nodgoРоссийский журнал детской гематологии и онкологии (РЖДГиО)Russian Journal of Pediatric Hematology and Oncology2311-12672413-5496LTD “Graphica”10.17650/2311-1267-2017-4-2-40-45nodgo-294Research ArticleОбзоры литературыПерспективы использования экзосом опухолевых клеток в диагностике, мониторинге и терапии злокачественных заболеванийProspects of exosomes use of tumor cells in the diagnosis, monitoring and therapy of malignant diseasesТихоноваМ. В.TikhonovaM. V.

117997, Москва, ул. Саморы Машела, 1

1 Samory Mashela St., Moscow, 117997

dr.tihonova@list.ruКарачунскийА. И.KarachunskiyA. I.

117997, Москва, ул. Саморы Машела, 1

1 Samory Mashela St., Moscow, 117997

ПоспеловВ. И.PospelovV. I.

105118, Москва, ул. Шоссе Энтузиастов, 25/18

25/18 Highway Enthusiasts, Moscow, 105118

РумянцевС. А.RumyantsevS. A.

117997, Москва, ул. Островитянова, 1

1 Ostrovityanova St., Moscow, 117997

РумянцевА. Г.RumyantsevA. G.

117997, Москва, ул. Саморы Машела, 1

1 Samory Mashela St., Moscow, 117997

ФГБУ «ННПЦ ДГОИ им. Дмитрия Рогачева» Минздрава РоссииРоссияDmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology Ministry of Health of RussiaRussian FederationЗАО «Генетические технологии и анализы»РоссияGenetic technologies and analyzesRussian FederationФГБОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава РоссииРоссияN.I. Pirogov Russian National Research Medical University, Ministry of Health of RussiaRussian Federation201716062017424045Copyright © Тихонова М.В., Карачунский А.И., Поспелов В.И., Румянцев С.А., Румянцев А.Г., 20172017Тихонова М.В., Карачунский А.И., Поспелов В.И., Румянцев С.А., Румянцев А.Г.Tikhonova M.V., Karachunskiy A.I., Pospelov V.I., Rumyantsev S.A., Rumyantsev A.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.nodgo.org/jour/article/view/294

Разработка неинвазивных методов исследования экзосом, содержащих нуклеиновые кислоты и специфические белки опухолевых клеток для скрининга, ранней диагностики и мониторинга опухолевого роста является актуальной проблемой онкологии. Это важно как для первичной диагностики злокачественных заболеваний, так и для контроля метастатических процессов, являющихся ключевым моментом контроля латентных опухолевых стволовых клеток, вступающих в пролиферацию и приводящих к летальному исходу через годы и десятилетия после типирования первичной опухоли.

Экзосомы, выделенные из опухолевых клеток биологических жидкостей, злокачественных выпотов и дендритных клеток онкологических больных, являясь близкими копиями исходных клеток по рецепторам, белкам и нуклеиновым кислотам, обладают иммуномодулирующей активностью и могут презентировать антигены, стимулируя антиген-специфический Т-клеточный ответ. Терапевтический потенциал экзосом исследуется при инфекциях, возбудители которых персистируют в клетках иммунной системы (токсоплазмоз, туберкулез, тяжелый острый респираторный синдром), опухолях, аутоиммунных и аутовоспалительных заболеваниях. Экспериментальные данные свидетельствуют о том, что экзосомы, содержащие антигены опухолевых клеток, ингибируют рост опухоли за счет индукции Т-клеточного специфического иммунного ответа, приводя к рецессии опухоли у экспериментальных животных. Перенос результатов исследований терапевтической активности экзосом с мышей на человека невозможен из-за различий в иммунной системе человека и мыши. Вместе с тем, использование экзосом в I фазе клинических испытаний при различных онкологических заболеваниях показало, что терапия экзосомами безопасна, нетоксична, хорошо переносится больными, эффективно сочетается с колониестимулирующими факторами, индуцирует врожденный и адаптивный иммунный ответ, стабилизирует заболевание и обеспечивает выживание в долгосрочной перспективе для ряда пациентов. Имеются и противоположные данные о супрессивном воздействии экзосом на активность эффекторных клеток и, следовательно, возможности ускорения роста опухоли. Общая тенденция развития терапевтических исследований во многом повторяет опыт использования противоопухолевых вакцин и их взаимоотношения с химиотерапией и таргетной иммунотерапией злокачественных заболеваний.

