How cancer cells dictate their microenvironment: present roles of extracellular vesicles

Cellular and Molecular Life Sciences

Volumn 74, Issue 4, 2017, Pages 697-713

  Naito, Yutaka ^a   Yoshioka, Yusuke ^a   Yamamoto, Yusuke ^a   Ochiya, Takahiro ^a  

^a NATIONAL CANCER CENTER RESEARCH INSTITUTE   (Japan)

Author keywords

Apoptotic body; Endothelial cells; Epithelial cells; Exosome; Fibroblasts; Immune cells; Mesenchymal stem cells; Microvesicle

Indexed keywords

ALPHA SMOOTH MUSCLE ACTIN; FIBROBLAST GROWTH FACTOR 2; STAT1 PROTEIN; TRANSFORMING GROWTH FACTOR BETA; VASCULOTROPIN; WNT1 PROTEIN;

ANCHORAGE INDEPENDENT GROWTH; CANCER CELL; CANCER GROWTH; CELL FUNCTION; CELL INTERACTION; CELL SURVIVAL; EPITHELIAL MESENCHYMAL TRANSITION; EXOSOME; FIBROBLAST; GENE EXPRESSION PROFILING; HUMAN; IMMUNOSURVEILLANCE; MEMBRANE PERMEABILITY; MOLECULAR DYNAMICS; MYOFIBROBLAST; PHENOTYPE; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; REVIEW; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT; ANIMAL; CELL COMMUNICATION; CELLULAR IMMUNITY; DISEASE COURSE; IMMUNE SYSTEM; IMMUNOLOGY; METABOLISM; NEOPLASM; PATHOLOGY;

ANIMALS; CELL COMMUNICATION; DISEASE PROGRESSION; EXOSOMES; EXTRACELLULAR VESICLES; HUMANS; IMMUNE SYSTEM; IMMUNITY, CELLULAR; NEOPLASMS; TUMOR MICROENVIRONMENT;

EID: 84984820340     PISSN: 1420682X     EISSN: 14209071     Source Type: Journal    
DOI: 10.1007/s00018-016-2346-3     Document Type: Review

References (140)

1. Bhowmick NA, Moses HL (2005) Tumor–stroma interactions. Curr Opin Genet Dev 15(1):97–101. doi:10.1016/j.gde.2004.12.003
2. Quail DF, Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19(11):1423–1437. doi:10.1038/nm.3394
3. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. doi:10.1016/j.cell.2011.02.013
4. Gould SJ, Raposo G (2013) As we wait: coping with an imperfect nomenclature for extracellular vesicles. J Extracell Vesicles. doi:10.3402/jev.v2i0.20389
5. Nawaz M, Camussi G, Valadi H, Nazarenko I, Ekstrom K, Wang X, Principe S, Shah N, Ashraf NM, Fatima F, Neder L, Kislinger T (2014) The emerging role of extracellular vesicles as biomarkers for urogenital cancers. Nat Rev Urol 11(12):688–701. doi:10.1038/nrurol.2014.301
6. Fujita Y, Yoshioka Y, Ochiya T (2016) Extracellular vesicle transfer of cancer pathogenic components. Cancer Sci 107(4):385–390. doi:10.1111/cas.12896
7. Yoshioka Y, Konishi Y, Kosaka N, Katsuda T, Kato T, Ochiya T (2013) Comparative marker analysis of extracellular vesicles in different human cancer types. J Extracell Vesicles 2:20424. doi:10.3402/jev.v2i0.20424
8. Raposo G, Stoorvogel W (2013) Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 200(4):373–383. doi:10.1083/jcb.201211138
9. Muralidharan-Chari V, Clancy JW, Sedgwick A, D’Souza-Schorey C (2010) Microvesicles: mediators of extracellular communication during cancer progression. J Cell Sci 123(Pt 10):1603–1611. doi:10.1242/jcs.064386
10. Akers JC, Gonda D, Kim R, Carter BS, Chen CC (2013) Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J Neurooncol 113(1):1–11. doi:10.1007/s11060-013-1084-8
11. Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35(4):495–516. doi:10.1080/01926230701320337
12. Bergsmedh A, Szeles A, Henriksson M, Bratt A, Folkman MJ, Spetz AL, Holmgren L (2001) Horizontal transfer of oncogenes by uptake of apoptotic bodies. Proc Natl Acad Sci USA 98(11):6407–6411. doi:10.1073/pnas.101129998
13. 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(6):654–659. doi:10.1038/ncb1596
14. Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nature reviews. Cancer 6(5):392–401. doi:10.1038/nrc1877
15. Calvo F, Ege N, Grande-Garcia A, Hooper S, Jenkins RP, Chaudhry SI, Harrington K, Williamson P, Moeendarbary E, Charras G, Sahai E (2013) Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat Cell Biol 15(6):637–646. doi:10.1038/ncb2756
