Biopolym. Cell. 2014; 30(6):426-435.
Огляди
Екзосоми як посередники пухлино–стромальних взаємодій
1, 2Шкаріна К. А., 1Чередник О. В., 3Волощенко І. І., 3Трембач О. М., 3Трембач І. О., 1Хоруженко А. І.
  1. Інститут молекулярної біології і генетики НАН України
    Вул. Академіка Заболотного, 150, Київ, Україна, 03680
  2. Навчально-науковий центр «Інститут біології»
    Київського національного університету імені Тараса Шевченка
    вул. Володимирська, 64/13, Київ, Україна, 01601
  3. "Інститут краси"
    вул. Богдана Хмельницького 9а, Київ, Україна, 01030

Abstract

Міжклітинні комунікації є одним з найважливіших факторів, які беруть участь у підтримці тканинного гомеостазу. Порушення міжклітинних взаємодій корелює з великою кількістю захворювань, серед яких канцерогенез. Існує кілька типів міжклітинних взаємодій. Насамперед, це безпосередній контакт клітина–клітина, що характерно для епітелія. Збій такої міжклітинної взаємодії має наслідком втрату міжклітинних контактів, контактів клітина–матрикс, порушення клітинної полярності і т. д. Інший спосіб міжклітинної взаємодії полягає у взаємному впливові, опосередкованому паракринними чинниками, які продукуються відповідними клітинами. Однак є ще один тип обміну інформаці- єю між клітинами, а саме – мікровезикулярний транспорт. Встановлено, що мікровезикули екзосом беруть участь у взаємодії клітин у нормальних тканинах, а також у злоякісних новоутвореннях. Представлений огляд надає сучасну інформацію щодо формування екзосом, їхнього складу і, особливо, їхньої причетності до пухлино-стромальних взаємодій.
Keywords: екзосоми, пухлино-стромальна взаємодія

References

[1] Mueller MM, Fusenig NE. Friends or foes - bipolar effects of the tumour stroma in cancer. Nat Rev Cancer. 2004;4(11):839-49.
[2] Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19(11):1423-37.
[3] Erez N, Truitt M, Olson P, Arron ST, Hanahan D. Cancer-Associated Fibroblasts Are Activated in Incipient Neoplasia to Orchestrate Tumor-Promoting Inflammation in an NF-kappaB-Dependent Manner. Cancer Cell. 2010;17(2):135-47.
[4] Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6(5):392-401.
[5] Rak J. Extracellular vesicles - biomarkers and effectors of the cellular interactome in cancer. Front Pharmacol. 2013;4:21. eCollection 2013.
[6] van der Pol E, B?ing AN, Harrison P, Sturk A, Nieuwland R. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev. 2012;64(3):676-705.
[7] Vlassov AV, Magdaleno S, Setterquist R, Conrad R. Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim Biophys Acta. 2012;1820(7):940-8.
[8] Villarroya-Beltri C, Baixauli F, Guti?rrez-V?zquez C, S?nchez-Madrid F, Mittelbrunn M. Sorting it out: regulation of exosome loading. Semin Cancer Biol. 2014;28:3-13.
[9] Choi DS, Kim DK, Kim YK, Gho YS. Proteomics, transcriptomics and lipidomics of exosomes and ectosomes. Proteomics. 2013;13(10-11):1554-71.
[10] 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.
[11] Subra C, Grand D, Laulagnier K, Stella A, Lambeau G, Paillasse M, De Medina P, Monsarrat B, Perret B, Silvente-Poirot S, Poirot M, Record M. Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins. J Lipid Res. 2010;51(8):2105-20.
[12] Rana S, Yue S, Stadel D, Z?ller M. Toward tailored exosomes: the exosomal tetraspanin web contributes to target cell selection. Int J Biochem Cell Biol. 2012;44(9):1574-84.
[13] Batista BS, Eng WS, Pilobello KT, Hendricks-Mu?oz KD, Mahal LK. Identification of a conserved glycan signature for microvesicles. J Proteome Res. 2011;10(10):4624-33.
