Cell and Tissue Research

, Volume 365, Issue 3, pp 621–641 | Cite as

Function of extracellular vesicle-associated miRNAs in metastasis

  • Bert Dhondt
  • Quentin Rousseau
  • Olivier De Wever
  • An Hendrix


Extracellular RNA (exRNA) is functionally transferrable from donor to recipient cells and is protected from RNAses by electrostatic interactions with proteins or by membrane encapsulation. In addition to bioactive RNA, extracellular vesicles (EVs) contain intraluminal and membrane-associated proteins. The cellular context and fitness affect the composition of EVs and thus the outcome of the communication between the EV-producer and recipient cells. Adaptive communication through EVs is particularly important between cancer cells and their local and distant environment and drives life-threatening metastatic progression. Small noncoding RNAs (miRNAs) have been reported in EV isolations and play a role in local invasion, angiogenesis, immune modulation, metastatic niche preparation, colonization and dormancy. The metastasis-related functions attributed to EV-associated miRNAs are currently increasing exponentially in the scientific literature. We must be aware that the correct and efficient separation of non-vesicular entities (soluble proteins, RNA-protein complexes and RNA-lipoprotein complexes) from EVs is necessary to determine the true contribution of EVs in any experiment that describes the molecular content or the functional consequences of the isolated material.


Extracellular vesicles Exosomes miRNA Pre-metastatic niche Cell-to-cell communication 


  1. Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355PubMedCrossRefGoogle Scholar
  2. Amos H, Kearns KE (1962) Synthesis of “bacterial” protein by cultured chick cells. Nature 195:806–808PubMedCrossRefGoogle Scholar
  3. Amos H, Kearns KE (1963) Influence of bacterial ribonucleic acid on animal cells in culture. II. Protamine enhancement of RNA uptake. Exp Cell Res 32:14–25PubMedCrossRefGoogle Scholar
  4. Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC, Gibson DF, Mitchell PS, Bennett CF, Pogosova-Agadjanyan EL, Stirewalt DL, Tait JF, Tewari M (2011) Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A 108:5003–5008PubMedCrossRefPubMedCentralGoogle Scholar
  5. Azab AK, Hu J, Quang P, Azab F, Pitsillides C, Awwad R, Thompson B, Maiso P, Sun JD, Hart CP, Roccaro AM, Sacco A, Ngo HT, Lin CP, Kung AL, Carrasco RD, Vanderkerken K, Ghobrial IM (2012) Hypoxia promotes dissemination of multiple myeloma through acquisition of epithelial to mesenchymal transition-like features. Blood 119:5782–5794PubMedPubMedCentralCrossRefGoogle Scholar
  6. Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233PubMedCentralCrossRefPubMedGoogle Scholar
  7. Boufraqech M, Zhang L, Jain M, Patel D, Ellis R, Xiong Y, He M, Nilubol N, Merino MJ, Kebebew E (2014) MiR-145 suppresses thyroid cancer growth and metastasis and targets AKT3. Endocr Relat Cancer 21:517–531PubMedCrossRefGoogle Scholar
  8. Camacho L, Guerrero P, Marchetti D (2013) MicroRNA and protein profiling of brain metastasis competent cell-derived exosomes. PLoS ONE 8:e73790PubMedPubMedCentralCrossRefGoogle Scholar
  9. Chen L, Han L, Zhang K, Shi Z, Zhang J, Zhang A, Wang Y, Song Y, Li Y, Jiang T, Pu P, Jiang C, Kang C (2012) VHL regulates the effects of miR-23b on glioma survival and invasion via suppression of HIF-1alpha/VEGF and beta-catenin/Tcf-4 signaling. Neuro-oncology 14:1026–1036PubMedPubMedCentralCrossRefGoogle Scholar
  10. Chen M, Wang M, Xu S, Guo X, Jiang J (2015) Upregulation of miR-181c contributes to chemoresistance in pancreatic cancer by inactivating the Hippo signaling pathway. Oncotarget 6:44466–44479PubMedPubMedCentralGoogle Scholar
