Tumor-derived microvesicles mediate human breast cancer invasion through differentially glycosylated EMMPRIN

Abstract

Tumor cells secrete not only a variety of soluble factors, but also extracellular vesicles that
are known to support the establishment of a favorable tumor niche by influencing the
surrounding stroma cells. Here we show that tumor-derived microvesicles (T-MV) also
directly influence the tumor cells by enhancing their invasion in both autologous and
heterologous way. Neither the respective vesicle-free supernatant nor MV from benign
mammary cells mediates invasion, suggesting that the uptake of T-MV is essential for the proinvasive
effect. We further identify the highly glycosylated form of the extracellular matrix
metalloproteinase inducer (EMMPRIN) as a marker for pro-invasive MV. EMMPRIN is also
present at high levels on MV from metastatic breast cancer patients in vivo. Anti-EMMPRIN
strategies, such as MV deglycosylation, gene knockdown, and specific blocking peptides,
inhibit MV-induced invasion. Interestingly, the effect of EMMPRIN-bearing MV is not
mediated by matrix metalloproteinases but by activation of the p38/MAPK signaling pathway
in the tumor cells. In conclusion, T-MV stimulate cancer cell invasion via a direct feedback
mechanism dependent on highly glycosylated EMMPRIN.

J Mol Cell Biol mju047 first published online December 11, 2014 doi:10.1093/jmcb/mju047

Keywords: breast cancer, microvesicles, invasion, EMMPRIN, glycosylation

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