16. Shimoda M, Principe S, Jackson HW, Luga V, Fang H, Molyneux SD, Shao YW, Aiken A, Waterhouse PD, Karamboulas C, Hess FM, Ohtsuka T, Okada Y, Ailles L, Ludwig A, Wrana JL, Kislinger T, Khokha R (2014) Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state. Nat Cell Biol 16(9):889–901. doi:10.1038/ncb3021
17. Procopio MG, Laszlo C, Al Labban D, Kim DE, Bordignon P, Jo SH, Goruppi S, Menietti E, Ostano P, Ala U, Provero P, Hoetzenecker W, Neel V, Kilarski WW, Swartz MA, Brisken C, Lefort K, Dotto GP (2015) Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation. Nat Cell Biol 17(9):1193–1204. doi:10.1038/ncb3228
18. Albrengues J, Bertero T, Grasset E, Bonan S, Maiel M, Bourget I, Philippe C, Herraiz Serrano C, Benamar S, Croce O, Sanz-Moreno V, Meneguzzi G, Feral CC, Cristofari G, Gaggioli C (2015) Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts. Nat Commun 6:10204. doi:10.1038/ncomms10204
19. Webber J, Steadman R, Mason MD, Tabi Z, Clayton A (2010) Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res 70(23):9621–9630. doi:10.1158/0008-5472.can-10-1722
20. Webber JP, Spary LK, Sanders AJ, Chowdhury R, Jiang WG, Steadman R, Wymant J, Jones AT, Kynaston H, Mason MD, Tabi Z, Clayton A (2015) Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes. Oncogene 34(3):290–302. doi:10.1038/onc.2013.560
21. Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR, Chiu E, Buchanan M, Hosein AN, Basik M, Wrana JL (2012) Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 151(7):1542–1556. doi:10.1016/j.cell.2012.11.024
22. Niehrs C (2012) The complex world of WNT receptor signalling. Nat Rev Mol Cell Biol 13(12):767–779. doi:10.1038/nrm3470
23. Boelens MC, Wu TJ, Nabet BY, Xu B, Qiu Y, Yoon T, Azzam DJ, Twyman-Saint Victor C, Wiemann BZ, Ishwaran H, Ter Brugge PJ, Jonkers J, Slingerland J, Minn AJ (2014) Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 159(3):499–513. doi:10.1016/j.cell.2014.09.051
24. Azzam DJ, Zhao D, Sun J, Minn AJ, Ranganathan P, Drews-Elger K, Han X, Picon-Ruiz M, Gilbert CA, Wander SA, Capobianco AJ, El-Ashry D, Slingerland JM (2013) Triple negative breast cancer initiating cell subsets differ in functional and molecular characteristics and in gamma-secretase inhibitor drug responses. EMBO Mol Med 5(10):1502–1522. doi:10.1002/emmm.201302558
25. Lawson DA, Bhakta NR, Kessenbrock K, Prummel KD, Yu Y, Takai K, Zhou A, Eyob H, Balakrishnan S, Wang CY, Yaswen P, Goga A, Werb Z (2015) Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature 526(7571):131–135. doi:10.1038/nature15260
26. Pang W, Su J, Wang Y, Feng H, Dai X, Yuan Y, Chen X, Yao W (2015) Pancreatic cancer-secreted miR-155 implicates in the conversion from normal fibroblasts to cancer-associated fibroblasts. Cancer Sci 106(10):1362–1369. doi:10.1111/cas.12747
27. 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 LW (2015) Stromal fibroblast-derived miR-409 promotes epithelial-to-mesenchymal transition and prostate tumorigenesis. Oncogene 34(21):2690–2699. doi:10.1038/onc.2014.212
28. Au Yeung CL, Co NN, Tsuruga T, Yeung TL, Kwan SY, Leung CS, Li Y, Lu ES, Kwan K, Wong KK, Schmandt R, Lu KH, Mok SC (2016) Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nat Commun 7:11150. doi:10.1038/ncomms11150
29. Kohlhapp FJ, Mitra AK, Lengyel E, Peter ME (2015) MicroRNAs as mediators and communicators between cancer cells and the tumor microenvironment. Oncogene 34(48):5857–5868. doi:10.1038/onc.2015.89
30. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science (New York, NY) 324(5930):1029–1033. doi:10.1126/science.1160809
31. Chiavarina B, Martinez-Outschoorn UE, Whitaker-Menezes D, Howell A, Tanowitz HB, Pestell RG, Sotgia F, Lisanti MP (2012) Metabolic reprogramming and two-compartment tumor metabolism: opposing role(s) of HIF1alpha and HIF2alpha in tumor-associated fibroblasts and human breast cancer cells. Cell Cycle (Georgetown, Tex) 11(17):3280–3289. doi:10.4161/cc.21643