  11. Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, Becker A, Hoshino A, Mark MT, Molina H, Xiang J, Zhang T, Theilen TM, Garcia-Santos G, Williams C, Ararso Y, Huang Y, Rodrigues G, Shen TL, Labori KJ, Lothe IM, Kure EH, Hernandez J, Doussot A, Ebbesen SH, Grandgenett PM, Hollingsworth MA, Jain M, Mallya K, Batra SK, Jarnagin WR, Schwartz RE, Matei I, Peinado H, Stanger BZ, Bromberg J, Lyden D (2015) Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol 17:816–826PubMedCrossRefGoogle Scholar
  12. De Wever O, Van Bockstal M, Mareel M, Hendrix A, Bracke M (2014) Carcinoma-associated fibroblasts provide operational flexibility in metastasis. Semin Cancer Biol 25:33–46PubMedCrossRefGoogle Scholar
  13. Demory Beckler M, Higginbotham JN, Franklin JL, Ham AJ, Halvey PJ, Imasuen IE, Whitwell C, Li M, Liebler DC, Coffey RJ (2013) Proteomic analysis of exosomes from mutant KRAS colon cancer cells identifies intercellular transfer of mutant KRAS. Mol Cell Proteomics 12:343–355PubMedCrossRefGoogle Scholar
  14. Ding G, Zhou L, Qian Y, Fu M, Chen J, Xiang J, Wu Z, Jiang G, Cao L (2015) Pancreatic cancer-derived exosomes transfer miRNAs to dendritic cells and inhibit RFXAP expression via miR-212-3p. Oncotarget 6:29877–29888PubMedPubMedCentralGoogle Scholar
  15. Fabbri M, Paone A, Calore F, Galli R, Gaudio E, Santhanam R, Lovat F, Fadda P, Mao C, Nuovo GJ, Zanesi N, Crawford M, Ozer GH, Wernicke D, Alder H, Caligiuri MA, Nana-Sinkam P, Perrotti D, Croce CM (2012) MicroRNAs bind to toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A 109:E2110–E2116PubMedPubMedCentralCrossRefGoogle Scholar
  16. Filipowicz W (2005) RNAi: the nuts and bolts of the RISC machine. Cell 122:17–20PubMedCrossRefGoogle Scholar
  17. Fong MY, Zhou W, Liu L, Alontaga AY, Chandra M, Ashby J, Chow A, O’Connor ST, Li S, Chin AR, Somlo G, Palomares M, Li Z, Tremblay JR, Tsuyada A, Sun G, Reid MA, Wu X, Swiderski P, Ren X, Shi Y, Kong M, Zhong W, Chen Y, Wang SE (2015) Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol 17:183–194PubMedCentralCrossRefPubMedGoogle Scholar
  18. Garofalo M, Quintavalle C, Romano G, Croce CM, Condorelli G (2012) MiR221/222 in cancer: their role in tumor progression and response to therapy. Curr Mol Med 12:27–33PubMedPubMedCentralCrossRefGoogle Scholar
  19. Goldfinch GM, Smith WD, Imrie L, McLean K, Inglis NF, Pemberton AD (2008) The proteome of gastric lymph in normal and nematode infected sheep. Proteomics 8:1909–1918PubMedCrossRefGoogle Scholar
  20. Grange C, Tapparo M, Collino F, Vitillo L, Damasco C, Deregibus MC, Tetta C, Bussolati B, Camussi G (2011) Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res 71:5346–5356PubMedCrossRefGoogle Scholar
  21. Greening DW, Gopal SK, Mathias RA, Liu L, Sheng J, Zhu H-J, Simpson RJ (2015) Emerging roles of exosomes during epithelial–mesenchymal transition and cancer progression. Semin Cell Dev Biol 40:60–71PubMedCrossRefGoogle Scholar
  22. Haier J, Strose A, Matuszcak C, Hummel R (2016) MiR clusters target cellular functional complexes by defining their degree of regulatory freedom. Cancer Metastasis Rev (in press)Google Scholar
  23. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674PubMedCrossRefGoogle Scholar
  24. Hendrix A, Maynard D, Pauwels P, Braems G, Denys H, Van den Broecke R, Lambert J, Van Belle S, Cocquyt V, Gespach C, Bracke M, Seabra MC, Gahl WA, De Wever O, Westbroek W (2010) Effect of the secretory small GTPase Rab27B on breast cancer growth, invasion, and metastasis. J Natl Cancer Inst 102:866–880PubMedPubMedCentralCrossRefGoogle Scholar
  25. Higginbotham JN, Demory Beckler M, Gephart JD, Franklin JL, Bogatcheva G, Kremers GJ, Piston DW, Ayers GD, McConnell RE, Tyska MJ, Coffey RJ (2011) Amphiregulin exosomes increase cancer cell invasion. Curr Biol 21:779–786PubMedPubMedCentralCrossRefGoogle Scholar
