EXOSOMES AND TRANSFER OF (EPI)GENETIC INFORMATION BY TUMOR CELLS

In this review, we will introduce the current knowledge about exosomes – vesicles that are generated in the cells and released into the extracellular space. Exosomes are forming in the cell plasma membrane and represent the spherical shapes restricted by their membrane and contained the various biomolecules including nucleic acids, proteins, lipids etc. The intent interest to exosomes is based on their ability to horizontal transfer between the cells, to permeate into vascular system reaching the different tissues and to incorporate into the recipient cells. It was shown that exosome incorporation into the cells lead to remarkable changes in the recipient cells both in genomic level (via the integration of exosomal DNA into the host DNA) and in epigenomic level (via the modulation of the content and/or activity of the signaling proteins, microRNA etc.). Undoubtedly, one of the most interesting and perspective achievements in the exosome study is the demonstration of exosome ability to provide the horizontal transfer of the genetic information from cell to cell – the fact supported in the different studies with the various cell models. Here, we will discuss the recent data regarding the main characteristics and properties of exosomes, the role of exosomes in the tumorigenesis including neoplastic transformation, metastasis, multi-drug resistance. The final part of the review involves the most growing area in the exosome study – the possible usage of exosomes in the cancer treatment, in particular – as the specific drug delivery system.

exosomes, malignant tumors, microRNA, neoplastic transformation, metastasis, multi-drug resistance, hormonal resistance, drug delivery

1. Trams E.G., Lauter C.J., Salem N. Jr, Heine U. Exfoliation of membrane ecto enzymes in the form of micro-vesicles. Biochim Biophys Acta 1981;645(1):63–70.

2. Keller S., Sanderson M.P., Stoeck A.,Altevogt P. Exosomes: from biogenesis and secretion to biological function. Immunol Lett 2006;107(2):102–8.

3. Harding C., Heuser J., Stahl P. Receptor mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol 1983;97(2):329–39.

4. Simons M., Raposo G. Exosomes –vesicular carriers for intercellular communication. Curr Opin Cell Biol2009;21(4):575–81.

5. Ogorevc E., Kralj-Iglic V., Veranic P.The role of extracellular vesicles in pheno-typic cancer transformation. Radiol Oncol2013;47(3):197–205.

6. Bellingham S.A., Guo B.B.,Coleman B.M., Hill A.F. Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases? Front Physiol 2012;3:124.

7. Holme P.A., Solum N.O., Brosstad F. et al. Demonstration of platelet-derived microvesicles in blood from patients withactivated coagulation and fibrinolysis using a filtration technique and western blotting. Thromb Haemost 1994;72(5):666–71.

8. Hess C., Sadallah S., Hefti A. et al. Ectosomes released by human neutrophils are specialized functional units. J Immunol1999;163(8):4564–73.

9. Cocucci E., Racchetti G., Meldolesi J. Shedding microvesicles: artefacts no more. Trends Cell Biol 2009;19(2):43–51.

10. Gyorgy B., Szab T.G., Pásztói M. et al. Membrane vesicles, current state-of-the-art:emerging role of extracellular vesicles. CellMol Life Sci 2011;68(16):2667–88.

11. Harding C., Heuser J., Stahl P. Endocytosis and intracellular processing of transferrin and colloidal gold-transferrinin rat reticulocytes: demonstration of a pathway for receptor shedding. Eur J Cell Biol 1984;35(2):256–63.

12. Pan B.T., Teng K., Wu C. et al. Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J Cell Biol1985;101(3):942–8.

13. Zitvogel L., Regnault A., Lozier A. et al.Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell derived exosomes. Nat Med 1998;4(5):594–600.

14. Raposo G., Nijman H.W., Stoorvogel W.et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med 1996;183(3):1161–72.

15. Thery C., Ostrowski M., Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol2009;9(8):581–93.

16. Piper R.C., Katzmann D.J. Biogenesisand function of multivesicular bodies. Annu Rev Cell Dev Biol 2007;23:519–47.

17. Taylor D.D., Gercel-Taylor C. Exosomes/microvesicles: mediators of cancer-associated immunosuppressive microenvironments. Semin Immunopathol 2011;33(5):441–54.

