The αvβ6 Integrin Is Transferred Intercellularly via Exosomes

• Published in: The Journal of biological chemistry Vol. 290; no. 8; pp. 4545 - 4551
• Main Authors: Fedele, Carmine, Singh, Amrita, Zerlanko, Brad J., Iozzo, Renato V., Languino, Lucia R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-02-2015; American Society for Biochemistry and Molecular Biology
• Subjects: Adhesion; Animals; Antigens, Neoplasm - biosynthesis; Antigens, Neoplasm - genetics; Cell Adhesion; Cell Line; Cell Movement - genetics; Exosome; Exosomes - chemistry; Extracellular Matrix; Gene Expression; Humans; Integrin; Integrins - biosynthesis; Integrins - genetics; Male; Mice; Mice, Knockout; Neoplasm Metastasis; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Paracrine Communication - genetics; Prostate Cancer; Tetraspanin; Transfection - methods; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Integrin; Extracellular Matrix; Exosome; Prostate Cancer; Adhesion; Cell Adhesion; Tetraspanin
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.C114.617662

Exosomes, cell-derived vesicles of endosomal origin, are continuously released in the extracellular environment and play a key role in intercellular crosstalk. In this study, we have investigated whether transfer of integrins through exosomes between prostate cancer (PrCa) cells occurs and whether transferred integrins promote cell adhesion and migration. Among others, we have focused on the αvβ6 integrin, which is not detectable in normal human prostate but is highly expressed in human primary PrCa as well as murine PrCa in Ptenpc−/− mice. After confirming the fidelity of the exosome preparations by electron microscopy, density gradient, and immunoblotting, we determined that the αvβ6 integrin is actively packaged into exosomes isolated from PC3 and RWPE PrCa cell lines. We also demonstrate that αvβ6 is efficiently transferred via exosomes from a donor cell to an αvβ6-negative recipient cell and localizes to the cell surface. De novo αvβ6 expression in an αvβ6-negative recipient cell is not a result of a change in mRNA levels but is a consequence of exosome-mediated transfer of this integrin between different PrCa cells. Recipient cells incubated with exosomes containing αvβ6 migrate on an αvβ6 specific substrate, latency-associated peptide-TGFβ, to a greater extent than cells treated with exosomes in which αvβ6 is stably or transiently down-regulated by shRNA or siRNA, respectively. Overall, this study shows that exosomes from PrCa cells may contribute to a horizontal propagation of integrin-associated phenotypes, which would promote cell migration, and consequently, metastasis in a paracrine fashion.
Background: The αvβ6 integrin is up-regulated in cancer progression and metastasis.
Results: This integrin is transferred via exosomes from prostate cancer cells expressing αvβ6 into αvβ6-negative cancer cells.
Conclusion: Exosomes containing the αvβ6 integrin impact neighboring cells by enhancing their ability to migrate.
Significance: Exosome transfer of αvβ6 integrin among cancer cells may contribute to a horizontal propagation of more aggressive integrin-associated phenotypes.