Glioblastoma stem-like cells give rise to tumour endothelium

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 (3-5). 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.sup.+] 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.sup.+] stem-like cell fraction is multipotent and capable of differentiation along tumour and endothelial lineages, possibly via an intermediate [CD133.sup.+]/[CD144.sup.+] 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.sup.+] 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.sup.+] 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 sternness, as well as the mechanisms of tumour neo-angiogenesis.
Blood vessels within GBM express a variety of markers, including CD31 and CD105 (also known as PECAM1 and ENG, respectively); CD105 is a proliferation-associated molecule expressed in angiogenic endothelium (9). [...]