Tumor-derived exosomes in cancer progression and treatment failure

Shaorong Yu, Haixia Cao, Bo Shen, Jifeng Feng, Shaorong Yu, Haixia Cao, Bo Shen, Jifeng Feng

Abstract

Exosomes have diameter within the range of 30-100 nm and spherical to cup-shaped nanoparticles with specific surface molecular characteristics, such as CD9 and CD63. These vesicles are present in nearly all human body fluids, including blood plasma/serum, saliva, breast milk, cerebrospinal fluid, urine, semen, and particularly enriched in tumor microenvironment. Exosomes contain multiple proteins, DNA, mRNA, miRNA, long non-coding RNA, and even genetic materials of viruses/prions. These materials are biochemically and functionally distinct and can be transferred to a recipient cell where they regulate protein expression and signaling pathways. Recently, exosomes are demonstrated to have a close relationship with tumor development and metastasis. Exosomes influence therapeutic effect in cancer patients. In this review, we describe the biogenesis, composition, and function of exosomes. The mechanism on how tumor-derived exosomes contribute to cancer progression and clinical treatment failure is also described, with special focus on their potential applications in cancer therapy.

Keywords: cancer; exosomes; treatment.

Conflict of interest statement

CONFLICTS OF INTEREST

None

Figures

Figure 1. Tumor-derived exosomes in tumor progression…
Figure 1. Tumor-derived exosomes in tumor progression and treatment failure

References

    1. Wickman G, Julian L, Olson M. How apoptotic cells aid in the removal of their own cold dead bodies. Cell Death & Differentiation. 2012;19(5):735–742.
    1. Heijnen HF, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood. 1999;94(11):3791–3799.
    1. Trams EG, Lauter CJ, Norman Salem J, Heine U. Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. Biochimica et Biophysica Acta (BBA)-Biomembranes. 1981;645(1):63–70.
    1. Théry C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nature Reviews Immunology. 2009;9(8):581–593.
    1. Pan BT, Johnstone RM. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell. 1983;33(3):967–978.
    1. Sun Y, Liu J. Potential of cancer cell-derived exosomes in clinical application: a review of recent research advances. Clin Ther. 2014;36(6):863–872.
    1. Khan S, Jutzy JM, Valenzuela MM, Turay D, Aspe JR, Ashok A, Mirshahidi S, Mercola D, Lilly MB, Wall NR. Plasma-derived exosomal survivin, a plausible biomarker for early detection of prostate cancer. PLoS One. 2012;7(10):e46737.
    1. Lasser C, Alikhani VS, Ekstrom K, Eldh M, Paredes PT, Bossios A, Sjostrand M, Gabrielsson S, Lotvall J, Valadi H. Human saliva, plasma and breast milk exosomes contain RNA: uptake by macrophages. J Transl Med. 2011;9:9.
    1. Admyre C, Johansson SM, Qazi KR, Filen JJ, Lahesmaa R, Norman M, Neve EP, Scheynius A, Gabrielsson S. Exosomes with immune modulatory features are present in human breast milk. J Immunol. 2007;179(3):1969–1978.
    1. Street JM, Barran PE, Mackay CL, Weidt S, Balmforth C, Walsh TS, Chalmers RT, Webb DJ, Dear JW. Identification and proteomic profiling of exosomes in human cerebrospinal fluid. J Transl Med. 2012;10:5.
    1. Pisitkun T, Shen RF, Knepper MA. Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci U S A. 2004;101(36):13368–13373.
    1. Vojtech L, Woo S, Hughes S, Levy C, Ballweber L, Sauteraud RP, Strobl J, Westerberg K, Gottardo R, Tewari M. Exosomes in human semen carry a distinctive repertoire of small non-coding RNAs with potential regulatory functions. Nucleic acids research. 2014:gku347.
    1. Rabinowits G, Gercel-Taylor C, Day JM, Taylor DD, Kloecker GH. Exosomal microRNA: a diagnostic marker for lung cancer. Clin Lung Cancer. 2009;10(1):42–46.
    1. Silva J, Garcia V, Rodriguez M, Compte M, Cisneros E, Veguillas P, Garcia JM, Dominguez G, Campos-Martin Y, Cuevas J, Pena C, Herrera M, Diaz R, Mohammed N, Bonilla F. Analysis of exosome release and its prognostic value in human colorectal cancer. Genes Chromosomes Cancer. 2012;51(4):409–418.
    1. Xu R, Greening DW, Rai A, Ji H, Simpson RJ. Highly-purified exosomes and shed microvesicles isolated from the human colon cancer cell line LIM1863 by sequential centrifugal ultrafiltration are biochemically and functionally distinct. Methods. doi: 10.1016/j.ymeth.2015.04.008. [Epub ahead of print]
    1. Mathivanan S, Fahner CJ, Reid GE, Simpson RJ. ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic acids research. 2012;40(D1):D1241–D1244.
    1. Mincheva-Nilsson L, Baranov V. The role of placental exosomes in reproduction. Am J Reprod Immunol. 2010;63(6):520–533.
    1. Vlassov AV, Magdaleno S, Setterquist R, Conrad R. Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochimica et Biophysica Acta (BBA)-General Subjects. 2012;1820(7):940–948.
    1. Denzer K, Kleijmeer MJ, Heijnen HF, Stoorvogel W, Geuze HJ. Exosome: from internal vesicle of the multivesicular body to intercellular signaling device. J Cell Sci. 2000;113(19):3365–3374.
    1. Cai Z, Yang F, Yu L, Yu Z, Jiang L, Wang Q, Yang Y, Wang L, Cao X, Wang J. Activated T cell exosomes promote tumor invasion via Fas signaling pathway. J Immunol. 2012;188(12):5954–5961.
    1. Liang B, Peng P, Chen S, Li L, Zhang M, Cao D, Yang J, Li H, Gui T, Li X, Shen K. Characterization and proteomic analysis of ovarian cancer-derived exosomes. J Proteomics. 2013;80:171–182.