  26. Hood JL, San RS, Wickline SA (2011) Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res 71:3792–3801PubMedCrossRefGoogle Scholar
  27. Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, Di Giannatale A, Ceder S, Singh S, Williams C, Soplop N, Uryu K, Pharmer L, King T, Bojmar L, Davies AE, Ararso Y, Zhang T, Zhang H, Hernandez J, Weiss JM, Dumont-Cole VD, Kramer K, Wexler LH, Narendran A, Schwartz GK, Healey JH, Sandstrom P, Labori KJ, Kure EH, Grandgenett PM, Hollingsworth MA, de Sousa M, Kaur S, Jain M, Mallya K, Batra SK, Jarnagin WR, Brady MS, Fodstad O, Muller V, Pantel K, Minn AJ, Bissell MJ, Garcia BA, Kang Y, Rajasekhar VK, Ghajar CM, Matei I, Peinado H, Bromberg J, Lyden D (2015) Tumour exosome integrins determine organotropic metastasis. Nature 527:329–335PubMedPubMedCentralCrossRefGoogle Scholar
  28. Hur K, Toiyama Y, Takahashi M, Balaguer F, Nagasaka T, Koike J, Hemmi H, Koi M, Boland CR, Goel A (2013) MicroRNA-200c modulates epithelial-to-mesenchymal transition (EMT) in human colorectal cancer metastasis. Gut 62:1315–1326PubMedCrossRefGoogle Scholar
  29. ISEV2014 (2014) Third International Meeting of ISEV 2014Rotterdam, The Netherlands, April 30th – May 3rd, 2014. J Extracell Vesicles 3:24214Google Scholar
  30. Ji H, Greening DW, Barnes TW, Lim JW, Tauro BJ, Rai A, Xu R, Adda C, Mathivanan S, Zhao W, Xue Y, Xu T, Zhu HJ, Simpson RJ (2013) Proteome profiling of exosomes derived from human primary and metastatic colorectal cancer cells reveal differential expression of key metastatic factors and signal transduction components. Proteomics 13:1672–1686PubMedCrossRefGoogle Scholar
  31. Jin L, Wessely O, Marcusson EG, Ivan C, Calin GA, Alahari SK (2013) Prooncogenic factors miR-23b and miR-27b are regulated by Her2/Neu, EGF, and TNF-alpha in breast cancer. Cancer Res 73:2884–2896PubMedCrossRefGoogle Scholar
  32. Josson S, Gururajan M, Sung SY, Hu P, Shao C, Zhau HE, Liu C, Lichterman J, Duan P, Li Q, Rogatko A, Posadas EM, Haga CL, Chung LWK (2014) Stromal fibroblast-derived miR-409 promotes epithelial-to-mesenchymal transition and prostate tumorigenesis. Oncogene 34:2690–2699PubMedCrossRefGoogle Scholar
  33. Jung T, Castellana D, Klingbeil P, Cuesta Hernandez I, Vitacolonna M, Orlicky DJ, Roffler SR, Brodt P, Zoller M (2009) CD44v6 dependence of premetastatic niche preparation by exosomes. Neoplasia 11:1093–1105PubMedPubMedCentralCrossRefGoogle Scholar
  34. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827PubMedPubMedCentralCrossRefGoogle Scholar
  35. Kim R, Emi M, Tanabe K (2007) Cancer immunoediting from immune surveillance to immune escape. Immunology 121:1–14PubMedCentralCrossRefPubMedGoogle Scholar
  36. Kim TH, Kim HI, Soung YH, Shaw LA, Chung J (2009) Integrin (alpha6beta4) signals through Src to increase expression of S100A4, a metastasis-promoting factor: implications for cancer cell invasion. Mol Cancer Res 7:1605–1612PubMedCrossRefGoogle Scholar
  37. Kobayashi M, Salomon C, Tapia J, Illanes SE, Mitchell MD, Rice GE (2014) Ovarian cancer cell invasiveness is associated with discordant exosomal sequestration of Let-7 miRNA and miR-200.J Transl Med 12:4PubMedPubMedCentralCrossRefGoogle Scholar
  38. Kogure T, Lin WL, Yan IK, Braconi C, Patel T (2011) Intercellular nanovesicle-mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth. Hepatology 54:1237–1248PubMedPubMedCentralCrossRefGoogle Scholar
  39. Kolodny GM (1971) Evidence for transfer of macromolecular RNA between mammalian cells in culture. Exp Cell Res 65:313–324PubMedCrossRefGoogle Scholar
  40. Kolodny GM (1972) Cell to cell transfer of RNA into transformed cells.J Cell Physiol 79:147–150PubMedCrossRefGoogle Scholar
  41. Korpal M, Ell BJ, Buffa FM, Ibrahim T, Blanco MA, Celia-Terrassa T, Mercatali L, Khan Z, Goodarzi H, Hua Y, Wei Y, Hu G, Garcia BA, Ragoussis J, Amadori D, Harris AL, Kang Y (2011) Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nat Med 17:1101–1108PubMedPubMedCentralCrossRefGoogle Scholar
  42. Kosaka N, Iguchi H, Hagiwara K, Yoshioka Y, Takeshita F, Ochiya T (2013) Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. J Biol Chem 288:10849–10859PubMedPubMedCentralCrossRefGoogle Scholar
  43. Le MT, Hamar P, Guo C, Basar E, Perdigao-Henriques R, Balaj L, Lieberman J (2014) MiR-200-containing extracellular vesicles promote breast cancer cell metastasis. J Clin Invest 124:5109–5128PubMedPubMedCentralCrossRefGoogle Scholar
  44. Lee JC, Zhao J-T, Gundara J, Serpell J, Bach LA, Sidhu S (2015) Papillary thyroid cancer–derived exosomes contain miRNA-146b and miRNA-222. J Surg Res 196:39–48PubMedCrossRefGoogle Scholar
  45. Li BL, Sun MJ, Gao F, Liu W, Yang YY, Liu H, Cheng Y, Liu C, Cai JM (2013) Up-regulated expression of miR-23a/b targeted the pro-apoptotic fas in radiation-induced thymic lymphoma. Cell Physiol Biochem 32:1729–1740CrossRefPubMedGoogle Scholar
  46. Li J, Yao L, Li G, Ma D, Sun C, Gao S, Zhang P, Gao F (2015) MiR-221 promotes epithelial-mesenchymal transition through targeting PTEN and forms a positive feedback loop with beta-catenin/c-Jun signaling pathway in extra-hepatic cholangiocarcinoma. PLoS ONE 10:e0141168PubMedPubMedCentralCrossRefGoogle Scholar
  47. Li L, Tang J, Zhang B, Yang W, LiuGao M, Wang R, Tan Y, Fan J, Chang Y, Fu J, Jiang F, Chen C, Yang Y, Gu J, Wu D, Guo L, Cao D, Li H, Cao G, Wu M, Zhang MQ, Chen L, Wang H (2015) Epigenetic modification of MiR-429 promotes liver tumour-initiating cell properties by targeting Rb binding protein 4. Gut 64:156–167PubMedCrossRefGoogle Scholar
  48. Li Y, Wang H, Li J, Yue W (2014) MiR-181c modulates the proliferation, migration, and invasion of neuroblastoma cells by targeting Smad7. Acta Biochim Biophys Sin Shanghai 46:48–55PubMedCrossRefGoogle Scholar
  49. Lim PK, Bliss SA, Patel SA, Taborga M, Dave MA, Gregory LA, Greco SJ, Bryan M, Patel PS, Rameshwar P (2011) Gap junction-mediated import of microRNA from bone marrow stromal cells can elicit cell cycle quiescence in breast cancer cells. Cancer Res 71:1550–1560PubMedCrossRefGoogle Scholar
  50. Liu D, Li C, Trojanowicz B, Li X, Shi D, Zhan C, Wang Z, Chen L (2015) CD97 promotion of gastric carcinoma lymphatic metastasis is exosome dependent. Gastric Cancer (in press)Google Scholar
  51. Loftus JC, Ross JT, Paquette KM, Paulino VM, Nasser S, Yang Z, Kloss J, Kim S, Berens ME, Tran NL (2012) MiRNA expression profiling in migrating glioblastoma cells: regulation of cell migration and invasion by miR-23b via targeting of Pyk2. PLoS One 7:e39818PubMedPubMedCentralCrossRefGoogle Scholar
  52. Lotvall J, Hill AF, Hochberg F, Buzas EI, Di Vizio D, Gardiner C, Gho YS, Kurochkin IV, Mathivanan S, Quesenberry P, Sahoo S, Tahara H, Wauben MH, Witwer KW, Thery C (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 3:26913PubMedCrossRefGoogle Scholar
  53. Lukanidin E, Sleeman JP (2012) Building the niche: the role of the S100 proteins in metastatic growth. Semin Cancer Biol 22:216–225PubMedCrossRefGoogle Scholar
  54. Ma G, Dai W, Sang A, Yang X, Gao C (2014) Upregulation of microRNA-23a/b promotes tumor progression and confers poor prognosis in patients with gastric cancer. Int J Clin Exp Pathol 7:8833–8840PubMedPubMedCentralGoogle Scholar
  55. Madhavan B, Yue S, Galli U, Rana S, Gross W, Müller M, Giese NA, Kalthoff H, Becker T, Büchler MW, Zöller M (2015) Combined evaluation of a panel of protein and miRNA serum-exosome biomarkers for pancreatic cancer diagnosis increases sensitivity and specificity. Int J Cancer 136:2616–2627PubMedCrossRefGoogle Scholar
  56. Majid S, Dar AA, Saini S, Arora S, Shahryari V, Zaman MS, Chang I, Yamamura S, Tanaka Y, Deng G, Dahiya R (2012) MiR-23b represses proto-oncogene Src kinase and functions as methylation-silenced tumor suppressor with diagnostic and prognostic significance in prostate cancer. Cancer Res 72:6435–6446PubMedPubMedCentralCrossRefGoogle Scholar
  57. Majid S, Dar AA, Saini S, Deng G, Chang I, Greene K, Tanaka Y, Dahiya R, Yamamura S (2013) MicroRNA-23b functions as a tumor suppressor by regulating Zeb1 in bladder cancer. PLoS One 8:e67686PubMedPubMedCentralCrossRefGoogle Scholar
  58. Maniataki E, Mourelatos Z (2005) A human, ATP-independent, RISC assembly machine fueled by pre-miRNA. Genes Dev 19:2979–2990PubMedCentralCrossRefPubMedGoogle Scholar
  59. Massague J, Obenauf AC (2016) Metastatic colonization by circulating tumour cells. Nature 529:298–306PubMedCrossRefGoogle Scholar
  60. Mori F, Sacconi A, Canu V, Ganci F, Novello M, Anelli V, Covello R, Ferraresi V, Muti P, Biagini R, Blandino G, Strano S (2015) MiR-181c associates with tumor relapse of high grade osteosarcoma. Oncotarget 6:13946–13961PubMedCrossRefGoogle Scholar
  61. Mosakhani N, Mustjoki S, Knuutila S (2013) Down-regulation of miR-181c in imatinib-resistant chronic myeloid leukemia. Mol Cytogenet 6:27PubMedPubMedCentralCrossRefGoogle Scholar
  62. O’Brien K, Rani S, Corcoran C, Wallace R, Hughes L, Friel AM, McDonnell S, Crown J, Radomski MW, O’Driscoll L (2013) Exosomes from triple-negative breast cancer cells can transfer phenotypic traits representing their cells of origin to secondary cells. Eur J Cancer 49:1845–1859PubMedCrossRefGoogle Scholar
  63. O’Brien K, Lowry MC, Corcoran C, Martinez VG, Daly M, Rani S, Gallagher WM, Radomski MW, MacLeod RA, O’Driscoll L (2015) MiR-134 in extracellular vesicles reduces triple-negative breast cancer aggression and increases drug sensitivity. Oncotarget 6:32774–32789PubMedPubMedCentralGoogle Scholar
  64. Ohshima K, Inoue K, Fujiwara A, Hatakeyama K, Kanto K, Watanabe Y, Muramatsu K, Fukuda Y, Ogura S, Yamaguchi K, Mochizuki T (2010) Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line. PLoS ONE 5:e13247PubMedPubMedCentralCrossRefGoogle Scholar
  65. Omenn GS (2005) Exploring the human plasma proteome. Proteomics 5:3223–3225PubMedCrossRefGoogle Scholar
  66. Ono M, Kosaka N, Tominaga N, Yoshioka Y, Takeshita F, Takahashi RU, Yoshida M, Tsuda H, Tamura K, Ochiya T (2014) Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci Signal 7:ra63PubMedCrossRefGoogle Scholar
  67. Ostenfeld MS, Jeppesen DK, Laurberg JR, Boysen AT, Bramsen JB, Primdal-Bengtson B, Hendrix A, Lamy P, Dagnaes-Hansen F, Rasmussen MH, Bui KH, Fristrup N, Christensen EI, Nordentoft I, Morth JP, Jensen JB, Pedersen JS, Beck M, Theodorescu D, Borre M, Howard KA, Dyrskjot L, Orntoft TF (2014) Cellular disposal of miR23b by RAB27-dependent exosome release is linked to acquisition of metastatic properties. Cancer Res 74:5758–5771PubMedCrossRefGoogle Scholar
  68. Paget S (1989) The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 8:98–101PubMedGoogle Scholar
  69. Patel SA, Gooderham NJ (2015) IL6 mediates immune and colorectal cancer cell cross-talk via miR-21 and miR-29b. Mol Cancer Res 13:1502–1508PubMedCrossRefGoogle Scholar
  70. Paterson EL, Kazenwadel J, Bert AG, Khew-Goodall Y, Ruszkiewicz A, Goodall GJ (2013) Down-regulation of the miRNA-200 family at the invasive front of colorectal cancers with degraded basement membrane indicates EMT is involved in cancer progression. Neoplasia 15:180–191PubMedPubMedCentralCrossRefGoogle Scholar
  71. Peinado H, Lavotshkin S, Lyden D (2011) The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol 21:139–146PubMedCrossRefGoogle Scholar
  72. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, Garcia-Santos G, Ghajar C, Nitadori-Hoshino A, Hoffman C, Badal K, Garcia BA, Callahan MK, Yuan J, Martins VR, Skog J, Kaplan RN, Brady MS, Wolchok JD, Chapman PB, Kang Y, Bromberg J, Lyden D (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18:883–891PubMedPubMedCentralCrossRefGoogle Scholar
  73. Pellegrino L, Krell J, Roca-Alonso L, Stebbing J, Castellano L (2013a) MicroRNA-23b regulates cellular architecture and impairs motogenic and invasive phenotypes during cancer progression. Bioarchitecture 3:119–124PubMedPubMedCentralCrossRefGoogle Scholar
  74. Pellegrino L, Stebbing J, Braga VM, Frampton AE, Jacob J, Buluwela L, Jiao LR, Periyasamy M, Madsen CD, Caley MP, Ottaviani S, Roca-Alonso L, El-Bahrawy M, Coombes RC, Krell J, Castellano L (2013b) MiR-23b regulates cytoskeletal remodeling, motility and metastasis by directly targeting multiple transcripts. Nucleic Acids Res 41:5400–5412PubMedPubMedCentralCrossRefGoogle Scholar
  75. Pemberton AD, Brown JK, Inglis NF (2010) Proteomic identification of interactions between histones and plasma proteins: implications for cytoprotection. Proteomics 10:1484–1493PubMedCrossRefGoogle Scholar
  76. Poste G, Nicolson GL (1980) Arrest and metastasis of blood-borne tumor cells are modified by fusion of plasma membrane vesicles from highly metastatic cells. Proc Natl Acad Sci U S A 77:399–403PubMedPubMedCentralCrossRefGoogle Scholar
  77. Psaila B, Lyden D (2009) The metastatic niche: adapting the foreign soil. Nat Rev Cancer 9:285–293PubMedPubMedCentralCrossRefGoogle Scholar
  78. Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19:1423–1437PubMedPubMedCentralCrossRefGoogle Scholar
  79. Rana S, Malinowska K, Zöller M (2013) Exosomal tumor microRNA modulates premetastatic organ cells. Neoplasia 15:281–295PubMedPubMedCentralCrossRefGoogle Scholar
  80. Rettig L, Haen SP, Bittermann AG, von Boehmer L, Curioni A, Kramer SD, Knuth A, Pascolo S (2010) Particle size and activation threshold: a new dimension of danger signaling. Blood 115:4533–4541PubMedCrossRefGoogle Scholar
  81. Roccaro AM, Sacco A, Thompson B, Leleu X, Azab AK, Azab F, Runnels J, Jia X, Ngo HT, Melhem MR, Lin CP, Ribatti D, Rollins BJ, Witzig TE, Anderson KC, Ghobrial IM (2009) MicroRNAs 15a and 16 regulate tumor proliferation in multiple myeloma. Blood 113:6669–6680PubMedPubMedCentralCrossRefGoogle Scholar
  82. Roccaro AM, Sacco A, Maiso P, Azab AK, Tai YT, Reagan M, Azab F, Flores LM, Campigotto F, Weller E, Anderson KC, Scadden DT, Ghobrial IM (2013) BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. J Clin Invest 123:1542–1555PubMedPubMedCentralCrossRefGoogle Scholar
  83. Ruan J, Lou S, Dai Q, Mao D, Ji J, Sun X (2015) Tumor suppressor miR-181c attenuates proliferation, invasion, and self-renewal abilities in glioblastoma. Neuroreport 26:66–73PubMedCrossRefGoogle Scholar
  84. Rupaimoole R, Calin GA, Lopez-Berestein G, Sood AK (2016) MiRNA deregulation in cancer cells and the tumor microenvironment. Cancer Discov 6:235–246PubMedPubMedCentralCrossRefGoogle Scholar
  85. Sanchez CA, Andahur EI, Valenzuela R, Castellon EA, Fulla JA, Ramos CG, Trivino JC (2015) Exosomes from bulk and stem cells from human prostate cancer have a differential microRNA content that contributes cooperatively over local and pre-metastatic niche. Oncotarget 7:3993-4008PubMedCentralGoogle Scholar
  86. Shah MY, Calin GA (2011) MicroRNAs miR-221 and miR-222: a new level of regulation in aggressive breast cancer. Genome Med 3:56PubMedPubMedCentralCrossRefGoogle Scholar
  87. Shibue T, Weinberg RA (2011) Metastatic colonization: settlement, adaptation and propagation of tumor cells in a foreign tissue environment. Semin Cancer Biol 21:99–106PubMedCrossRefGoogle Scholar
  88. Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT Jr, Carter BS, Krichevsky AM, Breakefield XO (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10:1470–1476PubMedPubMedCentralCrossRefGoogle Scholar
