Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells (original) (raw)

Nature volume 468, pages 824–828 (2010)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

Accession codes

Primary accessions

ArrayExpress

Data deposits

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

References

  1. Singh, S. K. et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004)
    Article ADS CAS Google Scholar
  2. Vescovi, A. L., Galli, R. & Reynolds, B. A. Brain tumour stem cells. Nature Rev. Cancer 6, 425–436 (2006)
    Article CAS Google Scholar
  3. Ricci-Vitiani, L. et al. Mesenchymal differentiation of glioblastoma stem cells. Cell Death Differ. 15, 1491–1498 (2008)
    Article CAS Google Scholar
  4. Wurmser, A. E. et al. Cell fusion-independent differentiation of neural stem cells to the endothelial lineage. Nature 430, 350–356 (2004)
    Article ADS CAS Google Scholar
  5. Bao, S. et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res. 66, 7843–7848 (2006)
    Article CAS Google Scholar
  6. Folkins, C. et al. Glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via vascular endothelial growth factor and stromal-derived factor 1. Cancer Res. 69, 7243–7251 (2009)
    Article CAS Google Scholar
  7. Calabrese, C. et al. A perivascular niche for brain tumor stem cells. Cancer Cell 11, 69–82 (2007)
    Article CAS Google Scholar
  8. Gilbertson, R. J. & Rich, J. N. Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nature Rev. Cancer 7, 733–736 (2007)
    Article CAS Google Scholar
  9. Lathia, J. D. et al. Integrin α6 regulates glioblastoma stem cells. Cell Stem Cell 6, 421–432 (2010)
    Article CAS Google Scholar
  10. Hida, K. et al. Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res. 64, 8249–8255 (2004)
    Article CAS Google Scholar
  11. Streubel, B. et al. Lymphoma-specific genetic aberrations in microvascular endothelial cells in B-cell lymphomas. N. Engl. J. Med. 351, 250–259 (2004)
    Article CAS Google Scholar
  12. Pezzolo, A. et al. Tumor origin of endothelial cells in human neuroblastoma. J. Clin. Oncol. 25, 376–383 (2007)
    Article CAS Google Scholar
  13. Singh, S. K. et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 63, 5821–5828 (2003)
    CAS PubMed Google Scholar
  14. Galli, R. et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 64, 7011–7021 (2004)
    Article CAS Google Scholar
  15. De Palma, M., Venneri, M. A. & Naldini, L. In vivo targeting of tumor endothelial cells by systemic delivery of lentiviral vectors. Hum. Gene Ther. 14, 1193–1206 (2003)
    Article CAS Google Scholar
  16. De Palma, M., Venneri, M. A., Roca, C. & Naldini, L. Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nature Med. 9, 789–795 (2003)
    Article CAS Google Scholar
  17. Hendrix, M. J., Seftor, E. A., Hess, A. R. & Seftor, R. E. Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nature Rev. Cancer 3, 411–421 (2003)
    Article CAS Google Scholar
  18. Dome, B., Hendrix, M. J., Paku, S., Tovari, J. & Timar, J. Alternative vascularization mechanisms in cancer: pathology and therapeutic implications. Am. J. Pathol. 170, 1–15 (2007)
    Article CAS Google Scholar
  19. Maniotis, A. J. et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am. J. Pathol. 155, 739–752 (1999)
    Article CAS Google Scholar
  20. Alvero, A. B. et al. Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance. Cell Cycle 8, 158–166 (2009)
    Article CAS Google Scholar
  21. Eramo, A. et al. Chemotherapy resistance of glioblastoma stem cells. Cell Death Differ. 13, 1238–1241 (2006)
    Article CAS Google Scholar
  22. Pallini, R. et al. Cancer stem cell analysis and clinical outcome in patients with glioblastoma multiforme. Clin. Cancer Res. 14, 8205–8212 (2008)
    Article CAS Google Scholar
  23. Ricci-Vitiani, L. et al. Absence of caspase 8 and high expression of PED protect primitive neural cells from cell death. J. Exp. Med. 200, 1257–1266 (2004)
    Article CAS Google Scholar

Download references

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.

Author information

Author notes

  1. Lucia Ricci-Vitiani and Roberto Pallini: These authors contributed equally to this work.

Authors and Affiliations

  1. 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
  2. Department of Neurosurgery, Catholic University of Rome, Largo Francesco Vito 1, Rome, 00168, Italy
    Roberto Pallini & Giulio Maira
  3. Department of Surgical and Oncological Sciences, University of Palermo, Via Liborio Giuffrè 5, Palermo, 90127, Italy
    Matilde Todaro & Giorgio Stassi
  4. U. O. Cerebrovascular Disease Cellular Neurobiology Laboratory, Fondazione IRCCS, Neurological Institute “Carlo Besta”, Via Celoria 11, Milan, 20133, Italy
    Gloria Invernici & Eugenio Agostino Parati
  5. Institute of Pathology, Catholic University of Rome, Largo Francesco Vito 1, Rome, 00168, Italy
    Tonia Cenci & Luigi Maria Larocca
  6. Cellular and Molecular Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Salvatore Maugeri, Via S. Maugeri 6, Pavia, 27100, Italy
    Giorgio Stassi
  7. Mediterranean Institute of Oncology, Via Penninazzo 7, 95029, Viagrande, Catania, Italy ,
    Ruggero De Maria

Authors

  1. Lucia Ricci-Vitiani
    You can also search for this author inPubMed Google Scholar
  2. Roberto Pallini
    You can also search for this author inPubMed Google Scholar
  3. Mauro Biffoni
    You can also search for this author inPubMed Google Scholar
  4. Matilde Todaro
    You can also search for this author inPubMed Google Scholar
  5. Gloria Invernici
    You can also search for this author inPubMed Google Scholar
  6. Tonia Cenci
    You can also search for this author inPubMed Google Scholar
  7. Giulio Maira
    You can also search for this author inPubMed Google Scholar
  8. Eugenio Agostino Parati
    You can also search for this author inPubMed Google Scholar
  9. Giorgio Stassi
    You can also search for this author inPubMed Google Scholar
  10. Luigi Maria Larocca
    You can also search for this author inPubMed Google Scholar
  11. Ruggero De Maria
    You can also search for this author inPubMed Google Scholar

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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Tables 1- 2 and Supplementary Figures 1-12 with legends. (PDF 3254 kb)

PowerPoint slides

Rights and permissions

About this article

Cite this article

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

Download citation

This article is cited by

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.

Associated content