    1. Raimondo F, Morosi L, Chinello C, Magni F, Pitto M. Advances in membranous vesicle and exosome proteomics improving biological understanding and biomarker discovery. Proteomics. 2011;11(4):709–720.
    1. Kruger S, Abd Elmageed ZY, Hawke DH, Worner PM, Jansen DA, Abdel-Mageed AB, Alt EU, Izadpanah R. Molecular characterization of exosome-like vesicles from breast cancer cells. BMC Cancer. 2014;14:44.
    1. Yuyama K, Sun H, Mitsutake S, Igarashi Y. Sphingolipid-modulated exosome secretion promotes clearance of amyloid-β by microglia. Journal of Biological Chemistry. 2012;287(14):10977–10989.
    1. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature cell biology. 2007;9(6):654–659.
    1. Ge Q, Zhou Y, Lu J, Bai Y, Xie X, Lu Z. miRNA in plasma exosome is stable under different storage conditions. Molecules. 2014;19(2):1568–1575.
    1. Li M, Zeringer E, Barta T, Schageman J, Cheng A, Vlassov AV. Analysis of the RNA content of the exosomes derived from blood serum and urine and its potential as biomarkers. Philosophical Transactions of the Royal Society B: Biological Sciences. 2014;369(1652):20130502.
    1. Taylor DD, Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecologic oncology. 2008;110(1):13–21.
    1. Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol. 2009;11(9):1143–1149.
    1. Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem. 2010;285(23):17442–17452.
    1. Chen TS, Lai RC, Lee MM, Choo AB, Lee CN, Lim SK. Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Res. 2010;38(1):215–224.
    1. Turchinovich A, Weiz L, Langheinz A, Burwinkel B. Characterization of extracellular circulating microRNA. Nucleic Acids Res. 2011;39(16):7223–7233.
    1. 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. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A. 2011;108(12):5003–5008.
    1. Gallo A, Tandon M, Alevizos I, Illei GG. The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS One. 2012;7(3):e30679.
    1. Zhang H-G, Grizzle WE. Exosomes: a novel pathway of local and distant intercellular communication that facilitates the growth and metastasis of neoplastic lesions. The American journal of pathology. 2014;184(1):28–41.
    1. Eichelser C, Stuckrath I, Muller V, Milde-Langosch K, Wikman H, Pantel K, Schwarzenbach H. Increased serum levels of circulating exosomal microRNA-373 in receptor-negative breast cancer patients. Oncotarget. 2014;5(20):9650–9663.
    1. Tanaka Y, Kamohara H, Kinoshita K, Kurashige J, Ishimoto T, Iwatsuki M, Watanabe M, Baba H. Clinical impact of serum exosomal microRNA‐21 as a clinical biomarker in human esophageal squamous cell carcinoma. Cancer. 2013;119(6):1159–1167.
    1. Chen WX, Liu XM, Lv MM, Chen L, Zhao JH, Zhong SL, Ji MH, Hu Q, Luo Z, Wu JZ, Tang JH. Exosomes from drug-resistant breast cancer cells transmit chemoresistance by a horizontal transfer of microRNAs. PLoS One. 2014;9(4):e95240.
    1. Qi P, Du X. The long non-coding RNAs, a new cancer diagnostic and therapeutic gold mine. Mod Pathol. 2013;26(2):155–165.
    1. Li Q, Shao Y, Zhang X, Zheng T, Miao M, Qin L, Wang B, Ye G, Xiao B, Guo J. Plasma long noncoding RNA protected by exosomes as a potential stable biomarker for gastric cancer. Tumor Biology. 2014:1–6.
    1. Takahashi K, Yan IK, Kogure T, Haga H, Patel T. Extracellular vesicle-mediated transfer of long non-coding RNA ROR modulates chemosensitivity in human hepatocellular cancer. FEBS Open Bio. 2014;4:458–467.
    1. Lázaro‐Ibáñez E, Sanz‐Garcia A, Visakorpi T, Escobedo‐Lucea C, Siljander P, Ayuso‐Sacido Á, Yliperttula M. Different gDNA content in the subpopulations of prostate cancer extracellular vesicles: apoptotic bodies, microvesicles, and exosomes. The Prostate. 2014;74(14):1379–1390.
    1. Thakur BK, Zhang H, Becker A, Matei I, Huang Y, Costa-Silva B, Zheng Y, Hoshino A, Brazier H, Xiang J, Williams C, Rodriguez-Barrueco R, Silva JM, Zhang W, Hearn S, Elemento O, et al. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res. 2014;24(6):766–769.
    1. Kahlert C, Melo SA, Protopopov A, Tang J, Seth S, Koch M, Zhang J, Weitz J, Chin L, Futreal A. Identification of Double-stranded Genomic DNA Spanning All Chromosomes with Mutated KRAS and p53 DNA in the Serum Exosomes of Patients with Pancreatic Cancer. Journal of Biological Chemistry. 2014;289(7):3869–3875.
    1. Vazirabadi G, Geiger TR, Coffin WF, 3rd, Martin JM. Epstein-Barr virus latent membrane protein-1 (LMP-1) and lytic LMP-1 localization in plasma membrane-derived extracellular vesicles and intracellular virions. J Gen Virol. 2003;84(Pt 8):1997–2008.
    1. Meckes DG, Jr, Shair KH, Marquitz AR, Kung CP, Edwards RH, Raab-Traub N. Human tumor virus utilizes exosomes for intercellular communication. Proc Natl Acad Sci U S A. 2010;107(47):20370–20375.
    1. Canitano A, Venturi G, Borghi M, Ammendolia MG, Fais S. Exosomes released in vitro from Epstein-Barr virus (EBV)-infected cells contain EBV-encoded latent phase mRNAs. Cancer Lett. 2013;337(2):193–199.