  89. Slavkin HC, Bringas P, Bavetta LA (1969) Ribonucleic acid within the extracellular matrix during embryonic tooth formation.J Cell Physiol 73:179–190PubMedCrossRefGoogle Scholar
  90. Sosa MS, Bragado P, Aguirre-Ghiso JA (2014) Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer 14:611–622PubMedPubMedCentralCrossRefGoogle Scholar
  91. Stinson S, Lackner MR, Adai AT, Yu N, Kim HJ, O’Brien C, Spoerke J, Jhunjhunwala S, Boyd Z, Januario T, Newman RJ, Yue P, Bourgon R, Modrusan Z, Stern HM, Warming S, de Sauvage FJ, Amler L, Yeh RF, Dornan D (2011) TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer. Sci Signal 4:ra41PubMedCrossRefGoogle Scholar
  92. Taverna S, Amodeo V, Saieva L, Russo A, Giallombardo M, De Leo G, Alessandro R (2014) Exosomal shuttling of miR-126 in endothelial cells modulates adhesive and migratory abilities of chronic myelogenous leukemia cells. Mol Cancer 13:169PubMedPubMedCentralCrossRefGoogle Scholar
  93. Tian L, Fang YX, Xue JL, Chen JZ (2013) Four microRNAs promote prostate cell proliferation with regulation of PTEN and its downstream signals in vitro. PLoS One 8:e75885PubMedPubMedCentralCrossRefGoogle Scholar
  94. Tominaga N, Kosaka N, Ono M, Katsuda T, Yoshioka Y, Tamura K, Lötvall J, Nakagama H, Ochiya T (2015) Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood–brain barrier. Nat Commun 6:6716PubMedPubMedCentralCrossRefGoogle Scholar
  95. Tsai JH, Yang J (2013) Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev 27:2192–2206PubMedPubMedCentralCrossRefGoogle Scholar
  96. Turchinovich A, Weiz L, Langheinz A, Burwinkel B (2011) Characterization of extracellular circulating microRNA. Nucleic Acids Res 39:7223–7233PubMedPubMedCentralCrossRefGoogle Scholar
  97. Umezu T, Ohyashiki K, Kuroda M, Ohyashiki JH (2012) Leukemia cell to endothelial cell communication via exosomal miRNAs. Oncogene 32:2747–2755PubMedCrossRefGoogle Scholar
  98. Umezu T, Tadokoro H, Azuma K, Yoshizawa S, Ohyashiki K, Ohyashiki JH (2014) Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1. Blood 124:3748–3757PubMedPubMedCentralCrossRefGoogle Scholar
  99. 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 9:654–659PubMedCrossRefGoogle Scholar
  100. Valencia K, Luis-Ravelo D, Bovy N, Anton I, Martinez-Canarias S, Zandueta C, Ormazabal C, Struman I, Tabruyn S, Rebmann V, De Las RJ, Guruceaga E, Bandres E, Lecanda F (2014) MiRNA cargo within exosome-like vesicle transfer influences metastatic bone colonization. Mol Oncol 8:689–703PubMedCrossRefGoogle Scholar
  101. Van Balkom BW, de Jong OG, Smits M, Brummelman J, den Ouden K, de Bree PM, van Eijndhoven MA, Pegtel DM, Stoorvogel W, Wurdinger T, Verhaar MC (2013) Endothelial cells require miR-214 to secrete exosomes that suppress senescence and induce angiogenesis in human and mouse endothelial cells. Blood 121:S1–S15Google Scholar
  102. Van Deun J, Mestdagh P, Sormunen R, Cocquyt V, Vermaelen K, Vandesompele J, Bracke M, De Wever O, Hendrix A (2014) The impact of disparate isolation methods for extracellular vesicles on downstream RNA profiling. J Extracell Vesicles 3:10.3402/jev.v3.24858PubMedCentralGoogle Scholar
  103. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033PubMedPubMedCentralCrossRefGoogle Scholar
  104. Villarroya-Beltri C, Baixauli F, Gutierrez-Vazquez C, Sanchez-Madrid F, Mittelbrunn M (2014) Sorting it out: regulation of exosome loading. Semin Cancer Biol 28:3–13PubMedPubMedCentralCrossRefGoogle Scholar
  105. Virchow R (1858) Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Gewebelehre. Hirschwald, BerlinGoogle Scholar
  106. Wang P, Zhang J, Zhang L, Zhu Z, Fan J, Chen L, Zhuang L, Luo J, Chen H, Liu L, Chen Z, Meng Z (2013) MicroRNA 23b regulates autophagy associated with radioresistance of pancreatic cancer cells. Gastroenterology 145:1133–1143PubMedCrossRefGoogle Scholar