18. Heijnen H.F., Schiel A.E., Fijnheer R.et al. Activated platelets release two typesof membrane vesicles: microvesicles bysurface shedding and exosomes derived fromexocytosis of multivesicular bodies and alpha-granules. Blood 1999;94(11):3791–9.

19. Deregibus M.C., Cantaluppi V.,Calogero R. et al. Endothelial progenitor cellderived microvesicles activate an angiogenicprogram in endothelial cells by a horizontaltransfer of mRNA. Blood 2007;110(7):2440–8.

20. Muralidharan-Chari V., Clancy J.,Plou C. et al. ARF6-regulated sheddingof tumor cell-derived plasma membrane microvesicles. Curr Biol 2009;19(22):1875–85.

21. Booth A.M., Fang Y., Fallon J.K. et al.Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane.J Cell Biol 2006;172(6):923–35.

22. Kesimer M., Scull M., Brighton B. et al. Characterization of exosome-like vesiclesreleased from human tracheobronchial ciliated epithelium: a possible role in innatedefense. FASEB J 2009;23(6):1858–68.

23. Mathivanan S., Ji H., Simpson R.J. Exosomes: extracellular organelles important in intercellular communication. J Proteomics2010;73(10):1907–20.

24. Mathivanan S., Lim J.W., Tauro B.J.et al. Proteomics analysis of A33 immuno-affinity-purified exosomes released from the human colon tumor cell line LIM1215 reveals a tissue-specific protein signature. Mol Cell Proteomics 2010;9(2):197–208.

25. Graner M.W., Alzate O.,Dechkovskaia A.M. et al. Proteomic and immunologic analyses of brain tumor exosomes. FASEB J 2009;23(5):1541–57.

26. Lasser C., Alikhani V.S., Ekström K. et al.Human saliva, plasma and breast milkexosomes contain RNA: uptake bymacrophages. J Transl Med 2011;9:9.

27. Street J.M., Barran P.E., Mackay C.L.et al. Identification and proteomic profiling of exosomes in human cerebrospinal fluid. J Transl Med 2012;10:5.

28. Pfeffer S.R. Two Rabs for exosomerelease. Nat Cell Biol 2010;12(1):3–4.

29. Choi D.S., Kim D.K., Kim Y.K.,Gho Y.S. Proteomics, transcriptomics and lipidomics of exosomes and ectosomes. Proteomics 2013;13(10–11):1554–71.

30. Thery C., Zitvogel L., Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol 2002;2(8):569–79.

31. Denzer K., van Eijk M., Kleijmeer M.J.et al. Follicular dendritic cells carry MHCclass II-expressing microvesicles at theirsurface. J Immunol 2000;165(3):1259–65.

32. Robbins P.D., Morelli A.E. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol 2014;14(3):195–208.

33. Garrus J.E., von Schwedler U.K., Pornillos O.W. et al. Tsg101 and the vacuolarprotein sorting pathway are essential for HIV-1 budding. Cell 2001;107(1):55–65.

34. van Niel G., Raposo G., Candalh C. et al. Intestinal epithelial cells secrete exosome-likevesicles. Gastroenterology 2001;121(2):337–49.

35. Prado N., Marazuela E.G., Segura E.et al. Exosomes from bronchoalveolar fluidof tolerized mice prevent allergic reaction. J Immunol 2008;181(2):1519–25.

36. Bakhti M., Winter C., Simons M. Inhibition of myelin membrane sheath formation by oligodendrocyte-derived exosome-like vesicles. J Biol Chem2011;286(1):787–96.

37. Kujala P., Raymond C.R., Romeijn M.et al. Prion uptake in the gut: identification of the first uptake and replication sites. PLoSPathog 2011;7(12):e1002449.

38. Lee R.H., Pulin A.A., Seo M.J. et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolizedin lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 2009;5(1):54–63.

39. Marhaba R., Klingbeil P., Nuebel T. et al.CD44 and EpCAM: cancer-initiating cell markers. Curr Mol Med 2008;8(8):784–804.