    1. Properzi F, Logozzi M, Abdel-Haq H, Federici C, Lugini L, Azzarito T, Cristofaro I, di Sevo D, Ferroni E, Cardone F, Venditti M, Colone M, Comoy E, Durand V, Fais S, Pocchiari M. Detection of exosomal prions in blood by immunochemistry techniques. J Gen Virol. 2015
    1. Ahmed W, Philip PS, Tariq S, Khan G. Epstein-Barr virus-encoded small RNAs (EBERs) are present in fractions related to exosomes released by EBV-transformed cells. PLoS One. 2014;9(6):e99163.
    1. Ramakrishnaiah V, Thumann C, Fofana I, Habersetzer F, Pan Q, de Ruiter PE, Willemsen R, Demmers JA, Raj VS, Jenster G. Exosome-mediated transmission of hepatitis C virus between human hepatoma Huh7. 5 cells. Proceedings of the National Academy of Sciences. 2013;110(32):13109–13113.
    1. Liu Z, Zhang X, Yu Q, He JJ. Exosome-associated hepatitis C virus in cell cultures and patient plasma. Biochem Biophys Res Commun. 2014;455(3-4):218–222.
    1. Bukong TN, Momen-Heravi F, Kodys K, Bala S, Szabo G. Exosomes from hepatitis C infected patients transmit HCV infection and contain replication competent viral RNA in complex with Ago2-miR122-HSP90. PLoS Pathog. 2014;10(10):e1004424.
    1. Hong BS, Cho J-H, Kim H, Choi E-J, Rho S, Kim J, Kim JH, Choi D-S, Kim Y-K, Hwang D. Colorectal cancer cell-derived microvesicles are enriched in cell cycle-related mRNAs that promote proliferation of endothelial cells. BMC genomics. 2009;10(1):556.
    1. Jenjaroenpun P, Kremenska Y, Nair VM, Kremenskoy M, Joseph B, Kurochkin IV. Characterization of RNA in exosomes secreted by human breast cancer cell lines using next-generation sequencing. PeerJ. 2013;1:e201.
    1. Kucharzewska P, Christianson HC, Welch JE, Svensson KJ, Fredlund E, Ringner M, Morgelin M, Bourseau-Guilmain E, Bengzon J, Belting M. Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proc Natl Acad Sci U S A. 2013;110(18):7312–7317.
    1. Xiao D, Ohlendorf J, Chen Y, Taylor DD, Rai SN, Waigel S, Zacharias W, Hao H, McMasters KM. Identifying mRNA, microRNA and protein profiles of melanoma exosomes. PLoS One. 2012;7(10):e46874.
    1. Corcoran C, Rani S, O'Driscoll L. miR‐34a is an intracellular and exosomal predictive biomarker for response to docetaxel with clinical relevance to prostate cancer progression. The Prostate. 2014;74(13):1320–1334.
    1. Hessvik NP, Phuyal S, Brech A, Sandvig K, Llorente A. Profiling of microRNAs in exosomes released from PC-3 prostate cancer cells. Biochim Biophys Acta. 2012;1819(11-12):1154–1163.
    1. Kogure T, Lin WL, Yan IK, Braconi C, Patel T. Intercellular nanovesicle‐mediated microRNA transfer: A mechanism of environmental modulation of hepatocellular cancer cell growth. Hepatology. 2011;54(4):1237–1248.
    1. Palazzolo G, Albanese NN, G DIC, Gygax D, Vittorelli ML, Pucci-Minafra I. Proteomic analysis of exosome-like vesicles derived from breast cancer cells. Anticancer Res. 2012;32(3):847–860.
    1. Mittelbrunn M, Gutiérrez-Vázquez C, Villarroya-Beltri C, González S, Sánchez-Cabo F, González MÁ, Bernad A, Sánchez-Madrid F. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nature communications. 2011;2:282.
    1. Liao J, Liu R, Yin L, Pu Y. Expression profiling of exosomal miRNAs derived from human esophageal cancer cells by Solexa high-throughput sequencing. International journal of molecular sciences. 2014;15(9):15530–15551.
    1. Keller S, Sanderson MP, Stoeck A, Altevogt P. Exosomes: from biogenesis and secretion to biological function. Immunology letters. 2006;107(2):102–108.
    1. Park JE, Tan HS, Datta A, Lai RC, Zhang H, Meng W, Lim SK, Sze SK. Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes. Mol Cell Proteomics. 2010;9(6):1085–1099.
    1. Clayton A, Turkes A, Navabi H, Mason MD, Tabi Z. Induction of heat shock proteins in B-cell exosomes. J Cell Sci. 2005;118(Pt 16):3631–3638.
    1. Savina A, Furlán M, Vidal M, Colombo MI. Exosome release is regulated by a calcium-dependent mechanism in K562 cells. Journal of Biological Chemistry. 2003;278(22):20083–20090.
    1. Lespagnol A, Duflaut D, Beekman C, Blanc L, Fiucci G, Marine J-C, Vidal M, Amson R, Telerman A. Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice. Cell Death & Differentiation. 2008;15(11):1723–1733.
    1. Xiao X, Yu S, Li S, Wu J, Ma R, Cao H, Zhu Y, Feng J. Exosomes: decreased sensitivity of lung cancer A549 cells to cisplatin. PLoS One. 2014;9(2):e89534.
    1. Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, Schwille P, Brügger B, Simons M. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319(5867):1244–1247.
    1. Li J, Jun Yu, Liu A, Wang Y. beta-Elemene against human lung cancer via up-regulation of P53 protein expression to promote the release of exosome. Lung Cancer. 2014;86(2):144–150.
    1. Ban JJ, Lee M, Im W, Kim M. Low pH increases the yield of exosome isolation. Biochem Biophys Res Commun. 2015;461(1):76–79.
    1. Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, Moita CF, Schauer K, Hume AN, Freitas RP, Goud B, Benaroch P, Hacohen N, Fukuda M, Desnos C, Seabra MC, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12(1):19–30. sup pp 11-13.
    1. Peinado H, Alečković M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, García-Santos G, Ghajar CM. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nature medicine. 2012;18(6):883–891.