[14] Escrevente C, Grammel N, Kandzia S, Zeiser J, Tranfield EM, Conradt HS, Costa J. Sialoglycoproteins and N-glycans from secreted exosomes of ovarian carcinoma cells. PLoS One. 2013;8(10):e78631.
[15] Valadi H, Ekstr?m K, Bossios A, Sj?strand M, Lee JJ, L?tvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654-9.
[16] Ramachandran S, Palanisamy V. Horizontal transfer of RNAs: exosomes as mediators of intercellular communication. Wiley Interdiscip Rev RNA. 2012;3(2):286-93.
[17] Kahlert C, Melo SA, Protopopov A, Tang J, Seth S, Koch M, Zhang J, Weitz J, Chin L, Futreal A, Kalluri R. Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J Biol Chem. 2014;289(7):3869-75.
[18] 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, Paknejad N, Manova-Todorova K, Welte K, Bromberg J, Peinado H, Lyden D. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res. 2014;24(6):766-9.
[19] Balaj L, Lessard R, Dai L, Cho YJ, Pomeroy SL, Breakefield XO, Skog J. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat Commun. 2011;2:180.
[20] Alonso R, Mazzeo C, Rodriguez MC, Marsh M, Fraile-Ramos A, Calvo V, Avila-Flores A, Merida I, Izquierdo M. Diacylglycerol kinase ? regulates the formation and polarisation of mature multivesicular bodies involved in the secretion of Fas ligand-containing exosomes in T lymphocytes. Cell Death Differ. 2011;18(7):1161-73.
[21] Moreno-Gonzalo O, Villarroya-Beltri C, S?nchez-Madrid F. Post-translational modifications of exosomal proteins. Front Immunol. 2014;5:383.
[22] de Gassart A, Geminard C, Fevrier B, Raposo G, Vidal M. Lipid raft-associated protein sorting in exosomes. Blood. 2003;102(13):4336-44.
[23] Bolukbasi MF, Mizrak A, Ozdener GB, Madlener S, Str?bel T, Erkan EP, Fan JB, Breakefield XO, Saydam O. miR-1289 and "Zipcode"-like Sequence Enrich mRNAs in Microvesicles. Mol Ther Nucleic Acids. 2012;1:e10.
[24] Villarroya-Beltri C, Guti?rrez-V?zquez C, S?nchez-Cabo F, P?rez-Hern?ndez D, V?zquez J, Martin-Cofreces N, Martinez-Herrera DJ, Pascual-Montano A, Mittelbrunn M, S?nchez-Madrid F. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun. 2013;4:2980.
[25] 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):1143-9.
[26] Squadrito ML, Baer C, Burdet F, Maderna C, Gilfillan GD, Lyle R, Ibberson M, De Palma M. Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells. Cell Rep. 2014;8(5):1432-46.
[27] Lehmann BD, Paine MS, Brooks AM, McCubrey JA, Renegar RH, Wang R, Terrian DM. Senescence-associated exosome release from human prostate cancer cells. Cancer Res. 2008;68(19):7864-71.
[28] Z?ller M. Pancreatic cancer diagnosis by free and exosomal miRNA. World J Gastrointest Pathophysiol. 2013;4(4):74-90.
[29] Urbanelli L, Magini A, Buratta S, Brozzi A, Sagini K, Polchi A, Tancini B, Emiliani C. Signaling pathways in exosomes biogenesis, secretion and fate. Genes (Basel). 2013;4(2):152-70.
[30] Stenqvist AC, Nagaeva O, Baranov V, Mincheva-Nilsson L. Exosomes secreted by human placenta carry functional Fas ligand and TRAIL molecules and convey apoptosis in activated immune cells, suggesting exosome-mediated immune privilege of the fetus. J Immunol. 2013;191(11):5515-23.
[31] Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A, Coscia C, Iessi E, Logozzi M, Molinari A, Colone M, Tatti M, Sargiacomo M, Fais S. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem. 2009;284(49):34211-22.
[32] Tian T, Zhu YL, Hu FH, Wang YY, Huang NP, Xiao ZD. Dynamics of exosome internalization and trafficking. J Cell Physiol. 2013;228(7):1487-95.
