The alphavbeta3 integrin is known to be highly up-regulated during cancer progression and promotes a migratory and metastatic phenotype in many types of tumors. We hypothesized that the alphavbeta3 integrin is transferred through exosomes and, upon transfer, has the ability to support functional aberrations in recipient cells. Here, for the first time, it is demonstrated that alphavbeta3 is present in exosomes released from metastatic PC3 and CWR22Pc prostate cancer cells. Exosomal alphavbeta3 is transferred as a protein from donor to non-tumorigenic and tumorigenic cells since the beta3 protein or mRNA levels remain unaffected upon transcription and translation inhibition in recipient cells. Furthermore, it is shown that upon exosome uptake, de novo expression of alphavbeta3 increases adhesion and migration of recipient cells on alphavbeta3 ligand, vitronectin. To evaluate the relevance of these findings, exosomes were purified from the blood of TRAMP mice carrying tumors where the expression of alphavbeta3 is found higher than in exosomes from wild-type mice. In addition, it is demonstrated that alphavbeta3 is co-expressed with synaptophysin, a biomarker for aggressive neuroendocrine prostate cancer.
Overall this study reveals that the alphavbeta3 integrin is transferred from tumorigenic to nontumorigenic and cancer cells via exosomes, and its de novo expression in recipient cells promotes cell migration on its ligand. The increased expression of alphavbeta3 in exosomes from mice bearing tumors points to its clinical relevance and potential use as a biomarker.
Molecular cancer research : MCR. 2016 Jul 20 [Epub ahead of print]
Amrita Singh, Carmine Fedele, Huimin Lu, Marja T Nevalainen, James H Keen, Lucia R Languino
Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University., Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University., Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University., Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University., Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University., Prostate Cancer Discovery and Development Program, Sidney Kimmel Cancer Center, Thomas Jefferson University .