  107. Wang M, Zhao C, Shi H, Zhang B, Zhang L, Zhang X, Wang S, Wu X, Yang T, Huang F, Cai J, Zhu Q, Zhu W, Qian H, Xu W (2014) Deregulated microRNAs in gastric cancer tissue-derived mesenchymal stem cells: novel biomarkers and a mechanism for gastric cancer. Br J Cancer 110:1199–1210CrossRefPubMedPubMedCentralGoogle Scholar
  108. Wu X, Somlo G, Yu Y, Palomares MR, Li AX, Zhou W, Chow A, Yen Y, Rossi JJ, Gao H, Wang J, Yuan YC, Frankel P, Li S, Ashing-Giwa KT, Sun G, Wang Y, Smith R, Robinson K, Ren X, Wang SE (2012) De novo sequencing of circulating miRNAs identifies novel markers predicting clinical outcome of locally advanced breast cancer. J Transl Med 10:42PubMedPubMedCentralCrossRefGoogle Scholar
  109. Yamada N, Nakagawa Y, Tsujimura N, Kumazaki M, Noguchi S, Mori T, Hirata I, Maruo K, Akao Y (2013) Role of intracellular and extracellular microRNA-92a in colorectal cancer. Transl Oncol 6:482–492PubMedPubMedCentralCrossRefGoogle Scholar
  110. Yamada N, Tsujimura N, Kumazaki M, Shinohara H, Taniguchi K, Nakagawa Y, Naoe T, Akao Y (2014) Colorectal cancer cell-derived microvesicles containing microRNA-1246 promote angiogenesis by activating Smad 1/5/8 signaling elicited by PML down-regulation in endothelial cells. Biochim Biophys Acta 1839:1256–1272PubMedCrossRefGoogle Scholar
  111. Yang M, Chen J, Su F, Yu B, Su F, Lin L, Liu Y, Huang J-D, Song E (2011) Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Mol Cancer 10:117PubMedCrossRefPubMedCentralGoogle Scholar
  112. Zaman MS, Thamminana S, Shahryari V, Chiyomaru T, Deng G, Saini S, Majid S, Fukuhara S, Chang I, Arora S, Hirata H, Ueno K, Singh K, Tanaka Y, Dahiya R (2012) Inhibition of PTEN gene expression by oncogenic miR-23b-3p in renal cancer. PLoS One 7:e50203PubMedPubMedCentralCrossRefGoogle Scholar
  113. Zhang L, Zhang S, Yao J, Lowery FJ, Zhang Q, Huang WC, Li P, Li M, Wang X, Zhang C, Wang H, Ellis K, Cheerathodi M, McCarty JH, Palmieri D, Saunus J, Lakhani S, Huang S, Sahin AA, Aldape KD, Steeg PS, Yu D (2015) Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527:100–104PubMedPubMedCentralCrossRefGoogle Scholar
  114. Zhang WL, Zhang JH (2015) MiR-181c promotes proliferation via suppressing PTEN expression in inflammatory breast cancer. Int J Oncol 46:2011–2020PubMedGoogle Scholar
  115. Zhou M, Chen J, Zhou L, Chen W, Ding G, Cao L (2014) Pancreatic cancer derived exosomes regulate the expression of TLR4 in dendritic cells via miR-203. Cell Immunol 292:65–69PubMedCrossRefGoogle Scholar
  116. Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, Yu Y, Chow A, O’Connor ST, Chin AR, Yen Y, Wang Y, Marcusson EG, Chu P, Wu J, Wu X, Li AX, Li Z, Gao H, Ren X, Boldin MP, Lin PC, Wang SE (2014) Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25:501–515PubMedPubMedCentralCrossRefGoogle Scholar
  117. Zhuang G, Wu X, Jiang Z, Kasman I, Yao J, Guan Y, Oeh J, Modrusan Z, Bais C, Sampath D, Ferrara N (2012) Tumour-secreted miR-9 promotes endothelial cell migration and angiogenesis by activating the JAK-STAT pathway. EMBO J 31:3513–3523PubMedPubMedCentralCrossRefGoogle Scholar
  118. Zomer A, Maynard C, Verweij FJ, Kamermans A, Schafer R, Beerling E, Schiffelers RM, de Wit E, Berenguer J, Ellenbroek SI, Wurdinger T, Pegtel DM, van Rheenen J (2015) In vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell 161:1046–1057PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Bert Dhondt
    • 1
    • 2
    • 3
  • Quentin Rousseau
    • 1
    • 3
  • Olivier De Wever
    • 1
    • 3
  • An Hendrix
    • 1
    • 3
  1. 1.Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer ResearchGhent UniversityGhentBelgium
  2. 2.Department of Uro-GynaecologyGhent University HospitalGhentBelgium
  3. 3.Cancer Research Institute Ghent (CRIG)GhentBelgium

Personalised recommendations