外泌体大牛Thery的哲学三问：胞外囊泡，你是谁？从哪里来？要到哪里去？

在多细胞生物体内，远处的细胞可以通过传递单个分子或细胞外囊泡（EVs; 也叫作 exosomes和microvesicles等）交换信息。外泌体领域大牛Thery于3月10日期的Cell上发表综述，介绍了一些EVs最引人注目的功能，以及我们目前对其生理作用认识的局限。尽管有初步研究表明，EVs在体内具有一些生理功能，但EVs的本质特性仍有待进一步澄清。这篇综述主要关注肿瘤细胞和微环境，但类似的结果和挑战也适用于EVs介导的病理/生理过程。

细胞可以通过细胞外囊泡（EVs）的分泌与邻近细胞或远处的细胞进行沟通。EVs具有脂质双分子层结构，包含跨膜蛋白、胞质蛋白和RNA等成分。根据它们的亚细胞起源不同可将EVs分成不同的类型（Colombo et al., 2014）。一部分EVs是通过从细胞质膜出芽释放的。这些EVs直径大约为100-1000 nm，在文献中通常被称作microvesicles, ectosomes或microparticles。其他类型的小泡外泌体是由多泡体（MVBs）内部产生，与质膜融合分泌而形成的。外泌体的直径一般小于150 nm，富含胞内体的成分。所有EVs都具有表面分子，使他们能够有针对性地到达受体细胞。一旦附着至靶细胞，EVs可以诱导经由受体配体相互作用的信号，或者可以通过内吞作用和/或吞噬作用与靶细胞膜内化或融合将其内容物递送到其细胞质中，由此改变受体细胞的生理状态。

在这篇review中 ，Thery特别讨论了最近研究火热的肿瘤的EVs，尤其是EVs在肿瘤转移中的作用的最新发现。人们通常用外泌体这个术语指定他们所分析的EVs。但是，我们现在知道，在文献中最常用的外泌体提取方法（差速超速离心，220纳米过滤[Thery等，2006]） 以及最近开发的试剂盒，都会将不同类型的EVs一起分离出来。因此，外泌体这术语一般是用来指小EVs（SEVS）的混合类群，没有它们的细胞内来源的进一步论证。实际上，研究发现的外泌体功能可能是反映泛EV的功能也可能是特定的外泌体的功能；然而，目前发表的数据并不能用来确定其精确特异性。因此，Thery在这里选择了使用通用术语EVs来概述外泌体及细胞外囊泡的最新进展。

图1. EV介导的促肿瘤生长、侵袭和转移效应

图2. 体内分析EV介导物质和信息传递的方法

参考文献：

Tkach, M. and C. Thery (2016). "Communication by Extracellular Vesicles: Where We Are and Where We Need to Go." Cell 164(6): 1226-1232.  IF=32.24

Thery大牛发过哪些paper，小编在这里罗列给大家：

1.Bobrie, A., M. Colombo, S. Krumeich, G. Raposo and C. Thery (2012). "Diverse subpopulations of vesicles secreted by different intracellular mechanisms are present in exosome preparations obtained by differential ultracentrifugation." J Extracell Vesicles 1.

2.Bobrie, A., M. Colombo, G. Raposo and C. Thery (2011). "Exosome secretion: molecular mechanisms and roles in immune responses." Traffic 12(12): 1659-1668.

3.Colombo, M., C. Moita, G. van Niel, J. Kowal, J. Vigneron, P. Benaroch, N. Manel, L. F. Moita, C. Thery and G. Raposo (2013). "Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles." J Cell Sci 126(Pt 24): 5553-5565.

4.Colombo, M., G. Raposo and C. Thery (2014). "Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles." Annu Rev Cell Dev Biol 30: 255-289.

5.Kowal, J., G. Arras, M. Colombo, M. Jouve, J. P. Morath, B. Primdal-Bengtson, F. Dingli, D. Loew, M. Tkach and C. Thery (2016). "Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes." Proc Natl Acad Sci U S A.

6.Kowal, J., M. Tkach and C. Thery (2014). "Biogenesis and secretion of exosomes." Curr Opin Cell Biol 29C: 116-125.