[33] Camussi G, Deregibus MC, Bruno S, Grange C, Fonsato V, Tetta C. Exosome/microvesicle-mediated epigenetic reprogramming of cells. Am J Cancer Res. 2011;1(1):98-110.
[34] Stoorvogel W, Kleijmeer MJ, Geuze HJ, Raposo G. The biogenesis and functions of exosomes. Traffic. 2002;3(5):321-30.
[35] Robbins PD, Morelli AE. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol. 2014;14(3):195-208.
[36] Fais S. NK cell-released exosomes: Natural nanobullets against tumors. Oncoimmunology. 2013;2(1):e22337.
[37] Chivet M, Hemming F, Pernet-Gallay K, Fraboulet S, Sadoul R. Emerging role of neuronal exosomes in the central nervous system. Front Physiol. 2012;3:145.
[38] Ghidoni R, Paterlini A, Albertini V, Glionna M, Monti E, Schiaffonati L, Benussi L, Levy E, Binetti G. Cystatin C is released in association with exosomes: a new tool of neuronal communication which is unbalanced in Alzheimer's disease. Neurobiol Aging. 2011;32(8):1435-42.
[39] Fr?hbeis C, Fr?hlich D, Kr?mer-Albers EM. Emerging roles of exosomes in neuron-glia communication. Front Physiol. 2012;3:119.
[40] Harada Y, Yoshida K, Kawano N, Miyado K. Critical role of exosomes in sperm–egg fusion and virus-induced cell–cell fusion. Reprod Med Biol. 2013; 12(4):117–26.
[41] Kshirsagar SK, Alam SM, Jasti S, Hodes H, Nauser T, Gilliam M, Billstrand C, Hunt JS, Petroff MG. Immunomodulatory molecules are released from the first trimester and term placenta via exosomes. Placenta. 2012;33(12):982-90.
[42] Mincheva-Nilsson L, Baranov V. The role of placental exosomes in reproduction. Am J Reprod Immunol. 2010;63(6):520-33.
[43] Rome S. Are extracellular microRNAs involved in type 2 diabetes and related pathologies? Clin Biochem. 2013;46(10-11):937-45.
[44] Gaceb A, Martinez MC, Andriantsitohaina R. Extracellular vesicles: new players in cardiovascular diseases. Int J Biochem Cell Biol. 2014;50:24-8.
[45] Russo I, Bubacco L, Greggio E. Exosomes-associated neurodegeneration and progression of Parkinson's disease. Am J Neurodegener Dis. 2012;1(3):217-25.
[46] Silverman JM, Reiner NE. Exosomes and other microvesicles in infection biology: organelles with unanticipated phenotypes. Cell Microbiol. 2011;13(1):1-9.
[47] Singh PP, Smith VL, Karakousis PC, Schorey JS. Exosomes isolated from mycobacteria-infected mice or cultured macrophages can recruit and activate immune cells in vitro and in vivo. J Immunol. 2012;189(2):777-85.
[48] Singh PP, LeMaire C, Tan JC, Zeng E, Schorey JS. Exosomes released from M. tuberculosis infected cells can suppress IFN-? mediated activation of na?ve macrophages. PLoS One. 2011;6(4):e18564.
[49] Izquierdo-Useros N, Naranjo-G?mez M, Erkizia I, Puertas MC, Borr?s FE, Blanco J, Martinez-Picado J. HIV and mature dendritic cells: Trojan exosomes riding the Trojan horse? PLoS Pathog. 2010;6(3):e1000740.
[50] Wurdinger T, Gatson NN, Balaj L, Kaur B, Breakefield XO, Pegtel DM. Extracellular vesicles and their convergence with viral pathways. Adv Virol. 2012;2012:767694.
[51] Dergai OV, Dergai MV, Skrypkina IYa, Tsyba LO, Yaruchik AM, Rynditch AV. Amphiphysin 1 and 2 interact with latent membrane protein 2A of Epstein-Barr virus and regulate its exosomal secretion. Biopolym Cell. 2012;28(3):234-8.
[52] 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):20370-5.
[53] Coleman BM, Hanssen E, Lawson VA, Hill AF. Prion-infected cells regulate the release of exosomes with distinct ultrastructural features. FASEB J. 2012;26(10):4160-73.
