title: Glioblastoma stem-like cells give rise to tumour endothelium.
abstract: Glioblastoma (GBM) is among the most aggressive of human cancers. A key feature of GBMs is the extensive network of abnormal vasculature characterized by glomeruloid structures and endothelial hyperplasia. Yet the mechanisms of angiogenesis and the origin of tumour endothelial cells remain poorly defined. Here we demonstrate that a subpopulation of endothelial cells within glioblastomas harbour the same somatic mutations identified within tumour cells, such as amplification of EGFR and chromosome 7. We additionally demonstrate that the stem-cell-like CD133(+) fraction includes a subset of vascular endothelial-cadherin (CD144)-expressing cells that show characteristics of endothelial progenitors capable of maturation into endothelial cells. Extensive in vitro and in vivo lineage analyses, including single cell clonal studies, further show that a subpopulation of the CD133(+) stem-like cell fraction is multipotent and capable of differentiation along tumour and endothelial lineages, possibly via an intermediate CD133(+)/CD144(+) progenitor cell. The findings are supported by genetic studies of specific exons selected from The Cancer Genome Atlas, quantitative FISH and comparative genomic hybridization data that demonstrate identical genomic profiles in the CD133(+) tumour cells, their endothelial progenitor derivatives and mature endothelium. Exposure to the clinical anti-angiogenesis agent bevacizumab or to a γ-secretase inhibitor as well as knockdown shRNA studies demonstrate that blocking VEGF or silencing VEGFR2 inhibits the maturation of tumour endothelial progenitors into endothelium but not the differentiation of CD133(+) cells into endothelial progenitors, whereas γ-secretase inhibition or NOTCH1 silencing blocks the transition into endothelial progenitors. These data may provide new perspectives on the mechanisms of failure of anti-angiogenesis inhibitors currently in use. The lineage plasticity and capacity to generate tumour vasculature of the putative cancer stem cells within glioblastoma are novel findings that provide new insight into the biology of gliomas and the definition of cancer stemness, as well as the mechanisms of tumour neo-angiogenesis.
authors.affiliation: Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.forename: Kalyani
authors.initials: K
authors.lastname: Chadalavada
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wilshire
authors.forename: Urszula
authors.initials: U
authors.lastname: Kowalik
authors.forename: Koos E
authors.initials: KE
authors.lastname: Hovinga
authors.forename: Adam
authors.initials: A
authors.lastname: Geber
authors.forename: Boris
authors.initials: B
authors.lastname: Fligelman
authors.forename: Margaret
authors.initials: M
authors.lastname: Leversha
authors.forename: Cameron
authors.initials: C
authors.lastname: Brennan
authors.forename: Viviane
authors.initials: V
authors.lastname: Tabar
mesh_terms: D000071916:AC133 Antigen; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000378:metabolism; D000068258:Bevacizumab; D015820:Cadherins / Q000172:deficiency / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D002869:Chromosome Aberrations; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005909:Glioblastoma / Q000098:blood supply* / Q000235:genetics / Q000473:pathology*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D039663:Integrin beta4 / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000473:pathology*; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000378:metabolism; D051881:Receptor, Notch1 / Q000172:deficiency / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D000099152:Cadherin 5
chemical_list: D000071916:AC133 Antigen; D053829:Amyloid Precursor Protein Secretases; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000068258:Bevacizumab; D015820:Cadherins; D006023:Glycoproteins; D039663:Integrin beta4; D010455:Peptides; D051881:Receptor, Notch1; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5; C000606023:PROM1 protein, human; C000606024:Prom1 protein, mouse