Представленный обзор отражает диагностические и терапевтические опции экзосом опухолевых клеток и возможность их использования в мониторинге и лечении опухолевых заболеваний человека. 

Development of non-invasive methods of studying of exosomes, containing nucleic acids and specific proteins of tumor cells for screening, early diagnostics and monitoring of tumor growth, is the actual problem of oncology. This is important both for primary diagnostics of malignant diseases and for control of metastatic processes, which are the key moment for control of latent tumor stem cells, starting the proliferation and leading to lethal outcome after years and decades after typing of primary tumor. Exosomes, extracted from the tumor cells of biological fluids, malignant exudates and dendritic cells of oncological patients, are the close copies of receptors, proteins and nucleic acids of initial cells, which have the immune modulating activity and able to represent antigens by stimulating of antigen-specific T-cells answer. Therapeutic potential of exosomes studying now in case of infections, which pathogens persist in cells of immune system (toxoplasmosis, tuberculosis, severe acute respiratory syndrome), tumors, autoimmune and autoinflammatory diseases. Experimental data indicate that exosomes, containing antigens of malignant cells, inhibit tumor growth by induction of T-cell specific immune answer, leading to tumor regression in experimental animal models. Transferring of results of study of therapeutic activity of exosomes from mice to humans is impossible due to difference in immune system of human and mouse. However, usage of exosomes in phase I of clinical trials in different oncological diseases showed that therapy with exosomes is safe, non-toxic, well-tolerated, can effectively be combined with colony stimulating factors, inducting congenital and adaptive immune answer, stabilizing disease and provides prolonged surviving for a number of patients. There are also the opposite data on suppressive effect of exosomes on activity of effector cells and, therefore, possible acceleration of tumor growth. General tendency of development of therapeutic studies largely repeats experience of usage of anti-cancer vaccines and it’s relationship with chemotherapy and target immune therapy of malignant disorders. This review reflects diagnostic and therapeutic options of exosomes tumor cells and possibility of usage in monitoring and treatment of malignant disorders of human.