32. Chaudhri VK, Salzler GG, Dick SA, Buckman MS, Sordella R, Karoly ED, Mohney R, Stiles BM, Elemento O, Altorki NK, McGraw TE (2013) Metabolic alterations in lung cancer-associated fibroblasts correlated with increased glycolytic metabolism of the tumor. Mol Cancer Res: MCR 11(6):579–592. doi:10.1158/1541-7786.mcr-12-0437-t
33. Zhao H, Yang L, Baddour J, Achreja A, Bernard V, Moss T, Marini JC, Tudawe T, Seviour EG, San Lucas FA, Alvarez H, Gupta S, Maiti SN, Cooper L, Peehl D, Ram PT, Maitra A, Nagrath D (2016) Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. eLife 5:e10250. doi:10.7554/eLife.10250
34. Warburg O (1956) On the origin of cancer cells. Science (New York, NY) 123(3191):309–314
35. 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(2):183–194. doi:10.1038/ncb3094
36. 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 (New York, NY) 11(10):1093–1105
37. 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(15):5346–5356. doi:10.1158/0008-5472.can-11-0241
38. 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(7578):329–335. doi:10.1038/nature15756
39. Hu Y, Yan C, Mu L, Huang K, Li X, Tao D, Wu Y, Qin J (2015) Fibroblast-derived exosomes contribute to chemoresistance through priming cancer stem cells in colorectal cancer. PLoS One 10(5):e0125625. doi:10.1371/journal.pone.0125625
40. de Visser KE, Eichten A, Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6(1):24–37. doi:10.1038/nrc1782
41. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A (2002) Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23(11):549–555
42. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, Worthen GS, Albelda SM (2009) Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16(3):183–194. doi:10.1016/j.ccr.2009.06.017
43. Jinushi M, Komohara Y (2015) Tumor-associated macrophages as an emerging target against tumors: creating a new path from bench to bedside. Biochim Biophys Acta 1855(2):123–130. doi:10.1016/j.bbcan.2015.01.002
44. Powell DR, Huttenlocher A (2016) Neutrophils in the tumor microenvironment. Trends Immunol 37(1):41–52. doi:10.1016/j.it.2015.11.008
45. Wieckowski EU, Visus C, Szajnik M, Szczepanski MJ, Storkus WJ, Whiteside TL (2009) Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes. J Immunol (Baltim, Md: 1950) 183(6):3720–3730. doi:10.4049/jimmunol.0900970
46. Szajnik M, Czystowska M, Szczepanski MJ, Mandapathil M, Whiteside TL (2010) Tumor-derived microvesicles induce, expand and up-regulate biological activities of human regulatory T cells (Treg). PLoS One 5(7):e11469. doi:10.1371/journal.pone.0011469
47. Andreola G, Rivoltini L, Castelli C, Huber V, Perego P, Deho P, Squarcina P, Accornero P, Lozupone F, Lugini L, Stringaro A, Molinari A, Arancia G, Gentile M, Parmiani G, Fais S (2002) Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. J Exp Med 195(10):1303–1316
48. Clayton A, Mitchell JP, Court J, Mason MD, Tabi Z (2007) Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res 67(15):7458–7466. doi:10.1158/0008-5472.can-06-3456
49. Clayton A, Mitchell JP, Court J, Linnane S, Mason MD, Tabi Z (2008) Human tumor-derived exosomes down-modulate NKG2D expression. J Immunol (Baltim, Md: 1950) 180(11):7249–7258
50. Klibi J, Niki T, Riedel A, Pioche-Durieu C, Souquere S, Rubinstein E, Le Moulec S, Guigay J, Hirashima M, Guemira F, Adhikary D, Mautner J, Busson P (2009) Blood diffusion and Th1-suppressive effects of galectin-9-containing exosomes released by Epstein–Barr virus-infected nasopharyngeal carcinoma cells. Blood 113(9):1957–1966. doi:10.1182/blood-2008-02-142596
51. Chalmin F, Ladoire S, Mignot G, Vincent J, Bruchard M, Remy-Martin JP, Boireau W, Rouleau A, Simon B, Lanneau D, De Thonel A, Multhoff G, Hamman A, Martin F, Chauffert B, Solary E, Zitvogel L, Garrido C, Ryffel B, Borg C, Apetoh L, Rebe C, Ghiringhelli F (2010) Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Investig 120(2):457–471. doi:10.1172/jci40483