    1. Ostenfeld MS, Jeppesen DK, Laurberg JR, Boysen AT, Bramsen JB, Primdal-Bengtson B, Hendrix A, Lamy P, Dagnaes-Hansen F, Rasmussen MH. Cellular disposal of miR23b by RAB27-dependent exosome release is linked to acquisition of metastatic properties. Cancer research. 2014;74(20):5758–5771.
    1. Savina A, Fader CM, Damiani MT, Colombo MI. Rab11 promotes docking and fusion of multivesicular bodies in a calcium-dependent manner. Traffic. 2005;6(2):131–143.
    1. Hsu C, Morohashi Y, Yoshimura S, Manrique-Hoyos N, Jung S, Lauterbach MA, Bakhti M, Gronborg M, Mobius W, Rhee J, Barr FA, Simons M. Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A-C. J Cell Biol. 2010;189(2):223–232.
    1. Aung T, Chapuy B, Vogel D, Wenzel D, Oppermann M, Lahmann M, Weinhage T, Menck K, Hupfeld T, Koch R, Trumper L, Wulf GG. Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3. Proc Natl Acad Sci U S A. 2011;108(37):15336–15341.
    1. Tsunemi T, Hamada K, Krainc D. ATP13A2/PARK9 regulates secretion of exosomes and alpha-synuclein. J Neurosci. 2014;34(46):15281–15287.
    1. Wei Jx, Lv Lh, Wan Yl, Cao Y, Li Gl, Lin Hm, Zhou R, Shang Cz, Cao J, He H. Vps4A functions as a tumor suppressor by regulating the secretion and uptake of exosomal microRNAs in human hepatoma cells. Hepatology. 2015;61:1284–94.
    1. Thery C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006 Chapter 3:Unit 3 22.
    1. Caradec J, Kharmate G, Hosseini-Beheshti E, Adomat H, Gleave M, Guns E. Reproducibility and efficiency of serum-derived exosome extraction methods. Clin Biochem. 2014;47(13-14):1286–1292.
    1. Zlotogorski-Hurvitz A, Dayan D, Chaushu G, Korvala J, Salo T, Sormunen R, Vered M. Human saliva-derived exosomes: comparing methods of isolation. J Histochem Cytochem. 2015;63(3):181–189.
    1. Logozzi M, De Milito A, Lugini L, Borghi M, Calabro L, Spada M, Perdicchio M, Marino ML, Federici C, Iessi E, Brambilla D, Venturi G, Lozupone F, Santinami M, Huber V, Maio M, et al. High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PloS one. 2009;4(4):e5219.
    1. Hong CS, Muller L, Boyiadzis M, Whiteside TL. Isolation and characterization of CD34+ blast-derived exosomes in acute myeloid leukemia. PloS one. 2014;9(8):e103310.
    1. Jakobsen KR, Paulsen BS, Bæk R, Varming K, Sorensen BS, Jørgensen MM. Exosomal proteins as potential diagnostic markers in advanced non-small cell lung carcinoma. Journal of extracellular vesicles. 2015;4:26659.
    1. Morelli AE, Larregina AT, Shufesky WJ, Sullivan ML, Stolz DB, Papworth GD, Zahorchak AF, Logar AJ, Wang Z, Watkins SC, Falo LD., Jr and Thomson AW. Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood. 2004;104(10):3257–3266.
    1. Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2(8):569–579.
    1. Hannafon BN, Ding WQ. Intercellular Communication by Exosome-Derived microRNAs in Cancer. Int J Mol Sci. 2013;14(7):14240–14269.
    1. Cossetti C, Lugini L, Astrologo L, Saggio I, Fais S, Spadafora C. Soma-to-germline transmission of RNA in mice xenografted with human tumour cells: possible transport by exosomes. PloS one. 2014;9(7):e101629.
    1. O'Brien K, Rani S, Corcoran C, Wallace R, Hughes L, Friel AM, McDonnell S, Crown J, Radomski MW, O'Driscoll L. Exosomes from triple-negative breast cancer cells can transfer phenotypic traits representing their cells of origin to secondary cells. European Journal of Cancer. 2013;49(8):1845–1859.
    1. Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer. 2009;9(4):274–284.
    1. Qu J-L, Qu X-J, Zhao M-F, Teng Y-E, Zhang Y, Hou K-Z, Jiang Y-H, Yang X-H, Liu Y-P. Gastric cancer exosomes promote tumour cell proliferation through PI3K/Akt and MAPK/ERK activation. Digestive and liver disease. 2009;41(12):875–880.
    1. Yang M, Chen J, Su F, Yu B, Lin L, Liu Y, Huang J, Song E. Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Mol Cancer. 2011;10(117):541–552.
    1. Zhu W, Huang L, Li Y, Zhang X, Gu J, Yan Y, Xu X, Wang M, Qian H, Xu W. Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo. Cancer Lett. 2012;315(1):28–37.
    1. Xiao H, Lässer C, Shelke GV, Wang J, Rådinger M, Lunavat TR, Malmhäll C, Lin LH, Li J, Li L. Mast cell exosomes promote lung adenocarcinoma cell proliferation-role of KIT-stem cell factor signaling. Cell communication and signaling: CCS. 2014;12(1):64–64.
    1. Atay S, Banskota S, Crow J, Sethi G, Rink L, Godwin AK. Oncogenic KIT-containing exosomes increase gastrointestinal stromal tumor cell invasion. Proc Natl Acad Sci U S A. 2014;111(2):711–716.
    1. Aga M, Bentz GL, Raffa S, Torrisi MR, Kondo S, Wakisaka N, Yoshizaki T, Pagano JS, Shackelford J. Exosomal HIF1alpha supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes. Oncogene. 2014;33(37):4613–4622.
    1. Demory Beckler M, Higginbotham JN, Franklin JL, Ham AJ, Halvey PJ, Imasuen IE, Whitwell C, Li M, Liebler DC, Coffey RJ. Proteomic analysis of exosomes from mutant KRAS colon cancer cells identifies intercellular transfer of mutant KRAS. Mol Cell Proteomics. 2013;12(2):343–355.