[54] Pietras K, Ostman A. Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res. 2010;316(8):1324-31.
[55] Ono M, Kosaka N, Tominaga N, Yoshioka Y, Takeshita F, Takahashi RU, Yoshida M, Tsuda H, Tamura K, Ochiya T. Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci Signal. 2014;7(332):ra63.
[56] Hoshino D, Kirkbride KC, Costello K, Clark ES, Sinha S, Grega-Larson N, Tyska MJ, Weaver AM. Exosome secretion is enhanced by invadopodia and drives invasive behavior. Cell Rep. 2013;5(5):1159-68.
[57] Yang L, Wu XH, Wang D, Luo CL, Chen LX. Bladder cancer cell-derived exosomes inhibit tumor cell apoptosis and induce cell proliferation in vitro. Mol Med Rep. 2013;8(4):1272-8.
[58] Hao S, Ye Z, Li F, Meng Q, Qureshi M, Yang J, Xiang J. Epigenetic transfer of metastatic activity by uptake of highly metastatic B16 melanoma cell-released exosomes. Exp Oncol. 2006;28(2):126-31.
[59] Sanderson MP, Keller S, Alonso A, Riedle S, Dempsey PJ, Altevogt P. Generation of novel, secreted epidermal growth factor receptor (EGFR/ErbB1) isoforms via metalloprotease-dependent ectodomain shedding and exosome secretion. J Cell Biochem. 2008;103(6):1783-97.
[60] Khan S, Jutzy JM, Aspe JR, McGregor DW, Neidigh JW, Wall NR. Survivin is released from cancer cells via exosomes. Apoptosis. 2011;16(1):1-12.
[61] 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):1595-604.
[62] Chen VY, Posada MM, Blazer LL, Zhao T, Rosania GR. The role of the VPS4A-exosome pathway in the intrinsic egress route of a DNA-binding anticancer drug. Pharm Res. 2006;23(8):1687-95.
[63] Ambudkar SV, Sauna ZE, Gottesman MM, Szakacs G. A novel way to spread drug resistance in tumor cells: functional intercellular transfer of P-glycoprotein (ABCB1). Trends Pharmacol Sci. 2005;26(8):385-7.
[64] Hopkins BD, Fine B, Steinbach N, Dendy M, Rapp Z, Shaw J, Pappas K, Yu JS, Hodakoski C, Mense S, Klein J, Pegno S, Sulis ML, Goldstein H, Amendolara B, Lei L, Maurer M, Bruce J, Canoll P, Hibshoosh H, Parsons R. A secreted PTEN phosphatase that enters cells to alter signaling and survival. Science. 2013;341(6144):399-402.
[65] King HW, Michael MZ, Gleadle JM. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer. 2012;12:421.
[66] Ramteke A, Ting H, Agarwal C, Mateen S, Somasagara R, Hussain A, Graner M, Frederick B, Agarwal R, Deep G. Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules. Mol Carcinog. 2013
[67] 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):1085-99.
[68] Al-Nedawi K, Meehan B, Kerbel RS, Allison AC, Rak J. Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR. Proc Natl Acad Sci U S A. 2009;106(10):3794-9.
[69] Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med (Berl). 2013;91(4):431-7.
[70] Sharghi-Namini S, Tan E, Ong LL, Ge R, Asada HH. Dll4-containing exosomes induce capillary sprout retraction in a 3D microenvironment. Sci Rep. 2014;4:4031.
[71] van Doormaal FF, Kleinjan A, Di Nisio M, B?ller HR, Nieuwland R. Cell-derived microvesicles and cancer. Neth J Med. 2009;67(7):266-73.
[72] Shimoda M, Khokha R. Proteolytic factors in exosomes. Proteomics. 2013;13(10-11):1624-36.
[73] Xiang X, Poliakov A, Liu C, Liu Y, Deng ZB, Wang J, Cheng Z, Shah SV, Wang GJ, Zhang L, Grizzle WE, Mobley J, Zhang HG. Induction of myeloid-derived suppressor cells by tumor exosomes. Int J Cancer. 2009;124(11):2621-33.
[74] Taylor DD, Gercel-Taylor C. Exosomes/microvesicles: mediators of cancer-associated immunosuppressive microenvironments. Semin Immunopathol. 2011;33(5):441-54.
[75] Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature. 2004;432(7015):332-7.
[76] Trimboli AJ, Cantemir-Stone CZ, Li F, Wallace JA, Merchant A, Creasap N, Thompson JC, Caserta E, Wang H, Chong JL, Naidu S, Wei G, Sharma SM, Stephens JA, Fernandez SA, Gurcan MN, Weinstein MB, Barsky SH, Yee L, Rosol TJ, Stromberg PC, Robinson ML, Pepin F, Hallett M, Park M, Ostrowski MC, Leone G. Pten in stromal fibroblasts suppresses mammary epithelial tumours. Nature. 2009;461(7267):1084-91.
[77] Suetsugu A, Honma K, Saji S, Moriwaki H, Ochiya T, Hoffman RM. Imaging exosome transfer from breast cancer cells to stroma at metastatic sites in orthotopic nude-mouse models. Adv Drug Deliv Rev. 2013;65(3):383-90.
[78] Webber JP, Spary LK, Sanders AJ, Chowdhury R, Jiang WG, Steadman R, Wymant J, Jones AT, Kynaston H, Mason MD, Tabi Z, Clayton A. Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes. Oncogene. 2014
[79] Gross JC, Chaudhary V, Bartscherer K, Boutros M. Active Wnt proteins are secreted on exosomes. Nat Cell Biol. 2012;14(10):1036-45.
[80] Borges FT, Melo SA, ?zdemir BC, Kato N, Revuelta I, Miller CA, Gattone VH 2nd, LeBleu VS, Kalluri R. TGF-?1-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis. J Am Soc Nephrol. 2013;24(3):385-92.
[81] Webber J, Steadman R, Mason MD, Tabi Z, Clayton A. Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res. 2010;70(23):9621-30.
[82] Cho JA, Park H, Lim EH, Kim KH, Choi JS, Lee JH, Shin JW, Lee KW. Exosomes from ovarian cancer cells induce adipose tissue-derived mesenchymal stem cells to acquire the physical and functional characteristics of tumor-supporting myofibroblasts. Gynecol Oncol. 2011;123(2):379-86.
[83] Cho JA, Park H, Lim EH, Lee KW. Exosomes from breast cancer cells can convert adipose tissue-derived mesenchymal stem cells into myofibroblast-like cells. Int J Oncol. 2012;40(1):130-8.
[84] Luga V, Wrana JL. 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.
[85] 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):1542-56.
[86] Pigati L, Yaddanapudi SC, Iyengar R, Kim DJ, Hearn SA, Danforth D, Hastings ML, Duelli DM. Selective release of microRNA species from normal and malignant mammary epithelial cells. PLoS One. 2010;5(10):e13515.
[87] Zhang HG, Grizzle WE. Exosomes: a novel pathway of local and distant intercellular communication that facilitates the growth and metastasis of neoplastic lesions. Am J Pathol. 2014;184(1):28-41.
[88] Vader P, Breakefield XO, Wood MJ. Extracellular vesicles: emerging targets for cancer therapy. Trends Mol Med. 2014;20(7):385-93.
[89] Marleau AM, Chen CS, Joyce JA, Tullis RH. Exosome removal as a therapeutic adjuvant in cancer. J Transl Med. 2012;10:134.
[90] Fais S, Logozzi M, Lugini L, Federici C, Azzarito T, Zarovni N, Chiesi A. Exosomes: the ideal nanovectors for biodelivery. Biol Chem. 2013;394(1):1-15.
[91] 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):185-91.
[92] Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29(4):341-5.
[93] Kooijmans SA, Vader P, van Dommelen SM, van Solinge WW, Schiffelers RM. Exosome mimetics: a novel class of drug delivery systems. Int J Nanomedicine. 2012;7:1525-41.
[94] Tan A, Rajadas J, Seifalian AM. Exosomes as nano-theranostic delivery platforms for gene therapy. Adv Drug Deliv Rev. 2013;65(3):357-67.