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Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells

An Erratum to this article was published on 01 June 2008

Abstract

Aggressive human brain tumours (gliomas) often express a truncated and oncogenic form of the epidermal growth factor receptor, known as EGFRvIII. Within each tumour only a small percentage of glioma cells may actually express EGFRvIII; however, most of the cells exhibit a transformed phenotype1. Here we show that EGFRvIII can be 'shared' between glioma cells by intercellular transfer of membrane-derived microvesicles ('oncosomes'). EGFRvIII expression in indolent glioma cells stimulates formation of lipid-raft related microvesicles containing EGFRvIII. Microvesicles containing this receptor are then released to cellular surroundings and blood of tumour-bearing mice, and can merge with the plasma membranes of cancer cells lacking EGFRvIII. This event leads to the transfer of oncogenic activity, including activation of transforming signalling pathways (MAPK and Akt), changes in expression of EGFRvIII-regulated genes (VEGF, Bcl-xL, p27), morphological transformation and increase in anchorage-independent growth capacity. Thus, membrane microvesicles of cancer cells can contribute to a horizontal propagation of oncogenes and their associated transforming phenotype among subsets of cancer cells.

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Figure 1: Production of EGFRvIII (oncogene)-containing microvesicles by human glioma cells.
Figure 2: Microvesicular transfer of the oncogenic EGFRvIII between glioma cells.
Figure 3: Activation of growth-promoting signalling pathways in cells that have acquired oncogenic EGFRvIII through microvesicle-mediated intercellular transfer.
Figure 4: Induction of cellular transformation by the uptake of EGFRvIII-containing microvesicles (a) EGFRvIII-dependent increase in VEGF secretion by U373 cells that have incorporated U373vIII microvesicles.

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Acknowledgements

This project was supported by grants to J. R. from the National Cancer Institute of Canada, the Canadian Cancer Society and the Terry Fox Foundations, and by a CIHR grant to A. G.; J. R. is the Jack Cole Chair in Paediatric Oncology. Infrastructure contribution came from FRSQ. We are most grateful to our families for their support.

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K. A. N. provided conceptual input, designed and performed experiments, analysed the data and wrote the manuscript; B. M. contributed to conceptual input, performed experiments and coined the term 'oncosomes'; V. L. and L. M. performed experiments; J. M. and A. G. provided reagents and expertise (A. G. in brain tumours), and analysed data; J. R. designed experiments, provided conceptual input and supervision, and wrote the manuscript.

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Correspondence to Janusz Rak.

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The authors declare no competing financial interests.

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Supplementary Figures S1, S2, S3, S4, S5 and Supplemental Materials & Methods (PDF 1691 kb)

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Al-Nedawi, K., Meehan, B., Micallef, J. et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 10, 619–624 (2008). https://doi.org/10.1038/ncb1725

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