    1. Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, Rak J. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol. 2008;10(5):619–624.
    1. Yang Y, Bucan V, Baehre H, von der Ohe J, Otte A, Hass R. Acquisition of new tumor cell properties by MSC-derived exosomes. Int J Oncol. 2015;47:244–52.
    1. Saleem SN, Abdel-Mageed AB. Tumor-derived exosomes in oncogenic reprogramming and cancer progression. Cell Mol Life Sci. 2015;72(1):1–10.
    1. Hood JL, San RS, Wickline SA. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res. 2011;71(11):3792–3801.
    1. Dutta S, Warshall C, Bandyopadhyay C, Dutta D, Chandran B. Interactions between Exosomes from Breast Cancer Cells and Primary Mammary Epithelial Cells Leads to Generation of Reactive Oxygen Species Which Induce DNA Damage Response, Stabilization of p53 and Autophagy in Epithelial Cells. PLoS One. 2014;9(5):e97580.
    1. Rana S, Malinowska K, Zoller M. Exosomal tumor microRNA modulates premetastatic organ cells. Neoplasia. 2013;15(3):281–295.
    1. 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, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. 2015;17:816–26.
    1. Wang X, Ding X, Nan L, Wang Y, Wang J, Yan Z, Zhang W, Sun J, Zhu W, Ni B, Dong S, Yu L. Investigation of the roles of exosomes in colorectal cancer liver metastasis. Oncol Rep. 2015;33(5):2445–2453.
    1. Harris AL. Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2(1):38–47.
    1. Ruan K, Song G, Ouyang G. Role of hypoxia in the hallmarks of human cancer. J Cell Biochem. 2009;107(6):1053–1062.
    1. Wang T, Gilkes DM, Takano N, Xiang L, Luo W, Bishop CJ, Chaturvedi P, Green JJ, Semenza GL. Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis. Proceedings of the National Academy of Sciences. 2014;111(31):E3234–E3242.
    1. King HW, Michael MZ, Gleadle JM. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer. 2012;12:421.
    1. Umezu T, Tadokoro H, Azuma K, Yoshizawa S, Ohyashiki K, Ohyashiki JH. Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1. Blood. 2014;124(25):3748–3757.
    1. Svensson KJ, Kucharzewska P, Christianson HC, Skold S, Lofstedt T, Johansson MC, Morgelin M, Bengzon J, Ruf W, Belting M. Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2-mediated heparin-binding EGF signaling in endothelial cells. Proc Natl Acad Sci U S A. 2011;108(32):13147–13152.
    1. Jackson MW, Rusthoven CG, Fisher CM, Schefter TE. Clinical potential of bevacizumab in the treatment of metastatic and locally advanced cervical cancer: current evidence. Onco Targets Ther. 2014;7:751–759.
    1. Poulsen HS, Urup T, Michaelsen SR, Staberg M, Villingshoj M, Lassen U. The impact of bevacizumab treatment on survival and quality of life in newly diagnosed glioblastoma patients. Cancer Manag Res. 2014;6:373–387.
    1. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–2342.
    1. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542–2550.
    1. Hoffmann TK, Dworacki G, Tsukihiro T, Meidenbauer N, Gooding W, Johnson JT, Whiteside TL. Spontaneous apoptosis of circulating T lymphocytes in patients with head and neck cancer and its clinical importance. Clin Cancer Res. 2002;8(8):2553–2562.
    1. Bauernhofer T, Kuss I, Henderson B, Baum AS, Whiteside TL. Preferential apoptosis of CD56dim natural killer cell subset in patients with cancer. Eur J Immunol. 2003;33(1):119–124.
    1. Dworacki G, Meidenbauer N, Kuss I, Hoffmann TK, Gooding W, Lotze M, Whiteside TL. Decreased ζ chain expression and apoptosis in CD3+ peripheral blood T lymphocytes of patients with melanoma. Cancer research. 2001;7(3 Supplement):947s–957s.
    1. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, Geuze HJ. B lymphocytes secrete antigen-presenting vesicles. J Exp Med. 1996;183(3):1161–1172.
    1. Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, Ricciardi-Castagnoli P, Raposo G, Amigorena S. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell derived exosomes. Nature medicine. 1998;4(5):594–600.
    1. 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. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med. 2001;7(3):297–303.
    1. Gastpar R, Gehrmann M, Bausero MA, Asea A, Gross C, Schroeder JA, Multhoff G. Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer research. 2005;65(12):5238–5247.
    1. Vega VL, Rodríguez-Silva M, Frey T, Gehrmann M, Diaz JC, Steinem C, Multhoff G, Arispe N, De Maio A. Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. The Journal of Immunology. 2008;180(6):4299–4307.
    1. Dai S, Wan T, Wang B, Zhou X, Xiu F, Chen T, Wu Y, Cao X. More efficient induction of HLA-A* 0201-restricted and carcinoembryonic antigen (CEA)-specific CTL response by immunization with exosomes prepared from heat-stressed CEA-positive tumor cells. Clinical cancer research. 2005;11(20):7554–7563.
    1. Taylor D, Gercel-Taylor C. Tumour-derived exosomes and their role in cancer-associated T-cell signalling defects. British journal of cancer. 2005;92(2):305–311.
    1. Filipazzi P, Bürdek M, Villa A, Rivoltini L, Huber V. Recent advances on the role of tumor exosomes in immunosuppression and disease progression. Seminars in cancer biology: Elsevier) 2012:342–349.
    1. Greening DW, Gopal SK, Xu R, Simpson RJ, Chen W. Exosomes and their roles in immune regulation and cancer. Seminars in cell & developmental biology: Elsevier) 2015:72–81.
    1. Yang C, Kim SH, Bianco NR, Robbins PD. Tumor-derived exosomes confer antigen-specific immunosuppression in a murine delayed-type hypersensitivity model. PLoS One. 2011;6(8):e22517.