экзосомы опухолевых клетокмикроРНК экзосомвозможности диагностикимониторинга и терапии онкологических заболеваний с использованием экзосомexosomes tumor cellsexosomal microRNAsdiagnosticsmonitoring and therapy of oncological diseases using exosomesReferencesSimons M., Raposo G. Exosomes – vesicular carriers for intercellular communication. Сuzz Opin Cell Biol 2009;21(4):575–81.Simons M., Raposo G. Exosomes – vesicular carriers for intercellular communication. Сuzz Opin Cell Biol 2009;21(4):575–81.Pisitkun T., Shen R.-F., Knepper M.A. Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci U S A 2004;101(36):13368–73.Pisitkun T., Shen R.-F., Knepper M.A. Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci U S A 2004;101(36):13368–73.Rotin D., Kumar S. Physiological functions of the HECT family of unbiquitin ligases. Nat Rev Mol Cell Biol 2009;10(6)398–409.Rotin D., Kumar S. Physiological functions of the HECT family of unbiquitin ligases. Nat Rev Mol Cell Biol 2009;10(6)398–409.Falcone G., Felsani A., D’Agnano I. Signaling by exosomal microRNAs in cancer. J Exp Clin Cancer Res 2015;34:32.Falcone G., Felsani A., D’Agnano I. Signaling by exosomal microRNAs in cancer. J Exp Clin Cancer Res 2015;34:32.Johnson S.M., Grosshans H., Shingara J. et al. RAS is regulated by the let-7 microRNA family. Cell 2005;120(5):635–47.Johnson S.M., Grosshans H., Shingara J. et al. RAS is regulated by the let-7 microRNA family. Cell 2005;120(5):635–47.Cimmino A., Calin G.A., Fabbri M. et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A 2005;102(29):13944–9.Cimmino A., Calin G.A., Fabbri M. et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A 2005;102(29):13944–9.Taylor D.D., Gercel-Taylor C. MicroRNA signatuers of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 2008;110(1):13–21.Taylor D.D., Gercel-Taylor C. MicroRNA signatuers of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 2008;110(1):13–21.Simpson R.J., Lim J.W., Moritz R.L., Mathivanan S. Exosomes: proteomic insights and diagnostic potential. Expert Rev Proteomics 2009;6(3):267–83.Simpson R.J., Lim J.W., Moritz R.L., Mathivanan S. Exosomes: proteomic insights and diagnostic potential. Expert Rev Proteomics 2009;6(3):267–83.Keller S., Ridinger J., Rupp A.K. et al. Body fluid derived exosomes as a novel template for clinical diagnostics. J Transl Med 2011;9:86.Keller S., Ridinger J., Rupp A.K. et al. Body fluid derived exosomes as a novel template for clinical diagnostics. J Transl Med 2011;9:86.Baj-Krzyworzeka M., Szatanek R., Weglarczyk K. Tumor-derived microvesicles modulate biological activity of human monocytes. Immunol Lett 2007;113(2):76–82.Baj-Krzyworzeka M., Szatanek R., Weglarczyk K. Tumor-derived microvesicles modulate biological activity of human monocytes. Immunol Lett 2007;113(2):76–82.Viaud S., Ullrich E., Zitvogel L., Chaput N. Exosomes for the treatment of human malignancies. Horm Metab Res 2008;40(2):82–8.Viaud S., Ullrich E., Zitvogel L., Chaput N. Exosomes for the treatment of human malignancies. Horm Metab Res 2008;40(2):82–8.Dai S., Wei D., Wu Z. et al. Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol Ther 2008;16(4):782–90.Dai S., Wei D., Wu Z. et al. Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol Ther 2008;16(4):782–90.Iero M., Valenti R., Huber V. et al. Tumor-released exosomes and their implications in cancer immunity. Cell Death Differ 2008:15(1):80–8.Iero M., Valenti R., Huber V. et al. Tumor-released exosomes and their implications in cancer immunity. Cell Death Differ 2008:15(1):80–8.Mytar B.I., Siedlar M., Woloszyn M. et al. Cross-talk between human monocytes and cancer cells during reactive oxygen intermediates generation: the essential role of hyaluronan. Int J Cancer 2001;94(5):727–32.Mytar B.I., Siedlar M., Woloszyn M. et al. Cross-talk between human monocytes and cancer cells during reactive oxygen intermediates generation: the essential role of hyaluronan. Int J Cancer 2001;94(5):727–32.Zhang H.-G., Kim H., Liu C. et al. Curcumin reverses breast tumor exosomes mediated immune suppression of NK cell tumor cytotoxicity. Biochim Biophys Acta 2007;1773(7):1116–23.Zhang H.