1932

Abstract

A great deal of interest has developed around evidence of a role for or a marker of extracellular vesicles (EVs)/exosomes and metastatic cancer. However, the strength of a functional connection between EVs and cancer has been hampered by inadequate characterization of EVs and a lack of mechanistic details describing the means by which molecular constituents are incorporated into target cells. Here we consider the mechanisms by which EVs may mediate intercellular communication through ligand-receptor interactions or membrane fusion at the surface of or within recipient cells. We highlight common pitfalls in EV purification procedures and describe how multistep methods combined with quantitative evaluation of EV purification are critical for attributing functional effects to EVs. We explain current limitations in our understanding of the functional internalization of EVs and discuss relevant biological and biochemical controls that may be applied to help strengthen the case for a meaningful effect on target cells.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-030617-050519
2018-03-04
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/2/1/annurev-cancerbio-030617-050519.html?itemId=/content/journals/10.1146/annurev-cancerbio-030617-050519&mimeType=html&fmt=ahah

Literature Cited

  1. Abramowicz A, Widlak P, Pietrowska M. 2016. Proteomic analysis of exosomal cargo: the challenge of high purity vesicle isolation. Mol. Biosyst. 12:1407–19 [Google Scholar]
  2. Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L. et al. 2008. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat. Cell Biol. 10:619–24 [Google Scholar]
  3. Alexander M, Hu R, Runtsch MC, Kagele DA, Mosbruger TL. et al. 2015. Exosome-delivered microRNAs modulate the inflammatory response to endotoxin. Nat. Commun. 6:7321 [Google Scholar]
  4. Allenson K, Castillo J, San Lucas FA, Scelo G, Kim DU. et al. 2017. High prevalence of mutant KRAS in circulating exosome-derived DNA from early stage pancreatic cancer patients. Ann. Oncol. 28:741–47 [Google Scholar]
  5. Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC. et al. 2011. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. PNAS 108:5003–8 [Google Scholar]
  6. Atay S, Banskota S, Crow J, Sethi G, Rink L, Godwin AK. 2014. Oncogenic KIT-containing exosomes increase gastrointestinal stromal tumor cell invasion. PNAS 111:711–16 [Google Scholar]
  7. Baranyai T, Herczeg K, Onodi Z, Voszka I, Modos K. et al. 2015. Isolation of exosomes from blood plasma: qualitative and quantitative comparison of ultracentrifugation and size exclusion chromatography methods. PLOS ONE 10:e0145686 [Google Scholar]
  8. Bobrie A, Colombo M, Krumeich S, Raposo G, Thery C. 2012.a Diverse subpopulations of vesicles secreted by different intracellular mechanisms are present in exosome preparations obtained by differential ultracentrifugation. J. Extracell. Vesicles 1:18397 [Google Scholar]
  9. Bobrie A, Krumeich S, Reyal F, Recchi C, Moita LF. et al. 2012.b Rab27a supports exosome-dependent and -independent mechanisms that modify the tumor microenvironment and can promote tumor progression. Cancer Res 72:4920–30 [Google Scholar]
  10. Boelens MC, Wu TJ, Nabet BY, Xu B, Qiu Y. et al. 2014. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 159:499–513 [Google Scholar]
  11. Booth AM, Fang Y, Fallon JK, Yang JM, Hildreth JE, Gould SJ. 2006. Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane. J. Cell Biol. 172:923–35 [Google Scholar]
  12. Chen AK, Sengupta P, Waki K, Van Engelenburg SB Ochiya T. et al. 2014. MicroRNA binding to the HIV-1 Gag protein inhibits Gag assembly and virus production. PNAS 111:E2676–83 [Google Scholar]
  13. Chevillet JR, Kang Q, Ruf IK, Briggs HA, Vojtech LN. et al. 2014. Quantitative and stoichiometric analysis of the microRNA content of exosomes. PNAS 111:14888–93 [Google Scholar]
  14. Christianson HC, Belting M. 2014. Heparan sulfate proteoglycan as a cell-surface endocytosis receptor. Matrix Biol 35:51–55 [Google Scholar]
  15. Christianson HC, Svensson KJ, van Kuppevelt TH, Li JP, Belting M. 2013. Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity. PNAS 110:17380–85 [Google Scholar]
  16. Colombo M, Raposo G, Thery C. 2014. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 30:255–89 [Google Scholar]
  17. Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H. et al. 2015. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 17:816–26 [Google Scholar]
  18. Demory Beckler M, Higginbotham JN, Franklin JL, Ham AJ, Halvey PJ. et al. 2013. Proteomic analysis of exosomes from mutant KRAS colon cancer cells identifies intercellular transfer of mutant KRAS. Mol. Cell Proteom. 12:343–55 [Google Scholar]
  19. Fabbri M, Paone A, Calore F, Galli R, Gaudio E. et al. 2012. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. PNAS 109:E2110–16 [Google Scholar]
  20. Fedele C, Singh A, Zerlanko BJ, Iozzo RV, Languino LR. 2015. The αvβ6 integrin is transferred intercellularly via exosomes. J. Biol. Chem. 290:4545–51 [Google Scholar]
  21. Fong MY, Zhou W, Liu L, Alontaga AY, Chandra M. et al. 2015. Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat. Cell Biol. 17:183–94 [Google Scholar]
  22. Gámez-Valero A, Monguió-Tortajada M, Carreras-Planella L, Franquesa M, Beyer K, Borràs FE. 2016. Size-exclusion chromatography-based isolation minimally alters extracellular vesicles' characteristics compared to precipitating agents. Sci. Rep. 6:33641 [Google Scholar]
  23. García-Romero N, Carrión-Navarro J, Esteban-Rubio S, Lázaro-Ibáñez E, Peris-Celda M. et al. 2017. DNA sequences within glioma-derived extracellular vesicles can cross the intact blood-brain barrier and be detected in peripheral blood of patients. Oncotarget 8:1416–28 [Google Scholar]
  24. Goloviznina NA, Verghese SC, Yoon YM, Taratula O, Marks DL, Kurre P. 2016. Mesenchymal stromal cell-derived extracellular vesicles promote myeloid-biased multipotent hematopoietic progenitor expansion via Toll-like receptor engagement. J. Biol. Chem. 291:24607–17 [Google Scholar]
  25. Gong J, Korner R, Gaitanos L, Klein R. 2016. Exosomes mediate cell contact–independent ephrin-Eph signaling during axon guidance. J. Cell Biol. 214:35–44 [Google Scholar]
  26. Gould SJ, Raposo G. 2013. As we wait: coping with an imperfect nomenclature for extracellular vesicles. J. Extracell. Vesicles 2:20389 [Google Scholar]
  27. Gross JC, Chaudhary V, Bartscherer K, Boutros M. 2012. Active Wnt proteins are secreted on exosomes. Nat. Cell Biol. 14:1036–45 [Google Scholar]
  28. Grove J, Marsh M. 2011. The cell biology of receptor-mediated virus entry. J. Cell Biol. 195:1071–82 [Google Scholar]
  29. Heusermann W, Hean J, Trojer D, Steib E, von Bueren S. et al. 2016. Exosomes surf on filopodia to enter cells at endocytic hot spots, traffic within endosomes, and are targeted to the ER. J. Cell Biol. 213:173–84 [Google Scholar]
  30. Hong CS, Funk S, Muller L, Boyiadzis M, Whiteside TL. 2016. Isolation of biologically active and morphologically intact exosomes from plasma of patients with cancer. J. Extracell. Vesicles 5:29289 [Google Scholar]
  31. Hornick NI, Doron B, Abdelhamed S, Huan J, Harrington CA. et al. 2016. AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB. Sci. Signal. 9:ra88 [Google Scholar]
  32. Hornick NI, Huan J, Doron B, Goloviznina NA, Lapidus J. et al. 2015. Serum exosome microRNA as a minimally-invasive early biomarker of AML. Sci. Rep. 5:11295 [Google Scholar]
  33. Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A. et al. 2015. Tumour exosome integrins determine organotropic metastasis. Nature 527:329–35 [Google Scholar]
  34. Huan J, Hornick NI, Goloviznina NA, Kamimae-Lanning AN, David LL. et al. 2015. Coordinate regulation of residual bone marrow function by paracrine trafficking of AML exosomes. Leukemia 29:2285–95 [Google Scholar]
  35. Huan J, Hornick NI, Shurtleff MJ, Skinner AM, Goloviznina NA. et al. 2013. RNA trafficking by acute myelogenous leukemia exosomes. Cancer Res 73:918–29 [Google Scholar]
  36. Hung ME, Leonard JN. 2016. A platform for actively loading cargo RNA to elucidate limiting steps in EV-mediated delivery. J. Extracell. Vesicles 5:31027 [Google Scholar]
  37. Jegou A, Ziyyat A, Barraud-Lange V, Perez E, Wolf JP. et al. 2011. CD9 tetraspanin generates fusion competent sites on the egg membrane for mammalian fertilization. PNAS 108:10946–51 [Google Scholar]
  38. Kalluri R. 2016. The biology and function of exosomes in cancer. J. Clin. Investig. 126:1208–15 [Google Scholar]
  39. Kim KM, Abdelmohsen K, Mustapic M, Kapogiannis D, Gorospe M. 2017. RNA in extracellular vesicles. Wiley Interdiscip. Rev. RNA 8:1413 [Google Scholar]
  40. Koch R, Demant M, Aung T, Diering N, Cicholas A. et al. 2014. Populational equilibrium through exosome-mediated Wnt signaling in tumor progression of diffuse large B-cell lymphoma. Blood 123:2189–98 [Google Scholar]
  41. Kosaka N, Iguchi H, Hagiwara K, Yoshioka Y, Takeshita F, Ochiya T. 2013.a Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. J. Biol. Chem. 288:10849–59 [Google Scholar]
  42. Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T. 2010. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J. Biol. Chem. 285:17442–52 [Google Scholar]
  43. Kosaka N, Yoshioka Y, Fujita Y, Ochiya T. 2016. Versatile roles of extracellular vesicles in cancer. J. Clin. Investig. 126:1163–72 [Google Scholar]
  44. Kosaka N, Yoshioka Y, Hagiwara K, Tominaga N, Ochiya T. 2013.b Functional analysis of exosomal microRNA in cell–cell communication research. Methods Mol. Biol. 1024:1–10 [Google Scholar]
  45. Kowal J, Arras G, Colombo M, Jouve M, Morath JP. et al. 2016. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. PNAS 113:E968–77 [Google Scholar]
  46. Kruger S, Abd Elmageed ZY, Hawke DH, Worner PM, Jansen DA. et al. 2014. Molecular characterization of exosome-like vesicles from breast cancer cells. BMC Cancer 14:44 [Google Scholar]
  47. Lai CP, Kim EY, Badr CE, Weissleder R, Mempel TR. et al. 2015. Visualization and tracking of tumour extracellular vesicle delivery and RNA translation using multiplexed reporters. Nat. Commun. 6:7029 [Google Scholar]
  48. Lai CP, Mardini O, Ericsson M, Prabhakar S, Maguire CA. et al. 2014. Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano 8:483–94 [Google Scholar]
  49. Lázaro-Ibáñnez E, Lunavat TR, Jang SC, Escobedo-Lucea C, Oliver-De La Cruz J. et al. 2017. Distinct prostate cancer-related mRNA cargo in extracellular vesicle subsets from prostate cell lines. BMC Cancer 17:92 [Google Scholar]
  50. Le MT, Hamar P, Guo C, Basar E, Perdigao-Henriques R. et al. 2014. miR-200-containing extracellular vesicles promote breast cancer cell metastasis. J. Clin. Investig. 124:5109–28 [Google Scholar]
  51. Li J, Liu K, Liu Y, Xu Y, Zhang F. et al. 2013. Exosomes mediate the cell-to-cell transmission of IFN-α-induced antiviral activity. Nat. Immunol. 14:793–803 [Google Scholar]
  52. Li W, Hu Y, Jiang T, Han Y, Han G. et al. 2014. Rab27A regulates exosome secretion from lung adenocarcinoma cells A549: involvement of EPI64. APMIS 122:1080–87 [Google Scholar]
  53. Li W, Mu D, Tian F, Hu Y, Jiang T. et al. 2013. Exosomes derived from Rab27a-overexpressing tumor cells elicit efficient induction of antitumor immunity. Mol. Med. Rep. 8:1876–82 [Google Scholar]
  54. Lobb RJ, Lima LG, Moller A. 2017. Exosomes: key mediators of metastasis and pre-metastatic niche formation. Semin. Cell Dev. Biol. 67:3–10 [Google Scholar]
  55. Lotvall J, Hill AF, Hochberg F, Buzas EI, Di Vizio D. et al. 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 [Google Scholar]
  56. Luberto C, Hassler DF, Signorelli P, Okamoto Y, Sawai H. et al. 2002. Inhibition of tumor necrosis factor-induced cell death in MCF7 by a novel inhibitor of neutral sphingomyelinase. J. Biol. Chem. 277:41128–39 [Google Scholar]
  57. Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR. et al. 2012. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 151:1542–56 [Google Scholar]
