title: Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells.
abstract: Glioblastoma is a highly angiogenetic malignancy, the neoformed vessels of which are thought to arise by sprouting of pre-existing brain capillaries. The recent demonstration that a population of glioblastoma stem-like cells (GSCs) maintains glioblastomas indicates that the progeny of these cells may not be confined to the neural lineage. Normal neural stem cells are able to differentiate into functional endothelial cells. The connection between neural stem cells and the endothelial compartment seems to be critical in glioblastoma, where cancer stem cells closely interact with the vascular niche and promote angiogenesis through the release of vascular endothelial growth factor (VEGF) and stromal-derived factor 1 (refs 5-9). Here we show that a variable number (range 20-90%, mean 60.7%) of endothelial cells in glioblastoma carry the same genomic alteration as tumour cells, indicating that a significant portion of the vascular endothelium has a neoplastic origin. The vascular endothelium contained a subset of tumorigenic cells that produced highly vascularized anaplastic tumours with areas of vasculogenic mimicry in immunocompromised mice. In vitro culture of GSCs in endothelial conditions generated progeny with phenotypic and functional features of endothelial cells. Likewise, orthotopic or subcutaneous injection of GSCs in immunocompromised mice produced tumour xenografts, the vessels of which were primarily composed of human endothelial cells. Selective targeting of endothelial cells generated by GSCs in mouse xenografts resulted in tumour reduction and degeneration, indicating the functional relevance of the GSC-derived endothelial vessels. These findings describe a new mechanism for tumour vasculogenesis and may explain the presence of cancer-derived endothelial-like cells in several malignancies.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Ricci-Vitiani
authors.forename: Roberto
authors.initials: R
authors.lastname: Pallini
authors.forename: Mauro
authors.initials: M
authors.lastname: Biffoni
authors.forename: Matilde
authors.initials: M
authors.lastname: Todaro
authors.forename: Gloria
authors.initials: G
authors.lastname: Invernici
authors.forename: Tonia
authors.initials: T
authors.lastname: Cenci
authors.forename: Giulio
authors.initials: G
authors.lastname: Maira
authors.forename: Eugenio Agostino
authors.initials: EA
authors.lastname: Parati
authors.forename: Giorgio
authors.initials: G
authors.lastname: Stassi
authors.forename: Luigi Maria
authors.initials: LM
authors.lastname: Larocca
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002869:Chromosome Aberrations; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D004730:Endothelium, Vascular / Q000473:pathology*; D005909:Glioblastoma / Q000098:blood supply* / Q000235:genetics / Q000473:pathology*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D008954:Models, Biological; D009368:Neoplasm Transplantation / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology*; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology*; D014183:Transplantation, Heterologous / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor