Journal Article

Glioblastoma stem-like cells give rise to tumour endothelium

Wilshire, Jennifer, Fligelman, Boris, Chadalavada, Kalyani, Leversha, Margaret, Wang, Rong, Hovinga, Koos E., Geber, Adam, Brennan, Cameron, Kowalik, Urszula, Tabar, Viviane

2010

Overview

Tumour cells that supply their own blood Glioblastomas are aggressive brain cancers that are nourished by an extensive network of blood vessels. Two groups now show that glioblastoma cells can differentiate into functional endothelial cells as part of the tumour vasculature. These endothelial cells are characterized by the same genetic alterations as the glioblastoma cells and seem to be derived from glioblastoma stem-like cells. This work suggests that some putative cancer stem cells promote cancer growth both directly and indirectly, and may explain the failure of certain anti-angiogenic cancer drugs and aid the design of new therapies. This is one of two papers showing that glioblastoma cells can differentiate into functional endothelial cells as part of the tumour vasculature. These endothelial cells are characterized by the same genetic alterations as the glioblastoma cells. The tumour-derived endothelial cells originate in putative glioblastoma-initiating cells and are functionally important for tumorigenesis. Glioblastoma (GBM) is among the most aggressive of human cancers 1 . A key feature of GBMs is the extensive network of abnormal vasculature characterized by glomeruloid structures and endothelial hyperplasia 2 . Yet the mechanisms of angiogenesis and the origin of tumour endothelial cells remain poorly defined 3 , 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 Atlas 6 , 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 7 or to a γ-secretase inhibitor 8 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/1689/1690 / 631/67/2328 / 631/67/71 / AC133 Antigen / Amyloid Precursor Protein Secretases - antagonists & inhibitors / Animals / Antibodies, Monoclonal - pharmacology / Antibodies, Monoclonal, Humanized / Antigens, CD - metabolism / Bevacizumab / Biological and medical sciences / Cadherins - deficiency / Cadherins - metabolism / Cancer / Cancer cells / Cell Differentiation / Cell Line, Tumor / Cell Lineage / Chromosome Aberrations / Coculture Techniques / Cytogenetics / Development and progression / Endothelial Cells - metabolism / Endothelial Cells - pathology / Endothelium / Female / Genetic aspects / Genomics / Glioblastoma - blood supply / Glioblastoma - genetics / Glioblastoma - pathology / Glioblastoma multiforme / Glycoproteins - metabolism / Growth / Humanities and Social Sciences / Humans / In Situ Hybridization, Fluorescence / Integrin beta4 - metabolism / letter / Male / Medical sciences / Mice / Mice, Inbred NOD / Mice, SCID / multidisciplinary / Mutation / Neovascularization, Pathologic - pathology / Neural Stem Cells - metabolism / Neural Stem Cells - pathology / Neurology / Oncology / Peptides - metabolism / Receptor, Notch1 - deficiency / Receptor, Notch1 - genetics / Science / Science (multidisciplinary) / Stem cells / Tumors / Tumors of the nervous system. Phacomatoses / Vascular Endothelial Growth Factor A - antagonists & inhibitors