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Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells

A Corrigendum to this article was published on 07 September 2011

An Erratum to this article was published on 19 January 2011

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 glioblastomas1,2 indicates that the progeny of these cells may not be confined to the neural lineage3. Normal neural stem cells are able to differentiate into functional endothelial cells4. 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.

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Figure 1: Microvascular endothelial cells isolated from glioblastoma harbour tumour-specific chromosomal aberrations.
Figure 2: GSCs cultured under endothelial differentiation conditions develop morphological, phenotypical and functional features of endothelial cells.
Figure 3: Human origin of endothelial cells in glioblastoma neurosphere xenografts.
Figure 4: Selective targeting of glioblastoma neurosphere-derived endothelial cells impairs the growth of subcutaneous tumour xenografts.

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ArrayExpress

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Data have been deposited at the European Bioinformatics Institute (http://www.ebi.ac.uk/arrayexpress/) under accession number E-MEXP-2891.

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Acknowledgements

We thank L. Naldini for providing the lentiviral vectors and S. Forte for gene array data elaboration. This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro.

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L.R.-V. and R.P. performed most of the experiments and coordinated the project; M.B. performed cell sorting and flow cytometric analysis; M.T. and G.S. detected and characterized human endothelial cells in mouse xenografts; G.I. and E.A.P. developed the functional assays of the endothelial cell cultures; G.M. recruited the patients and performed surgery; T.C. and L.M.L. were involved in pathology assessment and detection of genomic aberration in endothelial cells; R.D.M. conceived the study and wrote the paper.

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Correspondence to Roberto Pallini or Ruggero De Maria.

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The authors declare no competing financial interests.

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Ricci-Vitiani, L., Pallini, R., Biffoni, M. et al. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468, 824–828 (2010). https://doi.org/10.1038/nature09557

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