  58. Luyet PP, Falguieres T, Pons V, Pattnaik AK, Gruenberg J. 2008. The ESCRT-I subunit TSG101 controls endosome-to-cytosol release of viral RNA. Traffic 9:2279–90 [Google Scholar]
  59. Marsh M, Helenius A. 2006. Virus entry: open sesame. Cell 124:729–40 [Google Scholar]
  60. Meckes DG Jr., Shair KH, Marquitz AR, Kung CP, Edwards RH, Raab-Traub N. 2010. Human tumor virus utilizes exosomes for intercellular communication. PNAS 107:20370–75 [Google Scholar]
  61. Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST. et al. 2015. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 523:177–82 [Google Scholar]
  62. Millner LM, Strotman LN. 2016. The future of precision medicine in oncology. Clin. Lab. Med. 36:557–73 [Google Scholar]
  63. Miyado K, Yamada G, Yamada S, Hasuwa H, Nakamura Y. et al. 2000. Requirement of CD9 on the egg plasma membrane for fertilization. Science 287:321–24 [Google Scholar]
  64. Miyauchi K, Kim Y, Latinovic O, Morozov V, Melikyan GB. 2009. HIV enters cells via endocytosis and dynamin-dependent fusion with endosomes. Cell 137:433–44 [Google Scholar]
  65. Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan ML. et al. 2012. Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 119:756–66 [Google Scholar]
  66. Morello M, Minciacchi VR, de Candia P, Yang J, Posadas E. et al. 2013. Large oncosomes mediate intercellular transfer of functional microRNA. Cell Cycle 12:3526–36 [Google Scholar]
  67. Ostenfeld MS, Jeppesen DK, Laurberg JR, Boysen AT, Bramsen JB. et al. 2014. Cellular disposal of miR23b by RAB27-dependent exosome release is linked to acquisition of metastatic properties. Cancer Res 74:5758–71 [Google Scholar]
  68. Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G. et al. 2010. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat. Cell Biol. 12:19–30 [Google Scholar]
  69. Palma J, Yaddanapudi SC, Pigati L, Havens MA, Jeong S. et al. 2012. MicroRNAs are exported from malignant cells in customized particles. Nucleic Acids Res 40:9125–38 [Google Scholar]
  70. Pan BT, Johnstone RM. 1983. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 33:967–78 [Google Scholar]
  71. Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van Eijndhoven MA, Hopmans ES. et al. 2010. Functional delivery of viral miRNAs via exosomes. PNAS 107:6328–33 [Google Scholar]
  72. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B. et al. 2012. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 18:883–91 [Google Scholar]
  73. Piper RC, Katzmann DJ. 2007. Biogenesis and function of multivesicular bodies. Annu. Rev. Cell Dev. Biol. 23:519–47 [Google Scholar]
  74. Pitt JM, Kroemer G, Zitvogel L. 2016. Extracellular vesicles: masters of intercellular communication and potential clinical interventions. J. Clin. Investig. 126:1139–43 [Google Scholar]
  75. Rana S, Malinowska K, Zoller M. 2013. Exosomal tumor microRNA modulates premetastatic organ cells. Neoplasia 15:281–95 [Google Scholar]
  76. Roccaro AM, Sacco A, Maiso P, Azab AK, Tai YT. et al. 2013. BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. J. Clin. Investig. 123:1542–55 [Google Scholar]
  77. Shurtleff MJ, Temoche-Diaz MM, Karfilis KV, Ri S, Schekman R. 2016. Y-box protein 1 is required to sort microRNAs into exosomes in cells and in a cell-free reaction. eLife 5:19276 [Google Scholar]
  78. Shurtleff MJ, Yao J, Qin Y, Nottingham RM, Temoche-Diaz MM. et al. 2017. Broad role for YBX1 in defining the small noncoding RNA composition of exosomes. PNAS 114:E8987–95 [Google Scholar]
  79. Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L. et al. 2008. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 10:1470–76 [Google Scholar]
  80. Squadrito ML, Baer C, Burdet F, Maderna C, Gilfillan GD. et al. 2014. Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells. Cell Rep 8:1432–46 [Google Scholar]
  81. Steinbichler TB, Dudas J, Riechelmann H, Skvortsova II. 2017. The role of exosomes in cancer metastasis. Semin. Cancer Biol. 8:1432–46 [Google Scholar]