    1. Yang C, Ruffner MA, Kim SH, Robbins PD. Plasma-derived MHC class II+ exosomes from tumor-bearing mice suppress tumor antigen-specific immune responses. European journal of immunology. 2012;42(7):1778–1784.
    1. Ju S-T, Panka DJ, Cui H, Ettinger R, Ei-Khatib M, Sherr DH, Stanger BZ, Marshak-Rothstein A. Fas (CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature. 1995;373(6513):444–448.
    1. Suda T, Okazaki T, Naito Y, Yokota T, Arai N, Ozaki S, Nakao K, Nagata S. Expression of the Fas ligand in cells of T cell lineage. J Immunol. 1995;154(8):3806–3813.
    1. Arase H, Arase N, Saito T. Fas-mediated cytotoxicity by freshly isolated natural killer cells. J Exp Med. 1995;181(3):1235–1238.
    1. Nagata S. Apoptosis by death factor. Cell. 1997;88(3):355–365.
    1. Taylor DD, Lyons KS, Gercel-Taylor C. Shed membrane fragment-associated markers for endometrial and ovarian cancers. Gynecol Oncol. 2002;84(3):443–448.
    1. Ungefroren H, Voss M, Jansen M, Roeder C, Henne-Bruns D, Kremer B, Kalthoff H. Human pancreatic adenocarcinomas express Fas and Fas ligand yet are resistant to Fas-mediated apoptosis. Cancer Res. 1998;58(8):1741–1749.
    1. Martinez-Lorenzo MJ, Anel A, Gamen S, Monle n I, Lasierra P, Larrad L, Pineiro A, Alava MA, Naval J. Activated human T cells release bioactive Fas ligand and APO2 ligand in microvesicles. J Immunol. 1999;163(3):1274–1281.
    1. Taylor DD, Gerçel-Taylor Ç, Lyons KS, Stanson J, Whiteside TL. T-cell apoptosis and suppression of T-cell receptor/CD3-ζ by Fas ligand-containing membrane vesicles shed from ovarian tumors. Clinical cancer research. 2003;9(14):5113–5119.
    1. Kim JW, Wieckowski E, Taylor DD, Reichert TE, Watkins S, Whiteside TL. Fas ligand-positive membranous vesicles isolated from sera of patients with oral cancer induce apoptosis of activated T lymphocytes. Clin Cancer Res. 2005;11(3):1010–1020.
    1. 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. Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. J Exp Med. 2002;195(10):1303–1316.
    1. Huber V, Fais S, Iero M, Lugini L, Canese P, Squarcina P, Zaccheddu A, Colone M, Arancia G, Gentile M. Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: role in immune escape. Gastroenterology. 2005;128(7):1796–1804.
    1. Ye S-b, Li Z-L, Luo D-h, Huang B-j, Chen Y-S, Zhang X-s, Cui J, Zeng Y-x, Li J. Tumor-derived exosomes promote tumor progression and T-cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma. Oncotarget. 2014;5(14):5439.
    1. Clayton A, Al-Taei S, Webber J, Mason MD, Tabi Z. Cancer exosomes express CD39 and CD73, which suppress T cells through adenosine production. The Journal of Immunology. 2011;187(2):676–683.
    1. Valenti R, Huber V, Filipazzi P, Pilla L, Sovena G, Villa A, Corbelli A, Fais S, Parmiani G, Rivoltini L. Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. Cancer Res. 2006;66(18):9290–9298.
    1. Peng P, Yan Y, Keng S. Exosomes in the ascites of ovarian cancer patients: origin and effects on anti-tumor immunity. Oncol Rep. 2011;25(3):749–762.
    1. Clayton A, Mitchell JP, Court J, Mason MD, Tabi Z. Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res. 2007;67(15):7458–7466.
    1. Liu C, Yu S, Zinn K, Wang J, Zhang L, Jia Y, Kappes JC, Barnes S, Kimberly RP, Grizzle WE, Zhang HG. Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. J Immunol. 2006;176(3):1375–1385.
    1. Yu S, Liu C, Su K, Wang J, Liu Y, Zhang L, Li C, Cong Y, Kimberly R, Grizzle WE, Falkson C, Zhang HG. Tumor exosomes inhibit differentiation of bone marrow dendritic cells. J Immunol. 2007;178(11):6867–6875.
    1. Clayton A, Tabi Z. Exosomes and the MICA-NKG2D system in cancer. Blood Cells Mol Dis. 2005;34(3):206–213.
    1. Viaud S, Terme M, Flament C, Taieb J, Andre F, Novault S, Escudier B, Robert C, Caillat-Zucman S, Tursz T, Zitvogel L, Chaput N. Dendritic cell-derived exosomes promote natural killer cell activation and proliferation: a role for NKG2D ligands and IL-15Ralpha. PLoS One. 2009;4(3):e4942.
    1. Clayton A, Mitchell JP, Court J, Linnane S, Mason MD, Tabi Z. Human tumor-derived exosomes down-modulate NKG2D expression. J Immunol. 2008;180(11):7249–7258.
    1. Shedden K, Xie XT, Chandaroy P, Chang YT, Rosania GR. Expulsion of small molecules in vesicles shed by cancer cells: association with gene expression and chemosensitivity profiles. Cancer Res. 2003;63(15):4331–4337.
    1. Safaei R, Larson BJ, Cheng TC, Gibson MA, Otani S, Naerdemann W, Howell SB. Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells. Mol Cancer Ther. 2005;4(10):1595–1604.
    1. Corcoran C, Rani S, O'Brien K, O'Neill A, Prencipe M, Sheikh R, Webb G, McDermott R, Watson W, Crown J. Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes. PloS one. 2012;7(12):e50999.
    1. Lv M-m, Zhu X-y, Chen W-x, Zhong S-l, Hu Q, Ma T-f, Zhang J, Chen L, Tang J-h, Zhao J-h. Exosomes mediate drug resistance transfer in MCF-7 breast cancer cells and a probable mechanism is delivery of P-glycoprotein. Tumor Biology. 2014;35(11):10773–10779.
