Document Detail

Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells.
MedLine Citation:
PMID:  21788346     Owner:  NLM     Status:  MEDLINE    
One important function of endothelial cells in glioblastoma multiforme (GBM) is to create a niche that helps promote self-renewal of cancer stem-like cells (CSLC). However, the underlying molecular mechanism for this endothelial function is not known. Since activation of NOTCH signaling has been found to be required for propagation of GBM CSLCs, we hypothesized that the GBM endothelium may provide the source of NOTCH ligands. Here, we report a corroboration of this concept with a demonstration that NOTCH ligands are expressed in endothelial cells adjacent to NESTIN and NOTCH receptor-positive cancer cells in primary GBMs. Coculturing human brain microvascular endothelial cells (hBMEC) or NOTCH ligand with GBM neurospheres promoted GBM cell growth and increased CSLC self-renewal. Notably, RNAi-mediated knockdown of NOTCH ligands in hBMECs abrogated their ability to induce CSLC self-renewal and GBM tumor growth, both in vitro and in vivo. Thus, our findings establish that NOTCH activation in GBM CSLCs is driven by juxtacrine signaling between tumor cells and their surrounding endothelial cells in the tumor microenvironment, suggesting that targeting both CSLCs and their niche may provide a novel strategy to deplete CSLCs and improve GBM treatment.
Thant S Zhu; Mark A Costello; Caroline E Talsma; Callie G Flack; Jessica G Crowley; Lisa L Hamm; Xiaobing He; Shawn L Hervey-Jumper; Jason A Heth; Karin M Muraszko; Francesco DiMeco; Angelo L Vescovi; Xing Fan
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-07-25
Journal Detail:
Title:  Cancer research     Volume:  71     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-09-15     Completed Date:  2011-11-23     Revised Date:  2014-05-23    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6061-72     Citation Subset:  IM    
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MeSH Terms
Antigens, CD / metabolism
Brain Neoplasms / metabolism,  pathology*
Calcium-Binding Proteins / biosynthesis,  deficiency,  genetics
Cell Growth Processes / physiology
Endothelial Cells / metabolism,  pathology*
Gene Knockdown Techniques
Glioblastoma / metabolism,  pathology*
Glycoproteins / metabolism
Intercellular Signaling Peptides and Proteins / biosynthesis,  deficiency,  genetics
Intermediate Filament Proteins / metabolism
Membrane Proteins / biosynthesis,  deficiency,  genetics
Neoplastic Stem Cells / metabolism,  pathology*
Nerve Tissue Proteins / metabolism
Peptides / metabolism
RNA, Small Interfering / administration & dosage,  genetics
Receptors, Notch / biosynthesis,  deficiency,  genetics,  metabolism*
Stem Cell Niche*
Xenograft Model Antitumor Assays
Grant Support
R01 CA148621/CA/NCI NIH HHS; R01 CA163737/CA/NCI NIH HHS
Reg. No./Substance:
0/AC133 antigen; 0/Antigens, CD; 0/Calcium-Binding Proteins; 0/DLL4 protein, human; 0/Glycoproteins; 0/Intercellular Signaling Peptides and Proteins; 0/Intermediate Filament Proteins; 0/Membrane Proteins; 0/NES protein, human; 0/Nerve Tissue Proteins; 0/Nes protein, mouse; 0/Nestin; 0/Peptides; 0/RNA, Small Interfering; 0/Receptors, Notch; 134324-36-0/Serrate proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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