Sun, Tao and Patil, Rameshwar and Galstyan, Anna and Klymyshyn, Dmytro and Ding, Hui and Chesnokova, Alexandra and Cavenee, Webster K. and Furnari, Frank B. and Ljubimov, Vladimir A. and Shatalova, Ekaterina S. and Wagner, Shawn and Li, Debiao and Mamelak, Adam N. and Bannykh, Serguei I. and Patil, Chirag G. and Rudnick, Jeremy D. and Hu, Jethro and Grodzinski, Zachary B. and Rekechenetskiy, Arthur and Falahatian, Vida and Lyubimov, Alexander V. and Chen, Yongmei L. and Leoh, Lai S. and Daniels-Wells, Tracy R. and Penichet, Manuel L. and Holler, Eggehard and Ljubimov, Alexander V. and Black, Keith L. and Ljubimova, Julia Y. (2019) Blockade of a Laminin-411-Notch Axis with CRISPR/Cas9 or a Nanobioconjugate Inhibits Glioblastoma Growth through Tumor-Microenvironment Cross-talk. CANCER RESEARCH, 79 (6). pp. 1239-1251. ISSN 0008-5472, 1538-7445
Full text not available from this repository. (Request a copy)Abstract
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 (alpha 4 beta 1 gamma 1) 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 alpha 4 and beta 1 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 sup-pressed 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 GBMsignificantly increased animal survival and inhibited multiple CSC markers, including the Notch axis. This study describes an efficient strategy for GBMtreatment via targeting a critical component of the tumor microenvironment largely independent of heterogeneous genetic mutations in glioblastoma. Significance: Laminin-411 expression in the glioma microenvironment correlates with Notch and other cancer stem cell markers and can be targeted by a novel, clinically translatable nanobioconjugate to inhibit glioma growth.
Item Type: | Article |
---|---|
Uncontrolled Keywords: | CELL MIGRATION; IN-VITRO; EXPRESSION; BRAIN; LAMININ-8; TARGET; HETEROGENEITY; EFFICACY; INVASION; PATHWAYS; |
Subjects: | 500 Science > 570 Life sciences |
Divisions: | Biology, Preclinical Medicine > Institut für Biophysik und physikalische Biochemie Biology, Preclinical Medicine > Institut für Biophysik und physikalische Biochemie > Alumni or Retired > Prof. Dr. Eggehard Holler |
Depositing User: | Dr. Gernot Deinzer |
Date Deposited: | 15 Apr 2020 10:48 |
Last Modified: | 15 Apr 2020 10:48 |
URI: | https://pred.uni-regensburg.de/id/eprint/27359 |
Actions (login required)
![]() |
View Item |