52. de Vrij J, Maas SL, Kwappenberg KM, Schnoor R, Kleijn A, Dekker L, Luider TM, de Witte LD, Litjens M, van Strien ME, Hol EM, Kroonen J, Robe PA, Lamfers ML, Schilham MW, Broekman ML (2015) Glioblastoma-derived extracellular vesicles modify the phenotype of monocytic cells. Int J Cancer 137(7):1630–1642. doi:10.1002/ijc.29521
53. Baj-Krzyworzeka M, Szatanek R, Weglarczyk K, Baran J, Urbanowicz B, Branski P, Ratajczak MZ, Zembala M (2006) Tumour-derived microvesicles carry several surface determinants and mRNA of tumour cells and transfer some of these determinants to monocytes. Cancer Immunol Immunother: CII 55(7):808–818. doi:10.1007/s00262-005-0075-9
54. Song X, Ding Y, Liu G, Yang X, Zhao R, Zhang Y, Zhao X, Anderson GJ, Nie G (2016) Cancer cell-derived exosomes induce mitogen-activated protein kinase-dependent monocyte survival by transport of functional receptor tyrosine kinases. J Biol Chem 291(16):8453–8464. doi:10.1074/jbc.M116.716316
55. Yang M, Chen J, Su F, Yu B, Su F, Lin L, Liu Y, Huang JD, Song E (2011) Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Mol Cancer 10:117. doi:10.1186/1476-4598-10-117
56. Chow A, Zhou W, Liu L, Fong MY, Champer J, Van Haute D, Chin AR, Ren X, Gugiu BG, Meng Z, Huang W, Ngo V, Kortylewski M, Wang SE (2014) Macrophage immunomodulation by breast cancer-derived exosomes requires Toll-like receptor 2-mediated activation of NF-kappaB. Sci Rep 4:5750. doi:10.1038/srep05750
57. Wolfers J, Lozier A, Raposo G, Regnault A, Thery C, Masurier C, Flament C, Pouzieux S, Faure F, Tursz T, Angevin E, Amigorena S, Zitvogel L (2001) Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med 7(3):297–303. doi:10.1038/85438
58. Taylor DD, Gercel-Taylor C (2005) Tumour-derived exosomes and their role in cancer-associated T-cell signalling defects. Br J Cancer 92(2):305–311. doi:10.1038/sj.bjc.6602316
59. Dai S, Wei D, Wu Z, Zhou X, Wei X, Huang H, Li G (2008) Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol Therapy: J Am Soc Gene Ther 16(4):782–790. doi:10.1038/mt.2008.1
60. Harshyne LA, Hooper KM, Andrews EG, Nasca BJ, Kenyon LC, Andrews DW, Hooper DC (2015) Glioblastoma exosomes and IGF-1R/AS-ODN are immunogenic stimuli in a translational research immunotherapy paradigm. Cancer Immunol Immunother: CII 64(3):299–309. doi:10.1007/s00262-014-1622-z
61. Naslund TI, Gehrmann U, Qazi KR, Karlsson MC, Gabrielsson S (2013) Dendritic cell-derived exosomes need to activate both T and B cells to induce antitumor immunity. J Immunol (Baltim, Md: 1950) 190(6):2712–2719. doi:10.4049/jimmunol.1203082
62. Andre F, Chaput N, Schartz NE, Flament C, Aubert N, Bernard J, Lemonnier F, Raposo G, Escudier B, Hsu DH, Tursz T, Amigorena S, Angevin E, Zitvogel L (2004) Exosomes as potent cell-free peptide-based vaccine. I. Dendritic cell-derived exosomes transfer functional MHC class I/peptide complexes to dendritic cells. J Immunol (Baltim, Md: 1950) 172(4):2126–2136
63. Morse MA, Garst J, Osada T, Khan S, Hobeika A, Clay TM, Valente N, Shreeniwas R, Sutton MA, Delcayre A, Hsu DH, Le Pecq JB, Lyerly HK (2005) A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J Transl Med 3(1):9. doi:10.1186/1479-5876-3-9
64. Escudier B, Dorval T, Chaput N, Andre F, Caby MP, Novault S, Flament C, Leboulaire C, Borg C, Amigorena S, Boccaccio C, Bonnerot C, Dhellin O, Movassagh M, Piperno S, Robert C, Serra V, Valente N, Le Pecq JB, Spatz A, Lantz O, Tursz T, Angevin E, Zitvogel L (2005) Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of the first phase I clinical trial. J Transl Med 3(1):10. doi:10.1186/1479-5876-3-10
65. 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(1–2):65–69. doi:10.1016/j.cellimm.2014.09.004
66. Challagundla KB, Wise PM, Neviani P, Chava H, Murtadha M, Xu T, Kennedy R, Ivan C, Zhang X, Vannini I, Fanini F, Amadori D, Calin GA, Hadjidaniel M, Shimada H, Jong A, Seeger RC, Asgharzadeh S, Goldkorn A, Fabbri M (2015) Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy. J Natl Cancer Inst 107(7):djv135. doi:10.1093/jnci/djv135