40. Park J.E., Tan H.S., Datta A. et al. Hypoxic tumor cell modulates its microenvironment to enhance angiogenic and metastatic potential by secretion of proteins and exosomes. Mol Cell Proteomics2010;9(6):1085–99.

41. Graves L.E., Ariztia E.V., Navari J.R.et al. Proinvasive properties of ovarian cancer ascites-derived membrane vesicles. CancerRes 2004;64(19):7045–9.

42. Al-Nedawi K., Meehan B., Kerbel R.S.et al. Endothelial expression of autocrineVEGF upon the uptake of tumor-derivedmicrovesicles containing oncogenic EGFR. Proc Natl Acad Sci USA 2009;106(10):3794–9.

43. Ichim T.E., Zhong Z., Kaushal S. et al.Exosomes as a tumor immune escapemechanism: possible therapeutic implications. J Transl Med 2008;6:37.

44. Safaei R., Larson B.J., Cheng T.C. et al. Abnormal lysosomal trafficking and enhancedexosomal export of cisplatin in drug-resistant human ovarian carcinoma cells. Mol Cancer Ther 2005;4(10):1595–604.

45. Shedden K., Xie X.T., Chandaroy P. et al.Expulsion of small molecules in vesicles shedby cancer cells: association with geneexpression and chemosensitivity profiles. Cancer Res 2003;63(15):4331–7.

46. Skog, J., Würdinger T., van Rijn S. et al. Glioblastoma microvesicles transport RN Aand proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol2008;10(12):1470–6.

47. Viswanathan M., Sangiliyandi G.,Vinod S.S. et al. Genomic instability andtumor-specific alterations in oral squamouscell carcinomas assessed by inter-(simple sequence repeat) PCR. Clin CancerRes 2003;9(3):1057–62.

48. Camussi G., Deregibus M.C.,Tetta C. Paracrine/endocrine mechanism of stem cells on kidney repair: roleof microvesicle-mediated transfer of geneticinformation. Curr Opin Nephrol Hypertens2010;19(1):7–12.

49. Janowska-Wieczorek A., Wysoczynski M.,Kijowski J. et al. Microvesicles derived fromactivated platelets induce metastasis andangiogenesis in lung cancer. Int J Cancer2005;113(5):752–60.

50. Hao S., Ye Z., Li F. et al. Epigenetictransfer of metastatic activity by uptakeof highly metastatic B16 melanoma cell-released exosomes. Exp Oncol2006;28(2):126–31.

51. Jung T., Castellana D., Klingbeil P. et al.CD44v6 dependence of premetastatic nichepreparation by exosomes. Neoplasia2009;11(10):1093–105.

52. Qu J.L., Qu X.J., Qu J.L. et al. The roleof cbl family of ubiquitin ligases in gastriccancer exosome-induced apoptosis of JurkatT cells. Acta Oncol 2009;48(8):1173–80.

53. Wollert T., Hurley J.H. Molecularmechanism of multivesicular body biogenesisby ESCRT complexes. Nature2010;464(7290):864–9.

54. Katzmann D.J., Stefan C.J., Babst M.,Emr S.D. Vps27 recruits ESCRT machineryto endosomes during MVB sorting. J CellBiol 2003;162(3):413–23.

55. Roma-Rodrigues C., Fernandes A.R.,Baptista P.V. Exosome in tumourmicroenvironment: overview of the crosstalkbetween normal and cancer cells. Biomed ResInt 2014;2014:179486.

56. van Zijl F., Krupitza G., Mikulits W.Initial steps of metastasis: cell invasion andendothelial transmigration. Mutat Res2011;728(1–2):23–34.

57. Otranto M., Sarrazy V., Bonté F. et al.The role of the myofibroblast in tumorstroma remodeling. Cell Adh Migr2012;6(3):203–19.

58. Webber J.P., Spary L.K., Sanders A.J.et al. Differentiation of tumour-promotingstromal myofibroblasts by cancer exosomes.Oncogene 2015;34(3):290–302.