7.Lener, T., M. Gimona, L. Aigner, V. Borger, E. Buzas, G. Camussi, N. Chaput, D. Chatterjee, F. A. Court, H. A. Del Portillo, L. O'Driscoll, S. Fais, J. M. Falcon-Perez, U. Felderhoff-Mueser, L. Fraile, Y. S. Gho, A. Gorgens, R. C. Gupta, A. Hendrix, D. M. Hermann, A. F. Hill, F. Hochberg, P. A. Horn, D. de Kleijn, L. Kordelas, B. W. Kramer, E. M. Kramer-Albers, S. Laner-Plamberger, S. Laitinen, T. Leonardi, M. J. Lorenowicz, S. K. Lim, J. Lotvall, C. A. Maguire, A. Marcilla, I. Nazarenko, T. Ochiya, T. Patel, S. Pedersen, G. Pocsfalvi, S. Pluchino, P. Quesenberry, I. G. Reischl, F. J. Rivera, R. Sanzenbacher, K. Schallmoser, I. Slaper-Cortenbach, D. Strunk, T. Tonn, P. Vader, B. W. van Balkom, M. Wauben, S. E. Andaloussi, C. Thery, E. Rohde and B. Giebel (2015). "Applying extracellular vesicles based therapeutics in clinical trials - an ISEV position paper." J Extracell Vesicles 4: 30087.

8.Lotvall, J., A. F. Hill, F. Hochberg, E. I. Buzas, D. Di Vizio, C. Gardiner, Y. S. Gho, I. V. Kurochkin, S. Mathivanan, P. Quesenberry, S. Sahoo, H. Tahara, M. H. Wauben, K. W. Witwer and C. Thery (2014). "Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles." J Extracell Vesicles 3: 26913.

9.Lotvall, J., L. Rajendran, Y. S. Gho, C. Thery, M. Wauben, G. Raposo, M. Sjostrand, D. Taylor, E. Telemo and X. O. Breakefield (2012). "The launch of Journal of Extracellular Vesicles (JEV), the official journal of the International Society for Extracellular Vesicles - about microvesicles, exosomes, ectosomes and other extracellular vesicles." J Extracell Vesicles 1.

10.Sedlik, C., J. Vigneron, L. Torrieri-Dramard, F. Pitoiset, J. Denizeau, C. Chesneau, P. de la Rochere, O. Lantz, C. Thery and B. Bellier (2014). "Different immunogenicity but similar antitumor efficacy of two DNA vaccines coding for an antigen secreted in different membrane vesicle-associated forms." J Extracell Vesicles 3.

11.Thery, C. (2011). "Exosomes: secreted vesicles and intercellular communications." F1000 Biol Rep 3: 15.

12.Thery, C. (2015). "Cancer: Diagnosis by extracellular vesicles." Nature.

13.Thery, C., S. Amigorena, G. Raposo and A. Clayton (2006). "Isolation and characterization of exosomes from cell culture supernatants and biological fluids." Curr Protoc Cell Biol Chapter 3: Unit 3 22.

14.Thery, C., L. Duban, E. Segura, P. Veron, O. Lantz and S. Amigorena (2002). "Indirect activation of naive CD4+ T cells by dendritic cell-derived exosomes." Nat Immunol 3(12): 1156-1162.

15.Thery, C., M. Ostrowski and E. Segura (2009). "Membrane vesicles as conveyors of immune responses." Nat Rev Immunol 9(8): 581-593.

16.Thery, C., L. Zitvogel and S. Amigorena (2002). "Exosomes: composition, biogenesis and function." Nat Rev Immunol 2(8): 569-579.

17.Tkach, M. and C. Thery (2016). "Communication by Extracellular Vesicles: Where We Are and Where We Need to Go." Cell 164(6): 1226-1232.

18.Witwer, K. W., E. I. Buzas, L. T. Bemis, A. Bora, C. Lasser, J. Lotvall, E. N. Nolte-'t Hoen, M. G. Piper, S. Sivaraman, J. Skog, C. Thery, M. H. Wauben and F. Hochberg (2013). "Standardization of sample collection, isolation and analysis methods in extracellular vesicle research." J Extracell Vesicles 2.

19.Wolfers, J., A. Lozier, G. Raposo, A. Regnault, C. Thery, C. Masurier, C. Flament, S. Pouzieux, F. Faure, T. Tursz, E. Angevin, S. Amigorena and L. Zitvogel (2001). "Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming." Nat Med 7(3): 297-303.