67. Kataoka K, Shiraishi Y, Takeda Y, Sakata S, Matsumoto M, Nagano S, Maeda T, Nagata Y, Kitanaka A, Mizuno S, Tanaka H, Chiba K, Ito S, Watatani Y, Kakiuchi N, Suzuki H, Yoshizato T, Yoshida K, Sanada M, Itonaga H, Imaizumi Y, Totoki Y, Munakata W, Nakamura H, Hama N, Shide K, Kubuki Y, Hidaka T, Kameda T, Masuda K, Minato N, Kashiwase K, Izutsu K, Takaori-Kondo A, Miyazaki Y, Takahashi S, Shibata T, Kawamoto H, Akatsuka Y, Shimoda K, Takeuchi K, Seya T, Miyano S, Ogawa S (2016) Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers. Nature. doi:10.1038/nature18294
68. Fabian MR, Sonenberg N, Filipowicz W (2010) Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem 79:351–379. doi:10.1146/annurev-biochem-060308-103103
69. Chen L, Gibbons DL, Goswami S, Cortez MA, Ahn YH, Byers LA, Zhang X, Yi X, Dwyer D, Lin W, Diao L, Wang J, Roybal JD, Patel M, Ungewiss C, Peng D, Antonia S, Mediavilla-Varela M, Robertson G, Jones S, Suraokar M, Welsh JW, Erez B, Wistuba II, Chen L, Peng D, Wang S, Ullrich SE, Heymach JV, Kurie JM, Qin FX (2014) Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun 5:5241. doi:10.1038/ncomms6241
70. Fujita Y, Yagishita S, Hagiwara K, Yoshioka Y, Kosaka N, Takeshita F, Fujiwara T, Tsuta K, Nokihara H, Tamura T, Asamura H, Kawaishi M, Kuwano K, Ochiya T (2015) The clinical relevance of the miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer. Mol Ther: J Am Soc Gene Ther 23(4):717–727. doi:10.1038/mt.2015.10
71. Taylor DD, Gercel-Taylor C, Lyons KS, Stanson J, Whiteside TL (2003) T-cell apoptosis and suppression of T-cell receptor/CD3-zeta by Fas ligand-containing membrane vesicles shed from ovarian tumors. Clinical Cancer Res: Off J Am Assoc Cancer Res 9(14):5113–5119
72. Huber V, Fais S, Iero M, Lugini L, Canese P, Squarcina P, Zaccheddu A, Colone M, Arancia G, Gentile M, Seregni E, Valenti R, Ballabio G, Belli F, Leo E, Parmiani G, Rivoltini L (2005) Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: role in immune escape. Gastroenterology 128(7):1796–1804
73. Baj-Krzyworzeka M, Szatanek R, Weglarczyk K, Baran J, Zembala M (2007) Tumour-derived microvesicles modulate biological activity of human monocytes. Immunol Lett 113(2):76–82. doi:10.1016/j.imlet.2007.07.014
74. Deng Z, Rong Y, Teng Y, Zhuang X, Samykutty A, Mu J, Zhang L, Cao P, Yan J, Miller D, Zhang HG (2016) Exosomes miR-126a released from MDSC induced by DOX treatment promotes lung metastasis. Oncogene. doi:10.1038/onc.2016.229
75. Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, Ricciardi-Castagnoli P, Raposo G, Amigorena S (1998) Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med 4(5):594–600
76. Thery C, Regnault A, Garin J, Wolfers J, Zitvogel L, Ricciardi-Castagnoli P, Raposo G, Amigorena S (1999) Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J Cell Biol 147(3):599–610
77. Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407(6801):249–257. doi:10.1038/35025220
78. Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2(8):563–572. doi:10.1038/nrc865
79. Welti J, Loges S, Dimmeler S, Carmeliet P (2013) Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer. J Clin Investig 123(8):3190–3200. doi:10.1172/jci70212
80. Kim CW, Lee HM, Lee TH, Kang C, Kleinman HK, Gho YS (2002) Extracellular membrane vesicles from tumor cells promote angiogenesis via sphingomyelin. Cancer Res 62(21):6312–6317
81. Millimaggi D, Mari M, D’Ascenzo S, Carosa E, Jannini EA, Zucker S, Carta G, Pavan A, Dolo V (2007) Tumor vesicle-associated CD147 modulates the angiogenic capability of endothelial cells. Neoplasia (New York, NY) 9(4):349–357
82. Chan YK, Zhang H, Liu P, Tsao SW, Lung ML, Mak NK, Ngok-Shun Wong R, Ying-Kit Yue P (2015) Proteomic analysis of exosomes from nasopharyngeal carcinoma cell identifies intercellular transfer of angiogenic proteins. Int J Cancer 137(8):1830–1841. doi:10.1002/ijc.29562
83. 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(15):10849–10859. doi:10.1074/jbc.M112.446831
84. 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(23):17442–17452. doi:10.1074/jbc.M110.107821
85. Kosaka N, Iguchi H, Yoshioka Y, Hagiwara K, Takeshita F, Ochiya T (2012) Competitive interactions of cancer cells and normal cells via secretory microRNAs. J Biol Chem 287(2):1397–1405. doi:10.1074/jbc.M111.288662
86. 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(25):3748–3757. doi:10.1182/blood-2014-05-576116
87. Tadokoro H, Umezu T, Ohyashiki K, Hirano T, Ohyashiki JH (2013) Exosomes derived from hypoxic leukemia cells enhance tube formation in endothelial cells. J Biol Chem 288(48):34343–34351. doi:10.1074/jbc.M113.480822
88. Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell 127(4):679–695. doi:10.1016/j.cell.2006.11.001
89. Park JE, Tan HS, Datta A, Lai RC, Zhang H, Meng W, Lim SK, Sze SK (2010) Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes. Mol Cell Proteomics: MCP 9(6):1085–1099. doi:10.1074/mcp.M900381-MCP200
90. King HW, Michael MZ, Gleadle JM (2012) Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer 12:421. doi:10.1186/1471-2407-12-421
91. Hannafon BN, Carpenter KJ, Berry WL, Janknecht R, Dooley WC, Ding WQ (2015) Exosome-mediated microRNA signaling from breast cancer cells is altered by the anti-angiogenesis agent docosahexaenoic acid (DHA). Mol Cancer 14:133. doi:10.1186/s12943-015-0400-7
92. Arshad F, Wang L, Sy C, Avraham S, Avraham HK (2010) Blood-brain barrier integrity and breast cancer metastasis to the brain. Pathol Res Int 2011:920509. doi:10.4061/2011/920509
93. Ballabh P, Braun A, Nedergaard M (2004) The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 16(1):1–13. doi:10.1016/j.nbd.2003.12.016
94. Wrobel JK, Toborek M (2016) Blood-brain barrier remodeling during brain metastasis formation. Mol Med (Camb, Mass). doi:10.2119/molmed.2015.00207
95. Tominaga N, Kosaka N, Ono M, Katsuda T, Yoshioka Y, Tamura K, Lotvall J, Nakagama H, Ochiya T (2015) Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier. Nat Commun 6:6716. doi:10.1038/ncomms7716
96. 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(4):501–515. doi:10.1016/j.ccr.2014.03.007
97. 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(6):816–826. doi:10.1038/ncb3169
98. Gesierich S, Berezovskiy I, Ryschich E, Zoller M (2006) Systemic induction of the angiogenesis switch by the tetraspanin D6.1A/CO-029. Cancer Res 66(14):7083–7094. doi:10.1158/0008-5472.can-06-0391
99. Nazarenko I, Rana S, Baumann A, McAlear J, Hellwig A, Trendelenburg M, Lochnit G, Preissner KT, Zoller M (2010) Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res 70(4):1668–1678. doi:10.1158/0008-5472.can-09-2470
100. Ekstrom EJ, Bergenfelz C, von Bulow V, Serifler F, Carlemalm E, Jonsson G, Andersson T, Leandersson K (2014) WNT5A induces release of exosomes containing pro-angiogenic and immunosuppressive factors from malignant melanoma cells. Mol Cancer 13:88. doi:10.1186/1476-4598-13-88
101. Conigliaro A, Costa V, Lo Dico A, Saieva L, Buccheri S, Dieli F, Manno M, Raccosta S, Mancone C, Tripodi M, De Leo G, Alessandro R (2015) CD90 + liver cancer cells modulate endothelial cell phenotype through the release of exosomes containing H19 lncRNA. Mol Cancer 14:155. doi:10.1186/s12943-015-0426-x
102. 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(17):3513–3523. doi:10.1038/emboj.2012.183
103. Wagner W, Wein F, Seckinger A, Frankhauser M, Wirkner U, Krause U, Blake J, Schwager C, Eckstein V, Ansorge W, Ho AD (2005) Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Exp Hematol 33(11):1402–1416. doi:10.1016/j.exphem.2005.07.003
104. Bergfeld SA, DeClerck YA (2010) Bone marrow-derived mesenchymal stem cells and the tumor microenvironment. Cancer Metastasis Rev 29(2):249–261. doi:10.1007/s10555-010-9222-7
105. Keating A (2012) Mesenchymal stromal cells: new directions. Cell Stem Cell 10(6):709–716. doi:10.1016/j.stem.2012.05.015
106. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449(7162):557–563. doi:10.1038/nature06188
107. Tsai KS, Yang SH, Lei YP, Tsai CC, Chen HW, Hsu CY, Chen LL, Wang HW, Miller SA, Chiou SH, Hung MC, Hung SC (2011) Mesenchymal stem cells promote formation of colorectal tumors in mice. Gastroenterology 141(3):1046–1056. doi:10.1053/j.gastro.2011.05.045
108. Chowdhury R, Webber JP, Gurney M, Mason MD, Tabi Z, Clayton A (2015) Cancer exosomes trigger mesenchymal stem cell differentiation into pro-angiogenic and pro-invasive myofibroblasts. Oncotarget 6(2):715–731. doi:10.18632/oncotarget.2711
109. Paggetti J, Haderk F, Seiffert M, Janji B, Distler U, Ammerlaan W, Kim YJ, Adam J, Lichter P, Solary E, Berchem G, Moussay E (2015) Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts. Blood 126(9):1106–1117. doi:10.1182/blood-2014-12-618025
110. Kurtz JM, Spitalier JM, Amalric R (1983) Late breast recurrence after lumpectomy and irradiation. Int J Radiat Oncol Biol Phys 9(8):1191–1194
111. (EBCTCG) EBCTCG (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet (London, England) 365(9472):1687–1717. doi:10.1016/s0140-6736(05)66544-0
112. Sgroi DC, Sestak I, Cuzick J, Zhang Y, Schnabel CA, Schroeder B, Erlander MG, Dunbier A, Sidhu K, Lopez-Knowles E, Goss PE, Dowsett M (2013) Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population. Lancet Oncol 14(11):1067–1076. doi:10.1016/s1470-2045(13)70387-5
113. 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(332):ra63. doi:10.1126/scisignal.2005231
114. Rombouts K, Carloni V, Mello T, Omenetti S, Galastri S, Madiai S, Galli A, Pinzani M (2013) Myristoylated alanine-rich protein kinase C substrate (MARCKS) expression modulates the metastatic phenotype in human and murine colon carcinoma in vitro and in vivo. Cancer Lett 333(2):244–252. doi:10.1016/j.canlet.2013.01.040
115. Lee JK, Park SR, Jung BK, Jeon YK, Lee YS, Kim MK, Kim YG, Jang JY, Kim CW (2013) Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS One 8(12):e84256. doi:10.1371/journal.pone.0084256
116. Du T, Ju G, Wu S, Cheng Z, Cheng J, Zou X, Zhang G, Miao S, Liu G, Zhu Y (2014) Microvesicles derived from human Wharton’s jelly mesenchymal stem cells promote human renal cancer cell growth and aggressiveness through induction of hepatocyte growth factor. PLoS One 9(5):e96836. doi:10.1371/journal.pone.0096836
117. Zhu W, Huang L, Li Y, Zhang X, Gu J, Yan Y, Xu X, Wang M, Qian H, Xu W (2012) Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo. Cancer Lett 315(1):28–37. doi:10.1016/j.canlet.2011.10.002
118. 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 Investig 123(4):1542–1555. doi:10.1172/jci66517
119. Gu J, Qian H, Shen L, Zhang X, Zhu W, Huang L, Yan Y, Mao F, Zhao C, Shi Y, Xu W (2012) Gastric cancer exosomes trigger differentiation of umbilical cord derived mesenchymal stem cells to carcinoma-associated fibroblasts through TGF-beta/Smad pathway. PLoS One 7(12):e52465. doi:10.1371/journal.pone.0052465
120. De Veirman K, Wang J, Xu S, Leleu X, Himpe E, Maes K, De Bruyne E, Van Valckenborgh E, Vanderkerken K, Menu E, Van Riet I (2016) Induction of miR-146a by multiple myeloma cells in mesenchymal stromal cells stimulates their pro-tumoral activity. Cancer Lett 377(1):17–24. doi:10.1016/j.canlet.2016.04.024
121. 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(6):883–891. doi:10.1038/nm.2753
122. Vallabhaneni KC, Penfornis P, Dhule S, Guillonneau F, Adams KV, Mo YY, Xu R, Liu Y, Watabe K, Vemuri MC, Pochampally R (2015) Extracellular vesicles from bone marrow mesenchymal stem/stromal cells transport tumor regulatory microRNA, proteins, and metabolites. Oncotarget 6(7):4953–4967. doi:10.18632/oncotarget.3211
