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After EVs are released from cells, EV-associated miRNAs will be delivered to recipient cells through the body fluids. Surface proteins on EVs help EVs to first adhere to target cells, which is a fundamental step for EV-recipient cell communication. Tetraspanins are thought to have roles in adhesion, motility, signal transduction, and cell activation; and they are highly abundant on the exosome surface (Figure 3.4). These tetraspanins include CD9, CD53, CD63, CD81, and CD82; they may contribute to the spatial assembly of factors for antigen recognition and may partially dictate the signal induced by EVs (Simons and Raposo 2009; Mathivanan et al. 2010). In fact, the treatment of recipient cells with antibodies against CD81 or CD9 can reduce the uptake of EVs by recipient cells, which suggests that tetraspanins have a role in EV uptake. Owing to their endosomal origin, exosomes are commonly enriched in endosome-associated proteins. Some of these proteins, for example ALIX and TSG101, are involved in MVB biosynthesis and are normally used as exosome markers along with the tetraspanins CD63, CD81, and CD9. Integrins are also enriched in the exosome membrane and are related to exosome tropism. The exosomal integrins α6β4 and α6β1 are associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. In fact, targeting the integrins α6β4 and αvβ5 decreased respectively exosome uptake as well as lung and liver metastasis.

Figure 3.4 Schematic representation of the major components of exosomes. Common exosome markers include tetraspanins (CD9, CD63, and CD81), integrins, TSG101, and Alix. Exosomes also contain other proteins, different species of RNA, and DNA.

It is biologically important to determine the organ where metastasis might be facilitated by such a mechanism. Accumulating evidence suggests that exosome-mediated activities play an important role in various diseases, especially cancer.