-G., Kim H., Liu C. et al. Curcumin reverses breast tumor exosomes mediated immune suppression of NK cell tumor cytotoxicity. Biochim Biophys Acta 2007;1773(7):1116–23.Valenti R., Huber V., Iero M. et al. Tumor-released microvesicles as vehicles of immunosuppression. Cancer Res 2007;67(7):2912–5.Valenti R., Huber V., Iero M. et al. Tumor-released microvesicles as vehicles of immunosuppression. Cancer Res 2007;67(7):2912–5.Woodman P.G., Futter C.E. Multivesicular bodies: co-ordinated progression to maturity. Curr Opin Cell Biol 2008;20(4):408–14.Woodman P.G., Futter C.E. Multivesicular bodies: co-ordinated progression to maturity. Curr Opin Cell Biol 2008;20(4):408–14.Al-Nedawi K.I., Meehan B., Micallef J. et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 2008;10(5):619–24.Al-Nedawi K.I., Meehan B., Micallef J. et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 2008;10(5):619–24.Ciesla M., Skrzypek K., Kozakowska M. et al. MicroRNAs as biomarkers of disease onset. Anal Bioanal Chem 2011;401(7):2051–61.Ciesla M., Skrzypek K., Kozakowska M. et al. MicroRNAs as biomarkers of disease onset. Anal Bioanal Chem 2011;401(7):2051–61.Malladi S., Macalinao D.G., Jin X. et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 2016;165(1):45–60.Malladi S., Macalinao D.G., Jin X. et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 2016;165(1):45–60.Pollard J.W. Defining metastatic cell latency. N Engl J Med 2016;375(3):280–2.Pollard J.W. Defining metastatic cell latency. N Engl J Med 2016;375(3):280–2.Lee H.J., Kim J.A., Kwon M.H. et al. In situ single step detection of exosome microRNA using molecular beacon. Biomaterials 2015;54:116–25.Lee H.J., Kim J.A., Kwon M.H. et al. In situ single step detection of exosome microRNA using molecular beacon. Biomaterials 2015;54:116–25.He M., Crow J., Roth M. et al. Integrated immunoisolation and protein analysis of circulating exosomes using microfluidic technology. Lab Chip 2014;14(19):3773–80.He M., Crow J., Roth M. et al. Integrated immunoisolation and protein analysis of circulating exosomes using microfluidic technology. Lab Chip 2014;14(19):3773–80.Wubbolts R., Leckie R.S., Veenheizen P.T. et al. Proteomic and biochemal analyses of human B-cell derived exosomes. Potential implications for their function and multivesicular body formation. J Biol Chem 2003;278(13):10963–72.Wubbolts R., Leckie R.S., Veenheizen P.T. et al. Proteomic and biochemal analyses of human B-cell derived exosomes. Potential implications for their function and multivesicular body formation. J Biol Chem 2003;278(13):10963–72.Subra C., Laulagnier K., Perret B., Record M. Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies. Biochimie 2007;89(2):205–12.Subra C., Laulagnier K., Perret B., Record M. Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies. Biochimie 2007;89(2):205–12.Lamparski H.G., Metha-Damani A., Yao J.Y. et al. Production and characterization of clinical grade exosomes derived from dendritic cells. J Immunol Methods 2002;270(2):211–26.Lamparski H.G., Metha-Damani A., Yao J.Y. et al. Production and characterization of clinical grade exosomes derived from dendritic cells. J Immunol Methods 2002;270(2):211–26.Gonzales P.A., Zhou H., Pisitkun T. et al. Isolation and purification of exosomes in urine. Methods Mol Biol 2010;641:89–99.Gonzales P.A., Zhou H., Pisitkun T. et al. Isolation and purification of exosomes in urine. Methods Mol Biol 2010;641:89–99.Koga K., Matsumoto K., Akiyoshi T. et al. Purification, characterization and biological significance of tumor-derived exosomes. Anticancer Res 2005;25(6A):3703–7.Koga K., Matsumoto K., Akiyoshi T. et al. Purification, characterization and biological significance of tumor-derived exosomes. Anticancer Res 2005;25(6A):3703–7.Delcayre A., Le Pecq J.B. Exosomes as novel therapeutic nanodevices. Carr Opin Mol Ther 2006;8(1):21–38.Delcayre A., Le Pecq J.B. Exosomes as novel therapeutic nanodevices. Carr Opin Mol Ther 2006;8(1):21–38.Viaud S., Théry C., Ploix S. et al. Dendritic cell-derived exosomes for cancer immunotherapy: what’s next? Cancer Res 2010;70(4):1281–5.Viaud S., Théry C., Ploix S. et al. Dendritic cell-derived exosomes for cancer immunotherapy: what’s next? Cancer Res 2010;70(4):1281–5.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.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.

The authors declare that there are no conflicts of interest present.