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Glioblastoma stem-like cells give rise to tumour endothelium

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Abstract

Glioblastoma (GBM) is among the most aggressive of human cancers1. A key feature of GBMs is the extensive network of abnormal vasculature characterized by glomeruloid structures and endothelial hyperplasia2. Yet the mechanisms of angiogenesis and the origin of tumour endothelial cells remain poorly defined3,4,5. 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+ 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+ stem-like cell fraction is multipotent and capable of differentiation along tumour and endothelial lineages, possibly via an intermediate CD133+/CD144+ progenitor cell. The findings are supported by genetic studies of specific exons selected from The Cancer Genome Atlas6, quantitative FISH and comparative genomic hybridization data that demonstrate identical genomic profiles in the CD133+ tumour cells, their endothelial progenitor derivatives and mature endothelium. Exposure to the clinical anti-angiogenesis agent bevacizumab7 or to a γ-secretase inhibitor8 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+ 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 stemness, as well as the mechanisms of tumour neo-angiogenesis.

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Figure 1: CD105 + endothelial cells in GBM harbour genomic aberrations.
Figure 2: GBM-derived CD133 + cells include a fraction of endothelial progenitors
Figure 3: CD133 + /CD144 cells are multipotential and give rise to endothelial cells via an endothelial progenitor intermediate.
Figure 4: Cancer stem-like cells and endothelial progenitors give rise to tumour and endothelial cells in vivo.

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  • 09 December 2010

    A definition was completed in the first paragraph of the text.

References

  1. Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005)

    CAS  Google Scholar 

  2. Kleihues, P. et al. The WHO classification of tumors of the nervous system. J. Neuropathol. Exp. Neurol. 61, 215–225 (2002)

    Google Scholar 

  3. Kioi, M. et al. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J. Clin. Invest. 120, 694–705 (2010)

    CAS  Google Scholar 

  4. Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Med. 7, 1194–1201 (2001)

    CAS  Google Scholar 

  5. Du, R. et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 13, 206–220 (2008)

    CAS  Google Scholar 

  6. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008)

  7. Kreisl, T. N. et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J. Clin. Oncol. 27, 740–745 (2009)

    CAS  Google Scholar 

  8. Hovinga, K. E. et al. Inhibition of Notch Signaling in Glioblastoma Targets Cancer Stem Cells Via an Endothelial Cell Intermediate. Stem Cells 28, 1019–1029 (2010)

    CAS  Google Scholar 

  9. Dallas, N. A. et al. Endoglin (CD105): a marker of tumor vasculature and potential target for therapy. Clin. Cancer Res. 14, 1931–1937 (2008)

    CAS  Google Scholar 

  10. Voyta, J. C., Via, D. P., Butterfield, C. E. & Zetter, B. R. Identification and isolation of endothelial cells based on their increased uptake of acetylated-low density lipoprotein. J. Cell Biol. 99, 2034–2040 (1984)

    CAS  Google Scholar 

  11. Laib, A. M. et al. Spheroid-based human endothelial cell microvessel formation in vivo . Nature Protocols 4, 1202–1215 (2009)

    CAS  Google Scholar 

  12. Beaty, R. M. et al. PLXDC1 (TEM7) is identified in a genome-wide expression screen of glioblastoma endothelium. J. Neurooncol. 81, 241–248 (2007)

    CAS  Google Scholar 

  13. Verhaak, R. G. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1 . Cancer Cell 17, 98–110 (2010)

    CAS  Google Scholar 

  14. Singh, S. K. et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004)

    CAS  Google Scholar 

  15. Richardson, G. D. et al. CD133, a novel marker for human prostatic epithelial stem cells. J. Cell Sci. 117, 3539–3545 (2004)

    CAS  Google Scholar 

  16. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003)

    CAS  Google Scholar 

  17. Shmelkov, S. V., St, C. R., Lyden, D. & Rafii, S. AC133/CD133/Prominin-1. Int. J. Biochem. Cell Biol. 37, 715–719 (2005)

    CAS  Google Scholar 

  18. Uchida, N. et al. Direct isolation of human central nervous system stem cells. Proc. Natl Acad. Sci. USA 97, 14720–14725 (2000)

    CAS  Google Scholar 

  19. Koh, W., Mahan, R. D. & Davis, G. E. Cdc42- and Rac1-mediated endothelial lumen formation requires Pak2, Pak4 and Par3, and PKC-dependent signaling. J. Cell Sci. 121, 989–1001 (2008)

    CAS  Google Scholar 

  20. Kamei, M. et al. Endothelial tubes assemble from intracellular vacuoles in vivo . Nature 442, 453–456 (2006)

    CAS  Google Scholar 

  21. Shen, Q. et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304, 1338–1340 (2004)

    CAS  Google Scholar 

  22. Wurmser, A. E. et al. Cell fusion-independent differentiation of neural stem cells to the endothelial lineage. Nature 430, 350–356 (2004)

    CAS  Google Scholar 

  23. Hendrix, M. J. et al. Transendothelial function of human metastatic melanoma cells: role of the microenvironment in cell-fate determination. Cancer Res. 62, 665–668 (2002)

    CAS  Google Scholar 

  24. El Hallani, S. et al. A new alternative mechanism in glioblastoma vascularization: tubular vasculogenic mimicry. Brain 133, 973–982 (2010)

    Google Scholar 

  25. Akino, T. et al. Cytogenetic abnormalities of tumor-associated endothelial cells in human malignant tumors. Am. J. Pathol. 175, 2657–2667 (2009)

    CAS  Google Scholar 

  26. Iwamoto, F. M. et al. Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma. Neurology 73, 1200–1206 (2009)

    CAS  Google Scholar 

  27. Panchision, D. M. et al. Optimized flow cytometric analysis of central nervous system tissue reveals novel functional relationships among cells expressing CD133, CD15, and CD24. Stem Cells 25, 1560–1570 (2007)

    CAS  Google Scholar 

  28. Franco-Hernandez, C. et al. Gene dosage and mutational analyses of EGFR in oligodendrogliomas. Int. J. Oncol. 30, 209–215 (2007)

    CAS  Google Scholar 

  29. Mellinghoff, I. K. et al. Molecular Determinants of the response of glioblastomas to EGFR kinase inhibitors. N. Engl. J. Med. 353, 2012–2024 (2005)

    CAS  Google Scholar 

  30. Brennan, C. et al. Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations. PLoS ONE 4, e7752 (2009)

    Google Scholar 

  31. Guo, P. et al. Dual nature of the adaptive immune system in lampreys. Nature 459, 796–801 (2009)

    CAS  Google Scholar 

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Acknowledgements

We would like to thank J. Imai, H. Xu, G. Lee, M. Tomishima and L. Studer for critical reading of the manuscript, P. Gutin for assistance with tissue acquisition and discussions, B. Weksler for the brain endothelial cell line (hCMEC), S. Jhanwar for the clinical cytogenetics data and M. Sadelain and E. Papapetrou for the lentiviral vectors. Funding was provided in part through a grant from the New York State Stem Cell Science Fund (NYSTEM).

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R.W. and V.T. conceived the project, analysed the data and wrote the manuscript. R.W. and remaining authors performed experiments and analysed data.

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Correspondence to Viviane Tabar.

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The authors declare no competing financial interests.

Additional information

Microarray and CGH data are deposited in NCBI's Gene Expression Omnibus (GSE24244, GSE24446, GSE24452, GSE24557 and GSE24558).

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The file contains Supplementary Figures 1-9 with legends and Supplementary Tables 1-6. (PDF 6124 kb)

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Wang, R., Chadalavada, K., Wilshire, J. et al. Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468, 829–833 (2010). https://doi.org/10.1038/nature09624

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