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

yamani;

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 stromacells. Hereweshowthat tumor-derived microvesicles (T-MV) also directly
influence the tumorcells byenhancing their invasion in a both autologousand heterologous manner. Neither the respective vesicle-free supernatant nor MV from benign mammary cells mediate invasion. 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 proinvasive 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.