| Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. | |
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MedLine Citation:
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PMID: 21788346 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-07-25 |
Journal Detail:
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Title: Cancer research Volume: 71 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-09-15 Completed Date: 2011-11-23 Revised Date: 2012-09-28 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 6061-72 Citation Subset: IM |
Affiliation:
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Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals 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 Humans Intercellular Signaling Peptides and Proteins / biosynthesis, deficiency, genetics Intermediate Filament Proteins / metabolism Membrane Proteins / biosynthesis, deficiency, genetics Mice 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 | |
ID/Acronym/Agency:
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R01 CA148621/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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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/Nerve Tissue Proteins; 0/Peptides; 0/RNA, Small Interfering; 0/Receptors, Notch; 0/nestin; 134324-36-0/Serrate proteins |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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