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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.

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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.

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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.).

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Correspondence to Xandra O. Breakefield.

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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

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