    1. Altieri DC. Validating survivin as a cancer therapeutic target. Nature Reviews Cancer. 2003;3(1):46–54.
    1. Mita AC, Mita MM, Nawrocki ST, Giles FJ. Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res. 2008;14(16):5000–5005.
    1. Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Curry WT, Carter BS, Krichevsky AM, Breakefield XO. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nature cell biology. 2008;10(12):1470–1476.
    1. Valenzuela MM, Ferguson Bennit HR, Gonda A, Diaz Osterman CJ, Hibma A, Khan S, Wall NR. Exosomes Secreted from Human Cancer Cell Lines Contain Inhibitors of Apoptosis (IAP) Cancer Microenviron. 2015
    1. Challagundla KB, Wise PM, Neviani P, Chava H, Murtadha M, Xu T, Kennedy R, Ivan C, Zhang X, Vannini I. Exosome-Mediated Transfer of microRNAs Within the Tumor Microenvironment and Neuroblastoma Resistance to Chemotherapy. Journal of the National Cancer Institute. 2015;107(7):djv135.
    1. Hu Y, Yan C, Mu L, Huang K, Li X, Tao D, Wu Y, Qin J. Fibroblast-Derived Exosomes Contribute to Chemoresistance through Priming Cancer Stem Cells in Colorectal Cancer. PLoS One. 2015;10(5)
    1. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235–242.
    1. Tan D, Tan SY, Lim ST, Kim SJ, Kim WS, Advani R, Kwong YL. Management of B-cell non-Hodgkin lymphoma in Asia: resource-stratified guidelines. Lancet Oncol. 2013;14(12):e548–561.
    1. Oostra DR, Macrae ER. Role of trastuzumab emtansine in the treatment of HER2-positive breast cancer. Breast Cancer (Dove Med Press) 2014;6:103–113.
    1. Battke C, Ruiss R, Welsch U, Wimberger P, Lang S, Jochum S, Zeidler R. Tumour exosomes inhibit binding of tumour-reactive antibodies to tumour cells and reduce ADCC. Cancer Immunol Immunother. 2011;60(5):639–648.
    1. Ciravolo V, Huber V, Ghedini GC, Venturelli E, Bianchi F, Campiglio M, Morelli D, Villa A, Della Mina P, Menard S, Filipazzi P, Rivoltini L, Tagliabue E, Pupa SM. Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy. J Cell Physiol. 2012;227(2):658–667.
    1. Ahmed N, Abubaker K, Findlay J, Quinn M. Epithelial mesenchymal transition and cancer stem cell-like phenotypes facilitate chemoresistance in recurrent ovarian cancer. Curr Cancer Drug Targets. 2010;10(3):268–278.
    1. Vella LJ. The emerging role of exosomes in epithelial-mesenchymal-transition in cancer. Front Oncol. 2014;4:361.
    1. Hakulinen J, Sankkila L, Sugiyama N, Lehti K, Keski-Oja J. Secretion of active membrane type 1 matrix metalloproteinase (MMP-14) into extracellular space in microvesicular exosomes. Journal of cellular biochemistry. 2008;105(5):1211–1218.
    1. Mathias RA, Chen Y-S, Wang B, Ji H, Kapp EA, Moritz RL, Zhu H-J, Simpson RJ. Extracellular remodelling during oncogenic Ras-induced epithelial-mesenchymal transition facilitates MDCK cell migration. Journal of proteome research. 2010;9(2):1007–1019.
    1. Chairoungdua A, Smith DL, Pochard P, Hull M, Caplan MJ. Exosome release of β-catenin: a novel mechanism that antagonizes Wnt signaling. The Journal of cell biology. 2010;190(6):1079–1091.
    1. Jeppesen DK, Nawrocki A, Jensen SG, Thorsen K, Whitehead B, Howard KA, Dyrskjot L, Orntoft TF, Larsen MR, Ostenfeld MS. Quantitative proteomics of fractionated membrane and lumen exosome proteins from isogenic metastatic and nonmetastatic bladder cancer cells reveal differential expression of EMT factors. Proteomics. 2014;14(6):699–712.
    1. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nature Reviews Molecular Cell Biology. 2014;15(3):178–196.
    1. Gross JC, Chaudhary V, Bartscherer K, Boutros M. Active Wnt proteins are secreted on exosomes. Nat Cell Biol. 2012;14(10):1036–1045.
    1. Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR, Chiu E, Buchanan M, Hosein AN, Basik M, Wrana JL. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell. 2012;151(7):1542–1556.
    1. Menck K, Klemm F, Gross JC, Pukrop T, Wenzel D, Binder C. Induction and transport of Wnt 5a during macrophage-induced malignant invasion is mediated by two types of extracellular vesicles. Oncotarget. 2013;4(11):2057.
    1. Josson S, Gururajan M, Sung S, Hu P, Shao C, Zhau H, Liu C, Lichterman J, Duan P, Li Q. Stromal fibroblast-derived miR-409 promotes epithelial-to-mesenchymal transition and prostate tumorigenesis. Oncogene. 2014
    1. Greening DW, Gopal SK, Mathias RA, Liu L, Sheng J, Zhu H-J, Simpson RJ. Emerging roles of exosomes during epithelial-mesenchymal transition and cancer progression. Seminars in cell & developmental biology: Elsevier) 2015:60–71.
    1. Fais S, Venturi G, Gatenby B. Microenvironmental acidosis in carcinogenesis and metastases: new strategies in prevention and therapy. Cancer Metastasis Rev. 2014;33(4):1095–1108.
    1. Huber V, De Milito A, Harguindey S, Reshkin SJ, Wahl ML, Rauch C, Chiesi A, Pouyssegur J, Gatenby RA, Rivoltini L, Fais S. Proton dynamics in cancer. J Transl Med. 2010;8:57.
    1. Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A, Coscia C, Iessi E, Logozzi M, Molinari A. Microenvironmental pH is a key factor for exosome traffic in tumor cells. Journal of Biological Chemistry. 2009;284(49):34211–34222.
