence rate and shorter survival of GBM patients. We also showed that depletion of laminin-411 α4 and β1 chains with CRISPR/Cas9 in human GBM cells led to reduced growth of resultant intracranial tumors in mice and significantly increased survival of host animals compared with mice with untreated cells. Inhibition of laminin-411 suppressed Notch pathway in normal and malignant human brain cell types. A nanobioconjugate potentially suitable for clinical use and capable of crossing blood-brain barrier was designed to block laminin-411 expression. Nanobioconjugate treatment of mice carrying intracranial GBM significantly increased animal survival and inhibited multiple CSC markers, including the Notch axis. This study describes an efficient strategy for GBM treatment via targeting a critical component of the tumor microenvironment largely independent of heterogeneous genetic mutations in glioblastoma.
Identifiants
pubmed: 30659021
pii: 0008-5472.CAN-18-2725
doi: 10.1158/0008-5472.CAN-18-2725
pmc: PMC6625517
mid: NIHMS1519369
doi:
Substances chimiques
Biomarkers, Tumor
0
Laminin
0
Receptors, Notch
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1239-1251Subventions
Organisme : NCI NIH HHS
ID : R01 CA188743
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY013431
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA196266
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA206220
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA151815
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY023429
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA209921
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
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