59. Webber J., Steadman R., Mason M.D.et al. Cancer exosomes trigger fibroblastto myofibroblast differentiation. Cancer Res2010;70(23):9621–30.

60. Cho J.A., Park H., Lim E.H. et al.Exosomes from ovarian cancer cells induceadipose tissue-derived mesenchymal stemcells to acquire the physical and functionalcharacteristics of tumor-supportingmyofibroblasts. Gynecol Oncol2011;123(2):379–86.

61. Cho J.A., Park H., Lim E.H.,Lee K.W. Exosomes from breast cancer cellscan convert adipose tissue-derivedmesenchymal stem cells into myofibroblast-like cells. Int J Oncol 2012;40(1):130–8.

62. Gu J., Qian H., Shen L. et al. Gastriccancer exosomes trigger differentiationof umbilical cord derived mesenchymal stemcells to carcinoma-associated fibroblaststhrough TGF-β/Smad pathway. PLoS One2012;7(12):e52465.

63. Thuma F., Zoller M. Outsmart tumor exosomes to steal the cancer initiating cell its niche. Semin Cancer Biol 2014;28:39–50.

64. Luga V., Wrana J.L. Tumor-stroma interaction: Revealing fibroblast-secreted exosomes as potent regulators of Wnt-planar cell polarity signaling in cancer metastasis. Cancer Res 2013;73(23):6843–7.

65. Abd Elmageed Z.Y., Yang Y., Thomas R. et al. Neoplastic reprogramming of patientderived adipose stem cells by prostate cancer cell-associated exosomes. Stem Cells2014;32(4):983–97.

66. Melo S.A., Sugimoto H., O,Connell J.T.et al. Cancer exosomes perform cellindependent microRNA biogenesis and promote tumorigenesis. Cancer Cell2014;26(5):707–21.

67. Zhang X., Yuan X., Shi H. et al. Exosomes in cancer: small particle, big player. J Hematol Oncol 2015;8:83.

68. Antonyak M.A., Li B., Boroughs L.K. et al. Cancer cell-derived microvesicles induce transformation by transferring tissue transglutaminase and fibronectin to recipient cells. Proc Natl Acad Sci USA 2011;108(12):4852–7.

69. Ji H., Greening D.W., Barnes T.W. et al. 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 2013;13(10–11):1672–86.

70. Putz U., Howitt J., Doan A. et al. The tumor suppressor PTEN is exported in exosomes and has phosphatase activity in recipient cells. Sci Signal 2012;5(243):ra70.

71. Psaila B., Lyden D. The metastatic niche: adapting the foreign soil. Nat Rev Cancer 2009;9(4):285–93.

72. Peinado H., Lavotshkin S., Lyden D. The secreted factors responsible for premetastatic niche formation: old sayings and new thoughts. Semin Cancer Biol 2011;21(2):139–46.

73. Peinado H., Alečković M., Lavotshkin S. et al. Melanoma exosomes educate bone marrow progenitor cells toward a prometastatic phenotype through MET. Nat Med2012;18(6):883–91.

74. Zhou W., Fong M.Y., Min Y. et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 2014;25(4):501–15.

75. Rana S., Malinowska K., Zoller M. Exosomal tumor microRNA modulates premetastatic organ cells. Neoplasia 2013;15(3):281–95.

76. Luga V., Zhang L., Viloria-Petit A.M. et al. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 2012;151(7):1542–56.

77. Ono M., Kosaka N., Tominaga N. et al. Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci Signal 2014;7(332):ra63.

78. Schonenberger M.J., Kovacs W.J. Hypoxia signaling pathways: modulators of oxygen-related organelles. Front Cell Dev Biol 2015;3:42.

79. Zimna A., Kurpisz M. Hypoxia-inducible factor-1 in physiological and pathophysiological angiogenesis: applications and therapies. Biomed Res Int 2015;2015:549412.

80. Yang Y., Yang X., Yang Y. et al. Exosomes: a promising factor involved in cancer hypoxic microenvironments. Curr Med Chem 2015[Epub ahead of print].

