title: Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA.
authors.forename: Koos E
authors.initials: KE
authors.lastname: Hovinga
authors.forename: Fumiko
authors.initials: F
authors.lastname: Shimizu
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.forename: Georgia
authors.initials: G
authors.lastname: Panagiotakos
authors.forename: Maartje
authors.initials: M
authors.lastname: Van Der Heijden
authors.forename: Hamideh
authors.initials: H
authors.lastname: Moayedpardazi
authors.forename: Ana Sofia
authors.initials: AS
authors.lastname: Correia
authors.forename: Denis
authors.initials: D
authors.lastname: Soulet
authors.forename: Tamara
authors.initials: T
authors.lastname: Major
authors.forename: Jayanthi
authors.initials: J
authors.lastname: Menon
authors.forename: Viviane
authors.initials: V
authors.lastname: Tabar
mesh_terms: D017209:Apoptosis; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002469:Cell Separation / Q000379:methods*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005909:Glioblastoma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D046509:Tissue Culture Techniques / Q000379:methods*
chemical_list: D051880:Receptors, Notch