Microvesicles as Mediators of Intercellular Communication in Cancer

Abstract

The discovery that cancer cells generate large membrane-enclosed packets of epigenetic information, known as microvesicles (MVs), that can be transferred to other cells and influence their behavior (Antonyak et al., Small GTPases 3:219–224, 2012; Cocucci et al., Trends Cell Biol 19:43–51, 2009; Rak, Semin Thromb Hemost 36:888–906, 2010; Skog et al., Nat Cell Biol 10:1470–1476, 2008) has added a unique perspective to the classical paracrine signaling paradigm. This is largely because, in addition to growth factors and cytokines, MVs contain a variety of components that are not usually thought to be released into the extracellular environment by viable cells including plasma membrane-associated proteins, cytosolic- and nuclear-localized proteins, as well as nucleic acids, particularly RNA transcripts and micro-RNAs (Skog et al., Nat Cell Biol 10:1470–1476, 2008; Al-Nedawi et al., Nat Cell Biol 10:619–624, 2008; Antonyak et al., Proc Natl Acad Sci U S A 108:4852–4857, 2011; Balaj et al., Nat Commun 2:180, 2011; Choi et al., J Proteome Res 6:4646–4655, 2007; Del Conde et al., Blood 106:1604–1611, 2005; Gallo et al., PLoS One 7:e30679, 2012; Graner et al., FASEB J 23:1541–1557, 2009; Grange et al., Cancer Res 71:5346–5356, 2011; Hosseini-Beheshti et al., Mol Cell Proteomics 11:863–885, 2012; Martins et al., Curr Opin Oncol 25:66–75, 2013; Noerholm et al., BMC Cancer 12:22, 2012; Zhuang et al., EMBO J 31:3513–3523, 2012). When transferred between cancer cells, MVs have been shown to stimulate signaling events that promote cell growth and survival (Al-Nedawi et al., Nat Cell Biol 10:619–624, 2008). Cancer cell-derived MVs can also be taken up by normal cell types that surround the tumor, an outcome that helps shape the tumor microenvironment, trigger tumor vascularization, and even confer upon normal recipient cells the transformed characteristics of a cancer cell (Antonyak et al., Proc Natl Acad Sci U S A 108:4852–4857, 2011; Martins et al., Curr Opin Oncol 25:66–75, 2013; Al-Nedawi et al., Proc Natl Acad Sci U S A 106:3794–3799, 2009; Ge et al., Cancer Microenviron 5:323–332, 2012). Thus, the production of MVs by cancer cells plays crucial roles in driving the expansion of the primary tumor. However, it is now becoming increasingly clear that MVs are also stable in the circulation of cancer patients, where they can mediate long-range effects and contribute to the formation of the pre-metastatic niche, an essential step in metastasis (Skog et al., Nat Cell Biol 10:1470–1476, 2008; Noerholm et al., BMC Cancer 12:22, 2012; Peinado et al., Nat Med 18:883–891, 2012; Piccin et al., Blood Rev 21:157–171, 2007; van der Vos et al., Cell Mol Neurobiol 31:949–959, 2011). These findings, when taken together with the fact that MVs are being aggressively pursued as diagnostic markers, as well as being considered as potential targets for intervention against cancer (Antonyak et al., Small GTPases 3:219–224, 2012; Hosseini-Beheshti et al., Mol Cell Proteomics 11:863–885, 2012; Martins et al., Curr Opin Oncol 25:66–75, 2013; Ge et al., Cancer Microenviron 5:323–332, 2012; Peinado et al., Nat Med 18:883–891, 2012; Piccin et al., Blood Rev 21:157–171, 2007; Al-Nedawi et al., Cell Cycle 8:2014–2018, 2009; Cocucci and Meldolesi, Curr Biol 21:R940–R941, 2011; D’Souza-Schorey and Clancy, Genes Dev 26:1287–1299, 2012; Shao et al., Nat Med 18:1835–1840, 2012), point to critically important roles for MVs in human cancer progression that can potentially be exploited to develop new targeted approaches for treating this disease.