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Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells

Lucia Ricci-Vitiani1,8, Roberto Pallini2,8, Mauro Biffoni1, Matilde Todaro3, Gloria Invernici4, Tonia Cenci5, Giulio Maira2, Eugenio Agostino Parati4, Giorgio Stassi3,6, Luigi Maria Larocca5 & Ruggero De Maria1,7

1. Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome 00161, Italy
2. Department of Neurosurgery, Catholic University of Rome, Largo Francesco Vito 1, Rome 00168, Italy
3. Department of Surgical and Oncological Sciences, University of Palermo, Via Liborio Giuffrè 5, Palermo 90127, Italy
4. U. O. Cerebrovascular Disease Cellular Neurobiology Laboratory, Fondazione IRCCS, Neurological Institute “Carlo Besta”, Via Celoria 11, 20133 Milan, Italy
5. Institute of Pathology, Catholic University of Rome, Largo Francesco Vito 1, Rome 00168, Italy
6. Cellular and Molecular Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Salvatore Maugeri, Via S. Maugeri 6, Pavia 27100, Italy
7. Mediterranean Institute of Oncology, Via Penninazzo 7, 95029, Viagrande, Catania, Italy
8. These authors contributed equally to this work.

Correspondence to: Ruggero De Maria1,7 Email: demaria@iss.it

Correspondence to: Roberto Pallini2,8 Email: pallini@rm.unicatt.it

ature advance online publication 21 November 2010 | doi:10.1038/nature09557; Received 22 October 2009; Accepted 13 September 2010; Published online 21 November 2010

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.
Access : Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells : Nature