Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells (original) (raw)
- Letter
- Published: 21 November 2010
- Roberto Pallini2 na1,
- Mauro Biffoni1,
- Matilde Todaro3,
- Gloria Invernici4,
- Tonia Cenci5,
- Giulio Maira2,
- Eugenio Agostino Parati4,
- Giorgio Stassi3,6,
- Luigi Maria Larocca5 &
- …
- Ruggero De Maria1,7
Nature volume 468, pages 824–828 (2010)Cite this article
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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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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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Author notes
- Lucia Ricci-Vitiani and Roberto Pallini: These authors contributed equally to this work.
Authors and Affiliations
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, 00161, Italy
Lucia Ricci-Vitiani, Mauro Biffoni & Ruggero De Maria - Department of Neurosurgery, Catholic University of Rome, Largo Francesco Vito 1, Rome, 00168, Italy
Roberto Pallini & Giulio Maira - Department of Surgical and Oncological Sciences, University of Palermo, Via Liborio Giuffrè 5, Palermo, 90127, Italy
Matilde Todaro & Giorgio Stassi - U. O. Cerebrovascular Disease Cellular Neurobiology Laboratory, Fondazione IRCCS, Neurological Institute “Carlo Besta”, Via Celoria 11, Milan, 20133, Italy
Gloria Invernici & Eugenio Agostino Parati - Institute of Pathology, Catholic University of Rome, Largo Francesco Vito 1, Rome, 00168, Italy
Tonia Cenci & Luigi Maria Larocca - Cellular and Molecular Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Salvatore Maugeri, Via S. Maugeri 6, Pavia, 27100, Italy
Giorgio Stassi - Mediterranean Institute of Oncology, Via Penninazzo 7, 95029, Viagrande, Catania, Italy ,
Ruggero De Maria
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- Lucia Ricci-Vitiani
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Contributions
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.
Corresponding authors
Correspondence toRoberto 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
- Received: 22 October 2009
- Accepted: 13 September 2010
- Published: 21 November 2010
- Issue Date: 09 December 2010
- DOI: https://doi.org/10.1038/nature09557
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Editorial Summary
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.