Exosomal αvß6 integrin is required for monocyte M2 polarization in prostate cancer.

Therapeutic approaches aimed at curing prostate cancer are only partially successful given the occurrence of highly metastatic resistant phenotypes that frequently develop in response to therapies. Recently, we have described αvß6, a surface receptor of the integrin family as a novel therapeutic target for prostate cancer; this epithelial-specific molecule is an ideal target since, unlike other integrins, it is found in different types of cancer but not in normal tissues. We describe a novel αvß6-mediated signaling pathway that has profound effects on the microenvironment. We show that αvß6 is transferred from cancer cells to monocytes, including ß6-null monocytes, by exosomes and that monocytes from prostate cancer patients, but not from healthy volunteers, express αvß6. Cancer cell exosomes, purified via density gradients, promote M2 polarization, whereas αvß6 down-regulation in exosomes inhibits M2 polarization in recipient monocytes. Also, as evaluated by our proteomic analysis, αvß6 down-regulation causes a significant increase in donor cancer cells, and their exosomes, of two molecules that have a tumor suppressive role, STAT1 and MX1/2. Finally, using the Ptenpc-/- prostate cancer mouse model, which carries a prostate epithelial-specific Pten deletion, we demonstrate that αvß6 inhibition in vivo causes up-regulation of STAT1 in cancer cells. Our results provide evidence of a novel mechanism that regulates M2 polarization and prostate cancer progression through transfer of αvß6 from cancer cells to monocytes through exosomes.