Receptors such as epidermal growth factor receptor (
EGFR
) and
ERBB2
reside in specific areas of the plasma membrane that are associated with microvesicle formation, such as lipid rafts. Therefore, such receptors could be incorporated into microvesicles. Rak and colleagues were interested in glioblastoma mutiforme cells that express the highly transforming EGFR mutant EGFRvIII. They found that exogenous expression of EGFRvIII in a glioblastoma cell line increased the production of microvesicles. Further experiments indicated that the microvesicles contained EGFRvIII and, through the use of green fluorescent protein tagging, that this receptor was taken up by cells that come into contact with the microvesicles. Uptake was dependent on membrane fusion mediated by phosphatidylserine expression, and the uptake of EGFRvIII caused activation of downstream signalling pathways such as mitogen-activated protein kinase and Akt. Increased expression of the anti-apoptotic gene BCL-XL and vascular endothelial growth factor were also evident, along with a decrease in the expression of the cell cycle inhibitor p27, and this correlated with anchorage-independent growth in vitro.
So what is the significance of these findings? Only a subset of glioblastoma cells express the EGFRvIII mutant owing to a genetic mutation, but expression of this oncogene is associated with the growth of the tumour as a whole. Therefore, its expression in, and uptake through, microvesicles might explain how this oncogene is able to exert its transforming effect throughout the tumour. Further experiments are needed to ascertain whether other membrane-bound oncogenes can be transferred in this manner and whether this mechanism occurs in other tumour types.
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