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Glioblastoma stem-like cells give rise to tumour endothelium

Rong Wang1,2,3, Kalyani Chadalavada4, Jennifer Wilshire5, Urszula Kowalik1, Koos E. Hovinga1,6, Adam Geber1, Boris Fligelman1, Margaret Leversha4, Cameron Brennan1,3,7 & Viviane Tabar1,2,3

1. Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
2. Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
3. Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
4. Molecular Cytogenetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
5. Flow Cytometry Core, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
6. Neurosurgical Center Amsterdam, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands
7. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA

Correspondence to: Viviane Tabar1,2,3 Email: tabarv@mskcc.org


Abstract

Glioblastoma (GBM) is among the most aggressive of human cancers1. A key feature of GBMs is the extensive network of abnormal vasculature characterized by glomeruloid structures and endothelial hyperplasia2. Yet the mechanisms of angiogenesis and the origin of tumour endothelial cells remain poorly defined3, 4, 5. 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 Atlas6, 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 bevacizumab7 or to a γ-secretase inhibitor8 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.
Access : Glioblastoma stem-like cells give rise to tumour endothelium : Nature