title: Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells.
abstract: 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.
authors.affiliation: Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Thant S
authors.initials: TS
authors.lastname: Zhu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Costello
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Talsma
authors.forename: Callie G
authors.initials: CG
authors.lastname: Flack
authors.forename: Jessica G
authors.initials: JG
authors.lastname: Crowley
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Hamm
authors.forename: Xiaobing
authors.initials: X
authors.lastname: He
authors.forename: Shawn L
authors.initials: SL
authors.lastname: Hervey-Jumper
authors.forename: Jason A
authors.initials: JA
authors.lastname: Heth
authors.forename: Karin M
authors.initials: KM
authors.lastname: Muraszko
authors.forename: Francesco
authors.initials: F
authors.lastname: DiMeco
authors.forename: Angelo L
authors.initials: AL
authors.lastname: Vescovi
authors.forename: Xing
authors.initials: X
authors.lastname: Fan
mesh_terms: D000071916:AC133 Antigen; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D048708:Cell Growth Processes / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D010455:Peptides / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D051880:Receptors, Notch / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D055153:Stem Cell Niche; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D007381:Intermediate Filament Proteins; D008565:Membrane Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D010455:Peptides; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins