Russian Journal of BiotherapyRussian Journal of BiotherapyРоссийский биотерапевтический журнал1726-97841726-9792Publishing House ABV Press80210.17650/1726-9784-2016-15-2-6-15ORIGINAL REPORTSОРИГИНАЛЬНЫЕ СТАТЬИStimulation of metastatic activity of breast cancer cells by plasma exosomesСтимуляция метастатической активности клеток рака молочной железы экзосомами плазмыSamsonovR. B.СамсоновР. Б.
Russian Federation
KovalenkoI. M.КоваленкоИ. М.
Russian Federation
VasilyevD. A.ВасильевД. А.
Russian Federation
TsyrlinaE. V.ЦырлинаЕ. В.
Russian Federation
DashanG. A.ДашянГ. А.
Russian Federation
Shochat-CarvalhoCh. .Шохат-КарвальоХ. .
Russian Federation
KarasikD. .КарасикД. .
Russian Federation
BersteinL. M.БерштейнЛ. М.
Russian Federation
LutynskijV. V.ЛютынскийВ. В.
Russian Federation
MalekA. V.МалекАнастасия Валерьевна
Russian Federation
anastasia@malek.comOncosystem, LtdООО «Онкосистема»Petrov Institute of OncologyФГБУ «НИИонкологии им. Н.Н. Петрова» Минздрава РоссииBar-Ilan UniversityУниверситет им. Бар-ИланаOncosystem, LtdФГБУ «НИИонкологии им. Н.Н. Петрова» Минздрава РоссииCompany Algimed, LtdООО «Компания Альгимед»3006201615261510042018https://bioterapevt.abvpress.ru/jour/article/view/802

Background. Malignant phenotype of cancer cells and metastatic potency of the tumor are determined by genetic factors. In addition, normal biological environment, including the nano-vesicles or exosomes, plays an important role in regulation of the structural and functional characteristics of malignant cells. Objective: presented study was aimed to evaluate mechanisms and to estimate effect of interaction of plasma exosomes and breast cancer cells in experimental conditions. Materials and methods. We used breast cancer cell culture MDA-MB-231 and exosomes isolated from plasma and cultural medium. Exosomes were analyzed by dynamic light scattering method and western blotting. Functional effects of exosomes were evaluated in in vitro and in vivo models. Results. In the present study we demonstrated that plasma exosomes stimulate the adhesion and the motility of breast cancer cells and induce the process of metastatic dissemination. Contact interaction of exosomes with cell surface is sufficient for stimulatory effect that is mediated by exosomal fibronectin and FAK-dependent signaling cascade. Conclusions. Further investigation of plasma exosomes structure and functions is required to better understand their input in regulation of malignant cell phenotype. This research has a potential to provide novel approaches for cancer therapy.

рак молочной железыэкзосомыадгезияметастазыфибронектинbreast cancerexosomecell adhesionmetastasesfibronectinKowal J., Tkach M., Thery C. Biogenesis and secretion of exosomes. Curr Opin Cell Biol 2014;29:116-25.Abels E.R., Breakefield XO. Introduction to Extracellular Vesicles: Biogenesis, RNA Cargo Selection, Content, Release, and Uptake. Cell Mol Neurobiol 2016;36(3):301-12Mulcahy L.A., Pink R.C., Carter D.R. Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles 2014;4;3. doi: 10.3402/jev.v3.24641. eCollection 2014. PMID: 25143819.Iraci N., Leonardi T., Gessler F. et al. Focus on Extracellular Vesicles: Physiological Role and Signalling Properties of Extracellular Membrane Vesicles. Int J Mol Sci 2016;6;17(2). pii: E171. doi: 10.3390/ ijms17020171. PMID: 26861302.Mincheva-Nilsson L., Baranov V. Placenta-derived exosomes and syncytiotrophoblast microparticles and their role in human reproduction: immune modulation for pregnancy success. Am J Reprod Immunol 2014;72(5):440-57.Weilner S., Schraml E., Redl H. et al. Secretion of microvesicular miRNAs in cellular and organismal aging. Exp Gerontol 2013;48(7):626-33.Russo I, Bubacco L, Greggio E. Exosomes-associated neurodegeneration and progression of Parkinson's disease. Am J Neurodegener Dis 2012;1(3):217-25.Tsilioni I., Panagiotidou S., Theoharides T.C. Exosomes in neurologic and psychiatric disorders. Clin Ther 2014;36(6):882-8.Huber HJ, Holvoet P. Exosomes: emerging roles in communication between blood cells and vascular tissues during atherosclerosis. Curr Opin Lipidol 2015;26(5):412-9.Buzas EI, Gyorgy B, Nagy G et al. Emerging role of extracellular vesicles in inflammatory diseases. Nat Rev Rheumatol 2014;10(6):356-64.Alenquer M., Amorim M.J. Exosome Biogenesis, Regulation, and Function in Viral Infection. Viruses 2015;7(9):5066-83.