Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers

Abstract

Glioblastoma tumour cells release microvesicles (exosomes) containing mRNA, miRNA and angiogenic proteins. These microvesicles are taken up by normal host cells, such as brain microvascular endothelial cells. By incorporating an mRNA for a reporter protein into these microvesicles, we demonstrate that messages delivered by microvesicles are translated by recipient cells. These microvesicles are also enriched in angiogenic proteins and stimulate tubule formation by endothelial cells. Tumour-derived microvesicles therefore serve as a means of delivering genetic information and proteins to recipient cells in the tumour environment. Glioblastoma microvesicles also stimulated proliferation of a human glioma cell line, indicating a self-promoting aspect. Messenger RNA mutant/variants and miRNAs characteristic of gliomas could be detected in serum microvesicles of glioblastoma patients. The tumour-specific EGFRvIII was detected in serum microvesicles from 7 out of 25 glioblastoma patients. Thus, tumour-derived microvesicles may provide diagnostic information and aid in therapeutic decisions for cancer patients through a blood test.

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

Access options

Buy this article

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

Figure 1: Glioblastoma cells produce microvesicles containing RNA.
Figure 2: Characterization of the microvesicle RNA.
Figure 3: Glioblastoma microvesicles can deliver functional RNA to HBMVECs.
Figure 4: Glioblastoma microvesicles stimulate angiogenesis in vitro and contain angiogenic proteins.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

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

    Article  CAS  Google Scholar 

  2. Mazzocca, A., et al. A secreted form of ADAM9 promotes carcinoma invasion through tumor-stromal interactions. Cancer Res. 65, 4728–4738 (2005).

    Article  CAS  Google Scholar 

  3. Muerkoster, S., et al. Tumor stroma interactions induce chemoresistance in pancreatic ductal carcinoma cells involving increased secretion and paracrine effects of nitric oxide and interleukin-1β. Cancer Res. 64, 1331–1337 (2004).

    Article  Google Scholar 

  4. Singer, C. F., et al. Differential gene expression profile in breast cancer-derived stromal fibroblasts. Breast Cancer Res. Treat. 110, 273–281 (2008).

    Article  CAS  Google Scholar 

  5. Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).

    Article  CAS  Google Scholar 

  6. Gabrilovich, D. I. Molecular mechanisms and therapeutic reversal of immune suppression in cancer. Curr. Cancer Drug Targets 7, 1 (2007).

    CAS  PubMed  Google Scholar 

  7. Ratajczak, J., Wysoczynski, M., Hayek, F., Janowska-Wieczorek, A. & Ratajczak, M. Z. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication. Leukemia 20, 1487–1495 (2006).

    Article  CAS  Google Scholar 

  8. Thery, C., Zitvogel, L. & Amigorena, S. Exosomes: composition, biogenesis and function. Nature Rev. Immunol. 2, 569–579 (2002).

    Article  CAS  Google Scholar 

  9. Pan, B. T. & Johnstone, R. M. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 33, 967–978 (1983).

    Article  CAS  Google Scholar 

  10. Booth, A. M., et al. Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane. J. Cell Biol. 172, 923–935 (2006).

    Article  CAS  Google Scholar 

  11. Greco, V., Hannus, M. & Eaton, S. Argosomes: a potential vehicle for the spread of morphogens through epithelia. Cell 106, 633–645 (2001).

    Article  CAS  Google Scholar 

  12. Delves, G. H., Stewart, A. B., Cooper, A. J. & Lwaleed, B. A. Prostasomes, angiogenesis, and tissue factor. Semin. Thromb. Hemost. 33, 75–79 (2007).

    Article  CAS  Google Scholar 

  13. Mack, M., et al. Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: a mechanism for cellular human immunodeficiency virus 1 infection. Nature Med. 6, 769–775 (2000).

    Article  CAS  Google Scholar 

  14. Al-Nedawi, K., et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nature Cell Biol. 10, 619–624 (2008).

    Article  CAS  Google Scholar 

  15. Valadi, H., et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biol. 9, 654–659 (2007).

    Article  CAS  Google Scholar 

  16. Baj-Krzyworzeka, M., et al. Tumour-derived microvesicles carry several surface determinants and mRNA of tumour cells and transfer some of these determinants to monocytes. Cancer Immunol. Immunother. 55, 808–818 (2006).

    Article  CAS  Google Scholar 

  17. Chaput, N., Taieb, J., Andre, F. & Zitvogel, L. The potential of exosomes in immunotherapy. Exp. Opin. Biol. Ther. 5, 737–747 (2005).

    Article  CAS  Google Scholar 

  18. Wieckowski, E. & Whiteside, T. L. Human tumor-derived vs dendritic cell-derived exosomes have distinct biologic roles and molecular profiles. Immunol. Res. 36, 247–254 (2006).

    Article  CAS  Google Scholar 

  19. Clayton, A., Mitchell, J. P., Court, J., Mason, M. D. & Tabi, Z. Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res. 67, 7458–7466 (2007).