    1. Bellone M, Calcinotto A, Filipazzi P, De Milito A, Fais S, Rivoltini L. The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors. Oncoimmunology. 2013;2(1):e22058.
    1. Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwarz S, Rothe G, Hoves S, Renner K, Timischl B, Mackensen A, Kunz-Schughart L, Andreesen R, Krause SW, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood. 2007;109(9):3812–3819.
    1. Chen M, Zou X, Luo H, Cao J, Zhang X, Zhang B, Liu W. Effects and mechanisms of proton pump inhibitors as a novel chemosensitizer on human gastric adenocarcinoma (SGC7901) cells. Cell biology international. 2009;33(9):1008–1019.
    1. Chen M, Huang SL, Zhang XQ, Zhang B, Zhu H, Yang VW, Zou XP. Reversal effects of pantoprazole on multidrug resistance in human gastric adenocarcinoma cells by down-regulating the V-ATPases/mTOR/HIF-1alpha/P-gp and MRP1 signaling pathway in vitro and in vivo. J Cell Biochem. 2012;113(7):2474–2487.
    1. Udelnow A, Kreyes A, Ellinger S, Landfester K, Walther P, Klapperstueck T, Wohlrab J, Henne-Bruns D, Knippschild U, Wurl P. Omeprazole inhibits proliferation and modulates autophagy in pancreatic cancer cells. PloS one. 2011;6(5):e20143.
    1. Ferrari S, Perut F, Fagioli F, Brach Del Prever A, Meazza C, Parafioriti A, Picci P, Gambarotti M, Avnet S, Baldini N, Fais S. Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients’ bed. J Transl Med. 2013;11:268.
    1. Spugnini EP, Baldi A, Buglioni S, Carocci F, de Bazzichini GM, Betti G, Pantaleo I, Menicagli F, Citro G, Fais S. Lansoprazole as a rescue agent in chemoresistant tumors: a phase I/II study in companion animals with spontaneously occurring tumors. J Transl Med. 2011;9(221):b21.
    1. Spugnini EP, Buglioni S, Carocci F, Francesco M, Vincenzi B, Fanciulli M, Fais S. High dose lansoprazole combined with metronomic chemotherapy: a phase I/II study in companion animals with spontaneously occurring tumors. J Transl Med. 2014;12:225.
    1. Sun D, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C, Barnes S, Grizzle W, Miller D, Zhang H-G. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Molecular Therapy. 2010;18(9):1606–1614.
    1. Zhuang X, Xiang X, Grizzle W, Sun D, Zhang S, Axtell RC, Ju S, Mu J, Zhang L, Steinman L, Miller D, Zhang HG. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther. 2011;19(10):1769–1779.
    1. Putz U, Howitt J, Doan A, Goh C-P, Low L-H, Silke J, Tan S-S. The tumor suppressor PTEN is exported in exosomes and has phosphatase activity in recipient cells. Science signaling. 2012;5(243):ra70.
    1. Mizrak A, Bolukbasi MF, Ozdener GB, Brenner GJ, Madlener S, Erkan EP, Strobel T, Breakefield XO, Saydam O. Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growth. Mol Ther. 2013;21(1):101–108.
    1. Ohno S, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, Fujita K, Mizutani T, Ohgi T, Ochiya T, Gotoh N, Kuroda M. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther. 2013;21(1):185–191.
    1. Andre F, Schartz NE, Movassagh M, Flament C, Pautier P, Morice P, Pomel C, Lhomme C, Escudier B, Le Chevalier T, Tursz T, Amigorena S, Raposo G, Angevin E, Zitvogel L. Malignant effusions and immunogenic tumour-derived exosomes. Lancet. 2002;360(9329):295–305.
    1. 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, et al. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial. J Transl Med. 2005;3(1):10.
    1. Viaud S, Thery C, Ploix S, Tursz T, Lapierre V, Lantz O, Zitvogel L, Chaput N. Dendritic cell-derived exosomes for cancer immunotherapy: what's next? Cancer Res. 2010;70(4):1281–1285.
    1. 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. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J Transl Med. 2005;3(1):9.
    1. Dai S, Wei D, Wu Z, Zhou X, Wei X, Huang H, Li G. Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol Ther. 2008;16(4):782–790.
    1. Viaud S, Ploix S, Lapierre V, Thery C, Commere PH, Tramalloni D, Gorrichon K, Virault-Rocroy P, Tursz T, Lantz O, Zitvogel L, Chaput N. Updated technology to produce highly immunogenic dendritic cell-derived exosomes of clinical grade: a critical role of interferon-gamma. J Immunother. 2011;34(1):65–75.
    1. Taieb J, Chaput N, Schartz N, Roux S, Novault S, Menard C, Ghiringhelli F, Terme M, Carpentier AF, Darrasse-Jeze G, Lemonnier F, Zitvogel L. Chemoimmunotherapy of tumors: cyclophosphamide synergizes with exosome based vaccines. J Immunol. 2006;176(5):2722–2729.
    1. Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, Solary E, Le Cesne A, Zitvogel L, Chauffert B. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother. 2007;56(5):641–648.
    1. Lentz MR. Continuous whole blood UltraPheresis procedure in patients with metastatic cancer. J Biol Response Mod. 1989;8(5):511–527.
    1. Marleau AM, Chen C-S, Joyce JA, Tullis RH. Exosome removal as a therapeutic adjuvant in cancer. J Transl Med. 2012;10(1):134.
    1. Tullis RH, Duffin RP, Handley HH, Sodhi P, Menon J, Joyce JA, Kher V. Reduction of hepatitis C virus using lectin affinity plasmapheresis in dialysis patients. Blood purification. 2009;27(1):64–69.
    1. Federici C, Petrucci F, Caimi S, Cesolini A, Logozzi M, Borghi M, D'Ilio S, Lugini L, Violante N, Azzarito T, Majorani C, Brambilla D, Fais S. Exosome Release and Low pH Belong to a Framework of Resistance of Human Melanoma Cells to Cisplatin. PloS one. 2014;9(2):e88193.

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