  82. Sung BH, Ketova T, Hoshino D, Zijlstra A, Weaver AM. 2015. Directional cell movement through tissues is controlled by exosome secretion. Nat. Commun. 6:7164 [Google Scholar]
  83. Svensson KJ, Christianson HC, Wittrup A, Bourseau-Guilmain E, Lindqvist E. et al. 2013. Exosome uptake depends on ERK1/2-heat shock protein 27 signaling and lipid Raft-mediated endocytosis negatively regulated by caveolin-1. J. Biol. Chem. 288:17713–24 [Google Scholar]
  84. Takahashi RU, Prieto-Vila M, Hironaka A, Ochiya T. 2017. The role of extracellular vesicle microRNAs in cancer biology. Clin. Chem. Lab. Med. 55:648–66 [Google Scholar]
  85. Thind A, Wilson C. 2016. Exosomal miRNAs as cancer biomarkers and therapeutic targets. J. Extracell. Vesicles 5:31292 [Google Scholar]
  86. Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D. et al. 2008. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319:1244–47 [Google Scholar]
  87. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. 2007. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9:654–59 [Google Scholar]
  88. Valentino A, Reclusa P, Sirera R, Giallombardo M, Camps C. et al. 2017. Exosomal microRNAs in liquid biopsies: future biomarkers for prostate cancer. Clin. Transl. Oncol. 19:651–57 [Google Scholar]
  89. van der Vos KE, Abels ER, Zhang X, Lai C, Carrizosa E. et al. 2016. Directly visualized glioblastoma-derived extracellular vesicles transfer RNA to microglia/macrophages in the brain. Neuro-Oncology 18:58–69 [Google Scholar]
  90. Van Deun J, Mestdagh P, Sormunen R, Cocquyt V, Vermaelen K. et al. 2014. The impact of disparate isolation methods for extracellular vesicles on downstream RNA profiling. J. Extracell. Vesicles 3:24858 [Google Scholar]
  91. Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. 2011. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat. Cell Biol. 13:423–33 [Google Scholar]
  92. Wang H, Rana S, Giese N, Buchler MW, Zoller M. 2013. Tspan8, CD44v6 and alpha6beta4 are biomarkers of migrating pancreatic cancer-initiating cells. Int. J. Cancer 133:416–26 [Google Scholar]
  93. Wang J, Hendrix A, Hernot S, Lemaire M, De Bruyne E. et al. 2014. Bone marrow stromal cell–derived exosomes as communicators in drug resistance in multiple myeloma cells. Blood 124:555–66 [Google Scholar]
  94. Weber JA, Baxter DH, Zhang S, Huang DY, Huang KH. et al. 2010. The microRNA spectrum in 12 body fluids. Clin. Chem. 56:1733–41 [Google Scholar]
  95. Willms E, Johansson HJ, Mager I, Lee Y, Blomberg KE. et al. 2016. Cells release subpopulations of exosomes with distinct molecular and biological properties. Sci. Rep. 6:22519 [Google Scholar]
  96. Witwer KW. 2015. Circulating microRNA biomarker studies: pitfalls and potential solutions. Clin. Chem. 61:56–63 [Google Scholar]
  97. Witwer KW, Buzas EI, Bemis LT, Bora A, Lasser C. et al. 2013. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J. Extracell. Vesicles 2:20360 [Google Scholar]
  98. Xu R, Simpson RJ, Greening DW. 2017. A protocol for isolation and proteomic characterization of distinct extracellular vesicle subtypes by sequential centrifugal ultrafiltration. Methods Mol. Biol. 1545:91–116 [Google Scholar]
  99. Yeh YY, Ozer HG, Lehman AM, Maddocks K, Yu L. et al. 2015. Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling. Blood 125:3297–305 [Google Scholar]
  100. Zhang L, Zhang S, Yao J, Lowery FJ, Zhang Q. et al. 2015. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527:100–4 [Google Scholar]
  101. Zomer A, Maynard C, Verweij FJ, Kamermans A, Schafer R. et al. 2015. In vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell 161:1046–57 [Google Scholar]
  102. Zomer A, Steenbeek SC, Maynard C, van Rheenen J. 2016. Studying extracellular vesicle transfer by a Cre-loxP method. Nat. Protoc. 11:87–101 [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-030617-050519
Loading
/content/journals/10.1146/annurev-cancerbio-030617-050519
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error