PMID- 20506127
OWN - NLM
STAT- MEDLINE
DCOM- 20100913
LR  - 20220331
IS  - 1549-4918 (Electronic)
IS  - 1066-5099 (Print)
IS  - 1066-5099 (Linking)
VI  - 28
IP  - 6
DP  - 2010 Jun
TI  - Inhibition of notch signaling in glioblastoma targets cancer stem cells via an 
      endothelial cell intermediate.
PG  - 1019-29
LID - 10.1002/stem.429 [doi]
AB  - Glioblastoma multiforme (GBM) is a highly heterogeneous malignant tumor. Recent 
      data suggests the presence of a hierarchical organization within the GBM cell 
      population that involves cancer cells with stem-like behavior, capable of 
      repopulating the tumor and contributing to its resistance to therapy. Tumor stem 
      cells are thought to reside within a vascular niche that provides structural and 
      functional support. However, most GBM studies involve isolated tumor cells grown 
      under various culture conditions. Here, we use a novel three-dimensional 
      organotypic "explant" system of surgical GBM specimens that preserves 
      cytoarchitecture and tumor stroma along with tumor cells. Notch inhibition in 
      explants results in decreased proliferation and self-renewal of tumor cells but 
      is also associated with a decrease in endothelial cells. When endothelial cells 
      are selectively eliminated from the explants via a toxin conjugate, we also 
      observed a decrease in self-renewal of tumor stem cells. These findings support a 
      critical role for tumor endothelial cells in GBM stem cell maintenance, mediated 
      at least in part by Notch signaling. The explant system further highlighted 
      differences in the response to radiation between explants and isolated tumor 
      neurospheres. Combination treatment with Notch blockade and radiation resulted in 
      a substantial decrease in proliferation and in self-renewal in tumor explants 
      while radiation alone was less effective. This data suggests that the Notch 
      pathway plays a critical role in linking angiogenesis and cancer stem cell 
      self-renewal and is thus a potential therapeutic target. Three-dimensional 
      explant systems provide a novel approach for the study of tumor and 
      microenvironment interactions.
FAU - Hovinga, Koos E
AU  - Hovinga KE
AD  - Department of Neurosurgery, Memorial Sloan Kettering Cancer Center and Weill 
      Cornell Medical College, New York, NY, USA.
FAU - Shimizu, Fumiko
AU  - Shimizu F
FAU - Wang, Rong
AU  - Wang R
FAU - Panagiotakos, Georgia
AU  - Panagiotakos G
FAU - Van Der Heijden, Maartje
AU  - Van Der Heijden M
FAU - Moayedpardazi, Hamideh
AU  - Moayedpardazi H
FAU - Correia, Ana Sofia
AU  - Correia AS
FAU - Soulet, Denis
AU  - Soulet D
FAU - Major, Tamara
AU  - Major T
FAU - Menon, Jayanthi
AU  - Menon J
FAU - Tabar, Viviane
AU  - Tabar V
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Stem Cells
JT  - Stem cells (Dayton, Ohio)
JID - 9304532
RN  - 0 (Receptors, Notch)
SB  - IM
MH  - Apoptosis
MH  - Cell Proliferation/drug effects/radiation effects
MH  - Cell Separation/*methods
MH  - Endothelial Cells/cytology/*metabolism
MH  - Glioblastoma/blood supply/*metabolism/pathology
MH  - Humans
MH  - Neoplastic Stem Cells/cytology/drug effects/*metabolism/radiation effects
MH  - Receptors, Notch/antagonists & inhibitors/metabolism
MH  - *Signal Transduction/drug effects/radiation effects
MH  - Tissue Culture Techniques/*methods
PMC - PMC5532884
MID - NIHMS874623
COIS- Disclosure of Potential Conflict of Interests The authors indicate no potential 
      conflicts of interest.
EDAT- 2010/05/28 06:00
MHDA- 2010/09/14 06:00
PMCR- 2017/07/28
CRDT- 2010/05/28 06:00
PHST- 2010/05/28 06:00 [entrez]
PHST- 2010/05/28 06:00 [pubmed]
PHST- 2010/09/14 06:00 [medline]
PHST- 2017/07/28 00:00 [pmc-release]
AID - 10.1002/stem.429 [doi]
PST - ppublish
SO  - Stem Cells. 2010 Jun;28(6):1019-29. doi: 10.1002/stem.429.