Малек А.М., Берштейн Л.М., Филатов М.В., Беляев А.М. Система экзосомальных межклеточных коммуникаций и ее роль в процессе метастатической диссеминации. Вопросы онкологии 2014;60(4):429-36.Tchevkina Е.М., Shcherbakov А.М., Zhuravskaya A.Y. et al. Exosomes and transfer of (epi)genetic information by tumor cells. Advances in Molecular Oncology 2015;3(2):8-20.Rana S., Malinowska K., Zoller M. Exosomal tumor microRNA modulates premetastatic organ cells. Neoplasia 2013;15(3):281-95.Muller L., Mitsuhashi M., Simms P. et al. Tumor-derived exosomes regulate expression of immune function-related genes in human T cell subsets. Sci Rep 2016;6:20254.Whiteside T.L. Exosomes and tumor-mediated immune suppression. J Clin Invest 2016;126(4):1216-23.Fu H., Yang H., Zhang X., Xu W. The emerging roles of exosomes in tu-mor-stroma interaction. J Cancer Res Clin Oncol 2016;17. PMID: 26987524.Whiteside T.L. The potential of tumor-derived exosomes for noninvasive cancer monitoring. Expert Rev Mol Diagn 2015;15(10):1293-310.Marleau A.M., Chen C.S., Joyce J.A., Tullis R.H. Exosome removal as a therapeutic adjuvant in cancer. J Transl Med 2012;10:134.Ochieng J., Pratap S., Khatua A.K., Sakwe A.M. Anchorage-independent growth of breast carcinoma cells is mediated by serum exosomes. Exp Cell Res 2009;315(11):1875-88.Janowska-Wieczorek A., Wysoczynski M., Kijowski J. et al. Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer 200 5;113(5):752-60.Hu Y., Yan C., Mu L. et al. Fibroblast-Derived Exosomes Contribute to Chemoresistance through Priming Cancer Stem Cells in Colorectal Cancer. PLoS One 2015;10(5):e0125625.Malek A., Catapano C.V., Czubayko F., Aigner A. A sensitive polymerase chain reaction-based method for detection and quanti fication of metastasis in human xenograft mouse models. Clin Exp Metastasis 2010;27(4):261-71.White R.M., Sessa A., Burke C. et al. Transparent adult zebrafish as a tool for in vivo transplantation analysis. Cell stem cell 2008;2(2):183-89.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;3;Unit 3.22.Malek A.V., Sanmsonov R.B., Chiesi A. Development of cancer diagnostics and monitoring methods based on analysis of tumor-derived exosomes. Russian Journal of Biotherapy 2015;14(4): 9-18.Samsonov R.B., Shtam T.A., Burdakov V.S. et al. Extraction and analysis of the exosomal micro-RNA from the urine: new method of the prostate cancer diagnostics. Experimental and Clinical Urology 2015;4:28-32.Purushothaman A., Bandari S.K., Liu J. et al. Fibronectin on the Surface of Myeloma Cell-derived Exosomes Mediates Exosome-Cell Interactions. J Biol Chem 2016;291(4):1652-63.Akiyama S.K. Integrins in cell adhesion and signaling. Hum Cell 1996;9(3):181-6.Schaller M.D. Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions. J Cell Sci 2010;123(7):1007-13.Sulzmaier F.J., Jean C., Schlaepfer D.D. FAK in cancer: mechanistic findings and clinical applications. Nat Rev Cancer 2014;14(9):598-610.Luo M., Guan J.L. Focal adhesion kinase: a prominent determinant in breast cancer initiation, progression and metastasis. Cancer Lett 2010; 289(2): 127-39.Pupyshev A. B. Extracellular v esicles: intercellular information flow and medical applications. Tsitologiia 2015;57(8):551-62.Fais S., O'Driscoll L., Borras F.E. et al. Evidence-Based Clinical Use of Nanoscale Extracellular Vesicles in Nanomedicine. ACS Nano 2016;15.