123. Wang J, Hendrix A, Hernot S, Lemaire M, De Bruyne E, Van Valckenborgh E, Lahoutte T, De Wever O, Vanderkerken K, Menu E (2014) Bone marrow stromal cell-derived exosomes as communicators in drug resistance in multiple myeloma cells. Blood 124(4):555–566. doi:10.1182/blood-2014-03-562439
124. Katakowski M, Buller B, Zheng X, Lu Y, Rogers T, Osobamiro O, Shu W, Jiang F, Chopp M (2013) Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett 335(1):201–204. doi:10.1016/j.canlet.2013.02.019
125. Brandes AA, Franceschi E, Tosoni A, Hegi ME, Stupp R (2008) Epidermal growth factor receptor inhibitors in neuro-oncology: hopes and disappointments. Clin Cancer Res: Off J Am Assoc Cancer Res 14(4):957–960. doi:10.1158/1078-0432.ccr-07-1810
126. Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, Rak J (2008) Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 10(5):619–624. doi:10.1038/ncb1725
127. 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(12):1470–1476. doi:10.1038/ncb1800
128. Biernat W, Huang H, Yokoo H, Kleihues P, Ohgaki H (2004) Predominant expression of mutant EGFR (EGFRvIII) is rare in primary glioblastomas. Brain Pathol (Zurich, Switz) 14(2):131–136
129. Nathanson DA, Gini B, Mottahedeh J, Visnyei K, Koga T, Gomez G, Eskin A, Hwang K, Wang J, Masui K, Paucar A, Yang H, Ohashi M, Zhu S, Wykosky J, Reed R, Nelson SF, Cloughesy TF, James CD, Rao PN, Kornblum HI, Heath JR, Cavenee WK, Furnari FB, Mischel PS (2014) Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA. Science (New York, NY) 343(6166):72–76. doi:10.1126/science.1241328
130. 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 Investig 124(12):5109–5128. doi:10.1172/jci75695
131. Qu L, Ding J, Chen C, Wu ZJ, Liu B, Gao Y, Chen W, Liu F, Sun W, Li XF, Wang X, Wang Y, Xu ZY, Gao L, Yang Q, Xu B, Li YM, Fang ZY, Xu ZP, Bao Y, Wu DS, Miao X, Sun HY, Sun YH, Wang HY, Wang LH (2016) Exosome-transmitted lncARSR promotes sunitinib resistance in renal cancer by acting as a competing endogenous RNA. Cancer Cell 29(5):653–668. doi:10.1016/j.ccell.2016.03.004
132. Fedele C, Singh A, Zerlanko BJ, Iozzo RV, Languino LR (2015) The alphavbeta6 integrin is transferred intercellularly via exosomes. J Biol Chem 290(8):4545–4551. doi:10.1074/jbc.C114.617662
133. 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 (Baltimore, Md) 54(4):1237–1248. doi:10.1002/hep.24504
134. Singh R, Pochampally R, Watabe K, Lu Z, Mo YY (2014) Exosome-mediated transfer of miR-10b promotes cell invasion in breast cancer. Mol Cancer 13:256. doi:10.1186/1476-4598-13-256
135. Chen WX, Liu XM, Lv MM, Chen L, Zhao JH, Zhong SL, Ji MH, Hu Q, Luo Z, Wu JZ, Tang JH (2014) Exosomes from drug-resistant breast cancer cells transmit chemoresistance by a horizontal transfer of microRNAs. PLoS One 9(4):e95240. doi:10.1371/journal.pone.0095240
136. Felicetti F, De Feo A, Coscia C, Puglisi R, Pedini F, Pasquini L, Bellenghi M, Errico MC, Pagani E, Care A (2016) Exosome-mediated transfer of miR-222 is sufficient to increase tumor malignancy in melanoma. J Transl Med 14(1):56. doi:10.1186/s12967-016-0811-2
137. Johnston LA (2009) Competitive interactions between cells: death, growth, and geography. Science (New York, NY) 324(5935):1679–1682. doi:10.1126/science.1163862
138. Wagstaff L, Kolahgar G, Piddini E (2013) Competitive cell interactions in cancer: a cellular tug of war. Trends Cell Biol 23(4):160–167. doi:10.1016/j.tcb.2012.11.002
139. Antonyak MA, Li B, Boroughs LK, Johnson JL, Druso JE, Bryant KL, Holowka DA, Cerione RA (2011) Cancer cell-derived microvesicles induce transformation by transferring tissue transglutaminase and fibronectin to recipient cells. Proc Natl Acad Sci USA 108(12):4852–4857. doi:10.1073/pnas.1017667108
140. He M, Qin H, Poon TC, Sze SC, Ding X, Co NN, Ngai SM, Chan TF, Wong N (2015) Hepatocellular carcinoma-derived exosomes promote motility of immortalized hepatocyte through transfer of oncogenic proteins and RNAs. Carcinogenesis 36(9):1008–1018. doi:10.1093/carcin/bgv081