81. Vered M., Lehtonen M., Hotakainen L. et al. Caveolin-1 accumulation in the tongue cancer tumor microenvironment is significantly associated with poor prognosis: an in-vivo and in-vitro study. BMC Cancer 2015;15:25.

82. Ramteke A., Ting H., Agarwal C. et al. Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules. Mol Carcinog 2015;54(7):554–65.

83. Chiarini F., Lonetti A., Evangelisti C. et al. Advances in understanding the acute lymphoblastic leukemia bone marrow microenvironment: From biology to therapeutic targeting. Biochim Biophys Acta 2015. [Epub ahead of print].

84. Belting M., Christianson H.C. Role of exosomes and microvesicles in hypoxiaassociated tumour development and cardiovascular disease. J Intern Med 2015;278(3):251–63.

85. Yoon J.H., Kim J., Kim K.L. et al. Proteomic analysis of hypoxia-induced U373MG glioma secretome reveals novel hypoxia-dependent migration factors. Proteomics 2014;14(12):1494–502.

86. Svensson K.J., Kucharzewska P., Christianson H.C. et al. Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2-mediated heparinbinding EGF signaling in endothelial cells. Proc Natl Acad Sci USA 2011;108(32):13147–52.

87. King H.W., Michael M.Z., Gleadle J.M. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer 2012;12:421.

88. Umezu T., Tadokoro H., Azuma K. et al. Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1. Blood 2014;124(25):3748–57.

89. Aga M., Bentz G.L., Raffa S. et al. Exosomal HIF1α supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes. Oncogene 2014;33(37):4613–22.

90. Tadokoro H., Umezu T., Ohyashiki K. et al. Exosomes derived from hypoxic leukemia cells enhance tube formation inendothelial cells. J Biol Chem 2013;288(48):34343–51.

91. Pasquier J., Galas L., Boulangé-Lecomte C. et al. Different modalities of intercellular membrane exchanges mediate cell-to-cell p-glycoprotein transfers in MCF-7 breast cancer cells. J Biol Chem 2012;287(10):7374–87.

92. Corcoran C., Rani S., O,Brien K. et al. Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes. PLoS One 2012;7(12):e50999.

93. Ciravolo V., Huber V., Ghedini G.C. et al. Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy. J Cell Physiol 2012;227(2):658–67/

94. Dutta S., Reamtong O., Panvongsa W. et al. Proteomics profiling of cholangiocarcinoma exosomes: A potential role of oncogenic protein transferring in cancer progression. Biochim Biophys Acta 2015;1852(9):1989–99.

95. Keerthikumar S., Gangoda L., Liem M. et al. Proteogenomic analysis reveals exosomes are more oncogenic than ectosomes. Oncotarget 2015;6(17):15375–96.

96. Demory Beckler M., Higginbotham J.N., Franklin J.L. et al. Proteomic analysis of exosomes from mutant KRAS colon cancer cells identifies intercellular transfer of mutant KRAS. Mol Cell Proteomics 2013;12(2):343–55.

97. Villagrasa A., Álvarez P.J., Osuna A. et al. Exosomes derived from breast cancer cells, small trojan horses? J Mammary Gland Biol Neoplasia 2014;19(3–4):303–13.

98. Chen W.X., Liu X.M., Lv M.M. et al. Exosomes from drug-resistant breast cancer cells transmit chemoresistance by a horizontal transfer of microRNAs. PLoS One 2014;9(4):e95240.

99. Zhao J.J., Lin J., Yang H. et al. MicroRNA-221/222 negatively regulates estrogen receptor alpha and is associated with tamoxifen resistance in breast cancer. J Biol Chem 2008;283(45):31079–86.

100. Wei Y., Lai X., Yu S. et al. Exosomal miR-221/222 enhances tamoxifen resistance in recipient ER-positive breast cancer cells. Breast Cancer Res Treat 2014;147(2):423–31.

101. Семина С.Е., Багров Д.В., Красильников М.А. Межклеточные взаимодействия и развитие гормональной резистентности клеток рака молочной железы. Успехи молекулярной онкологии 2015;2(2):50–5. [Semina S.E., Bagrov D.V., Krasil,nikov M.A. Intercellular interactions and progression of hormonal resistance of breast cancer cells. Uspekhi molekulyarnoy onkologii = Advances in Molecular Oncology 2015;2(2):50–5. (In Russ.)].

102. Zhang W., Meng Y., Liu N. et al. Insights into chemoresistance of prostate cancer. Int J Biol Sci 2015;11(10):1160–70.

103. Hong S., Tan M., Wang S. et al. Efficacy and safety of angiogenesis inhibitors in advanced non-small cell lung cancer: a systematic review and meta-analysis. J Cancer Res Clin Oncol 2015;141(5):909–21.

104. Fakhoury M. Drug delivery approaches for the treatment of glioblastoma multiforme. Artif Cells Nanomed Biotechnol 2015:1–9.

105. Batrakova E.V., Kim M.S. Using exosomes, naturally-equipped nanocarriers, for drug delivery. J Control Release 2015. [Epub ahead of print].

106. Tila D., Ghasemi S., Yazdani-Arazi S.N. et al. Functional liposomes in the cancertargeted drug delivery. J Biomater Appl 2015;30(1):3–16.

107. Urbanelli L., Buratta S., Sagini K. et al. Exosome-based strategies for diagnosis and therapy. Recent Pat CNS Drug Discov 2015;10(1):10–27.

108. Guo L., Guo N. Exosomes: Potent regulators of tumor malignancy and potential bio-tools in clinical application. Crit Rev Oncol Hematol 2015;95(3):346–58.

109. Lasser C. Exosomes in diagnostic and therapeutic applications: biomarker, vaccine and RNA interference delivery vehicle. Exp Opin Biol Ther 2015;15(1):103–17.

110. Gyorgy B., Hung M.E., Breakefield X.O., Leonard J.N. Therapeutic applications of extracellular vesicles: clinical promise and open questions. Annu Rev Pharmacol Toxicol 2015;55:439–64.

111. Tian Y., Li S., Song J. et al. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials 2014;35(7):2383–90.

112. Yang Y., Chen Y., Zhang F. et al. Increased anti-tumour activity by exosomes derived from doxorubicin-treated tumour cells via heat stress. Int J Hyperthermia 2015;31(5):498–506.

113. Pascucci L., Coccè V., Bonomi A. et al. Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: a new approach for drug delivery. J Control Release 2014;192:262–70.

114. Duchi S., Dambruoso P., Martella E. et al. Thiophene-based compounds as fluorescent tags to study mesenchymal stem cell uptake and release of taxanes. Bioconjug Chem 2014;25(4):649–55.

115. Sun D., Zhuang X., Xiang X. et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol Ther 2010;18(9):1606–14.

116. Dai S., Wei D., Wu Z. et al. Phase I clinical trial of autologous ascitesderived exosomes combined with GM-CSF for colorectal cancer. Mol Ther 2008; 16(4):782–90.

117. Escudier B., Dorval T., Chaput N. et al. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived exosomes: results of the first phase I clinical trial. J Transl Med 2005;3(1):10.

118. Núñez-Sánchez M.A., González-Sarrías A., Romo-Vaquero M. et al. Dietary phenolics against colorectal cancer – from promising preclinical results to poor translation into clinical trials: Pitfalls and future needs. Mol Nutr Food Res 2015;59(7):1274–91.

119. Bandyopadhyay D. Farmer to pharmacist: curcumin as an anti-invasive and antimetastatic agent for the treatment of cancer. Front Chem 2014;2:113.

120. Shehzad A., Wahid F., Lee Y.S. Curcumin in cancer chemoprevention: molecular targets, pharmacokinetics, bioavailability, and clinical trials. Arch Pharm(Weinheim) 2010;343(9): 489–99.

121. Pitt J.M., Charrier M., Viaud S. et al. Dendritic cell-derived exosomes as immunotherapies in the fight against cancer. J Immunol 2014;193(3):1006–11.

122. Shender V.O., Pavlyukov M.S., Ziganshin R.H. et al. Proteome-metabolome profiling of ovarian cancer ascites reveals novel components involved in intercellular communication. Mol Cell Proteomics 2014;13(12):3558–71.