    Article  CAS  Google Scholar 

  20. Ginestra, A., et al. The amount and proteolytic content of vesicles shed by human cancer cell lines correlates with their in vitro invasiveness. Anticancer Res. 18, 3433–3437 (1998).

    CAS  PubMed  Google Scholar 

  21. Liu, C., et al. Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. J. Immunol. 176, 1375–1385 (2006).

    Article  CAS  Google Scholar 

  22. Janowska-Wieczorek, A., et al. Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int. J. Cancer 113, 752–760 (2005).

    Article  CAS  Google Scholar 

  23. Millimaggi, D., et al. Tumor vesicle-associated CD147 modulates the angiogenic capability of endothelial cells. Neoplasia 9, 349–357 (2007).

    Article  CAS  Google Scholar 

  24. Tannous, B. A., Kim, D. E., Fernandez, J. L., Weissleder, R. & Breakefield, X. O. Codon-optimized Gaussia luciferase cDNA for mammalian gene expression in culture and in vivo. Mol. Ther. 11, 435–443 (2005).

    Article  CAS  Google Scholar 

  25. Pelloski, C. E., et al. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J. Clin. Oncol. 25, 2288–2294 (2007).

    Article  CAS  Google Scholar 

  26. Nishikawa, R., et al. Immunohistochemical analysis of the mutant epidermal growth factor, δEGFR, in glioblastoma. Brain Tumor Pathol. 21, 53–56 (2004).

    Article  CAS  Google Scholar 

  27. Chan, J. A., Krichevsky, A. M. & Kosik, K. S. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 65, 6029–6033 (2005).

    Article  CAS  Google Scholar 

  28. Brat, D. J., Bellail, A. C. & Van Meir, E. G. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro-oncology 7, 122–133 (2005).

    Article  CAS  Google Scholar 

  29. Eberle, K., et al. The expression of angiogenin in tissue samples of different brain tumours and cultured glioma cells. Anticancer Res. 20, 1679–1684 (2000).

    CAS  PubMed  Google Scholar 

  30. Rolhion, C., et al. Interleukin-6 overexpression as a marker of malignancy in human gliomas. J. Neurosurg. 94, 97–101 (2001).

    Article  CAS  Google Scholar 

  31. Taraboletti, G., et al. Bioavailability of VEGF in tumor-shed vesicles depends on vesicle burst induced by acidic pH. Neoplasia 8, 96–103 (2006).

    Article  CAS  Google Scholar 

  32. Xu, Z. P., Tsuji, T., Riordan, J. F. & Hu, G. F. Identification and characterization of an angiogenin-binding DNA sequence that stimulates luciferase reporter gene expression. Biochemistry 42, 121–128 (2003).

    Article  CAS  Google Scholar 

  33. Kislauskis, E. H., Zhu, X. & Singer, R. H. Sequences responsible for intracellular localization of β-actin messenger RNA also affect cell phenotype. J. Cell Biol. 127, 441–451 (1994).

    Article  CAS  Google Scholar 

  34. Mallardo, M., et al. Isolation and characterization of Staufen-containing ribonucleoprotein particles from rat brain. Proc. Natl Acad. Sci. USA 100, 2100–2105 (2003).

    Article  CAS  Google Scholar 

  35. Sonabend, A. M., Dana, K. & Lesniak, M. S. Targeting epidermal growth factor receptor variant III: a novel strategy for the therapy of malignant glioma. Exp. Rev. Anticancer Ther. 7, S45–S50 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  37. Badr, C. E., Hewett, J. W., Breakefield, X. O. & Tannous, B. A. A highly sensitive assay for monitoring the secretory pathway and ER stress. PLoS ONE 2, e571 (2007).

    Article  Google Scholar 

Download references

Acknowledgements

We wish to express our gratitude to B. Tannous for supplying the Gluc lentivirus construct, C. Maguire, M. Broekman, K. Miranda, L. Russo and O. Saydam for fruitful discussions. We also would like to thank Applied Biosystems for supplying the miRNA qRT–PCR primers and S. Idema (Neuro-oncology Research Group, Cancer Center Amsterdam) for supplying some of the serum/biopsy samples. This work was supported by the Wenner-Gren Foundation (J.S.) Stiftelsen Olle Engkvist Byggmästare (J.S.), NCI CA86355 (X.O.B. and M.S.E.), NCI CA69246 (X.O.B., M.S.E. and B.S.C.), The Goldhirs Foundation (B.S.C.) the Brain Tumor Society (A.M.K.) and the American Brain Tumor Association (T.W.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Xandra O. Breakefield.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 608 kb)

Supplementary Information

Supplementary Table 1 (XLS 1611 kb)

Supplementary Information

Supplementary Table 2 (XLS 15529 kb)

Supplementary Information

Supplementary Table 3 (XLS 138 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Skog, J., Würdinger, T., van Rijn, S. et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10, 1470–1476 (2008). https://doi.org/10.1038/ncb1800

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1800

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing