Russian Journal of BiotherapyRussian Journal of BiotherapyРоссийский биотерапевтический журнал1726-97841726-9792Publishing House ABV Press145010.17650/1726-9784-2024-23-2-47-59REVIEWОБЗОР ЛИТЕРАТУРЫProspects for anti-EVs therapy in the context of skin melanomaПерспективы анти-EVs-терапии в аспекте меланомы кожиhttps://orcid.org/0009-0007-7520-3397SheetikovV. A.ШитиковВ. А.
Russian Federation

Vasiliy A. Sheetikov

24 Kashirskoe Shosse, Moscow 115522

Василий Андреевич Шитиков 

115522 Москва, Каширское шоссе, 24

vasilbox@yandex.ruhttps://orcid.org/0000-0002-4660-8519KosobokovaE. N.КособоковаЕ. Н.
Russian Federation

Ekaterina N. Kosobokova

24 Kashirskoe Shosse, Moscow 115522

115522 Москва, Каширское шоссе, 24

N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина» Минздрава России2606202423247592606202426062024https://bioterapevt.abvpress.ru/jour/article/view/1450

Background. Extracellular vesicles (EVs) play a major role in the progression of skin melanoma: contributing to immune evasion, acquisition of resistance to drug therapy and metastasis. By affecting the assembly process of EVs as well as the secreted vesicles of tumor cells and their microenvironment, a significant reduction in the number of vesicles capable of transmitting signals and transporting macromolecules can be achieved. Thus, blocking this information transmission system at its different levels may be a new way of drug therapy of malignant neoplasms. Currently, there are a number of small synthetic molecules that disrupt the synthesis of exosomes and microvesicles (inhibitors of neutral sphingomyelinase, calpain, Rho-associated protein kinases) and their conjugates to combat exosomal mechanisms of resistance to immune checkpoint inhibitor therapy. In addition to inhibition of EVs assembly, membrane proteins of EVs (heat shock protein family HSPA / HSP70, laminin-binding integrins α3β1 and α6β) are considered as targets of targeted therapy. Some receptors providing specific fusion of vesicles with recipient cells have also been identified (CD46 receptor involved in the internalization of exosomes of a tumor cell line with brain metastases, SK-Mel-28, many adhesive molecules belonging to the family of integrins, immunoglobulins and selectins, as well as CD44 and tetraspanins.

Aim. To review the available attempts to influence the biogenesis of tumor EVs (EVs) in order to develop a possible therapeutic strategy for the treatment of skin melanoma that has escaped the control of immune and targeting drugs.

Materials and methods. In this work we present the results of research on melanoma of skin EVs and ways to influence EVs communication. The relevant sources were searched in web of Science, PubMed, eLibrary.ru. The Elicit tool for searching scientific articles was also used.

Conclusion. In this work we analyzed the effect of small synthetic molecules, monoclonal antibodies and regulatory RNAs on different parts of tumor EVs biogenesis: assembly, secretion of EVs, and their transport. Conclusions are drawn about the validity of anti-EVs therapy to date and the possibility of its application in the aspect of skin melanoma.

Введение. Внеклеточные везикулы (EVs) играют большую роль в прогрессировании меланомы кожи: способствуют ускользанию от иммунитета, приобретению резистентности к лекарственной терапии и метастазированию. Воздействуя на процесс сборки EVs, а также выделившиеся везикулы опухолевых клеток и их микроокружения, можно добиться значительного снижения количества везикул, способных передавать сигналы и транспортировать макромолекулы. Таким образом, блокирование данной системы передачи информации на разных ее уровнях может быть новым способом лекарственной терапии злокачественных новообразований. На данный момент существует ряд малых синтетических молекул, нарушающих синтез экзосом и микровезикул (ингибиторы нейтральной сфингомиелиназы, кальпаина, Rho-ассоциированных протеинкиназ), а также их конъюгаты для борьбы с экзосомальными механизмами устойчивости к терапии ингибиторами контрольных точек иммунитета. Помимо угнетения сборки EVs в качестве мишени таргетной терапии рассматривают мембранные белки EVs (семейство белков теплового шока HSPA / HSP70, ламининсвязывающих интегринов α3β1 и α6β). Идентифицированы также некоторые рецепторы, обеспечивающие специфическое слияние везикул с клетками-реципиентами (CD46-рецептор, участвующий в интернализации экзосом линии клеток опухоли с метастазами в мозг, SK-Mel-28, множество адгезивных молекул, принадлежащих к семейству интегринов, иммуноглобулинов и селектинов, а также CD44 и тетраспанинов).

Цель исследования – рассмотрение имеющегося опыта воздействия на биогенез EVs опухолей для разработки возможной терапевтической стратегии лечения меланомы кожи, вышедшей из-под контроля иммунных и таргетных препаратов.

Материалы и методы. В работе представлены результаты исследований EVs меланомы кожи и способов влияния на EVs-коммуникацию. Поиск соответствующих источников произведен в системах web of Science, PubMed, eLibrary.ru. Использовали также инструмент Elicit для поиска научных статей.

Заключение. В данной работе проанализировано действие малых синтетических молекул, моноклональных антител и регуляторных РНК на разные звенья биогенеза EVs опухоли: сборку, секрецию EVs, а также их транспорт. Сделаны выводы о состоятельности анти-EVs-терапии на сегодняшний момент и возможности ее применения в аспекте меланомы кожи.

EVs extracellular vesicles skin melanoma treatmentEVs внеклеточные везикулы меланома кожи терапияThe work was carried out with the financial support of the Ministry of Health of Russia in the framework of the research No 1022040600453-9-3.2.21;3.4.2.Работа была выполнена при финансовой поддержке Минздрава России в рамках исследования № 1022040600453-9-3.2.21;3.4.2.Yanfang L., Yan G., Xuetao C. The exosomes in tumor immunity. OncoImmunology 2015;4(9):6. DOI: 10.1080/2162402X.2015.1027472Yang Q., Xu J., Gu J. et al. Extracellular vesicles in cancer drug resistance: Roles, mechanisms, and implications. Adv Sci (Weinh) 2022;9(34):e2201609. DOI: 10.1002/advs.202201609Tucci M., Mannavola F., Passarelli A. et al. Exosomes in melanoma: A role in tumor progression, metastasis and impaired immune system activity. Oncotarget 2018;9(29):20826–37. DOI: 10.18632/oncotarget.24846Samireh J., Ephraim A.A., Sharad K. et al. Inhibition of microvesiculation sensitizes prostate cancer cells to chemotherapy and reduces docetaxel dose required to limit tumor growth in vivo. Sci Rep 2015;5(2):13. DOI: 10.1038/srep13006Kosaka N., Iguchi H., Hagiwara K. et al. Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. J Biol Chem 2013;288(15):10849–59. DOI: 10.1074/jbc.M112.446831Brinton L.T., Sloane H.S., Kester M. et al. Formation and role of exosomes in cancer. Cell Mol Life Sci 2015;72(4):659–71. DOI: 10.1007/s00018-014-1764-3Kilinc S., Paisner R., Camarda R. et al. Oncogene regulated release of extracellular vesicles. Dev Cell 2021;56(13):1989–2006. DOI: 10.1016/j.devcel.2021.05.014Poggio M., Hu T., Chien-Chun P. et al. Suppression of exosomal PD-L1 induces systemic anti-tumor immunity and memory. Cell 2019;177(2):414–27. DOI: 10.1016/j.cell.2019.02.016Namee N.M., Catalano M., Mukhopadhya A. et al. An extensive study of potential inhibitors of extracellular vesicles release in triple-negative breast cancer. BMC Cancer 2023;23(654):12. DOI: 10.1186/s12885-023-11160-2Kalra H., Gregor P.C., Mathivanan D. et al. Focus on extracellular vesicles: Introducing the next small big thing. Mol Sci 2016;17(2):170. DOI: 10.3390/ijms17020170Catalano M., O’Driscoll L. Inhibiting extracellular vesicles formation and release: A review of EV inhibitors. Extracell 2019;9(1):22. DOI: 10.1080/20013078.2019.1703244Matsumoto A., Takahashi Y., Nishikawa M. et al. Accelerated growth of B16BL6 tumor in mice through efficient uptake of their own exosomes by B16BL6 cells. Cancer Sci 2017;108(9):1803–10. DOI: 10.1111/cas.13310Wang G., Xie L., Li B. et al. A nanounit strategy reverses immune suppression of exosomal PD-L1 and is associated with enhanced ferroptosis. Nat Commun 2021;12(1):12. DOI: 10.1038/s41467-021-25990-wVan Niel G., D’Angelo G., Raposo G. Shedding light on the cell biology of extracellular vesicles. Mol Cell Biol 2018;19(4):213–28. DOI: 10.1038/nrm.2017.125SenthilKumar G., Katunaric B., Zirgibel Z. et al. Necessary role of acute ceramide formation in the human microvascular endothelium during health and disease. bioRxiv 2023;1(1):34. DOI: 10.1101/2023.06.02.543341Wheeler D., Knapp E., Bandaru V.R. TNFα-induced neutral sphingomyelinase-2 modulates synaptic plasticity by controlling the membrane insertion of NMDA receptors. J Neurochem 2009;109(5):1237–49. DOI: 10.1111/j.1471-4159.2009.06038.xTabatadze N., Savonenko A., Song H. Inhibition of neutral sphingomyelinase-2 perturbs brain sphingolipid balance and spatial memory in mice. J Neurosci Res 2010;88(13):2940–51. DOI: 10.1002/jnr.2243818Stenmark H. Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol 2009;10(8):513–25. DOI: 10.1038/nrm2728Savina A., Vidal M., Colombo M. The exosome pathway in K562 cells is regulated by Rab11. J Cell Sci 2002;115(12):2505–15. DOI: 10.1242/jcs.115.12.2505Peinado H., Aleckovic M., Lavotshkin S. et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 2012;18(6):883–91. DOI: 10.1038/nm.2753Bahadoran P., Aberdam E., Mantoux F. Rab27a: A key to melanosome transport in human melanocytes. J Cell Biol 2001;152(4):843–50. DOI: 10.1083/jcb.152.4.84322Guo D., Lui G.Y.L., Lai S.L. et al. RAB27A promotes melanoma cell invasion and metastasis via regulation of pro-invasive exosomes. Int J Cancer 2019;144(12):3070–85. DOI:10.1002/ijc.32064Ostrowski M., Carmo N.B., Krumeich S. et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol 2010;12(1):19–30. DOI: 10.1038/ncb2000Poste G., Nicolson G.L. Arrest and metastasis of blood-borne tumor cells are modified by fusion of plasma membrane vesicles from highly metastatic cells. Proc Natl Acad Sci USA 1980;77(1):399–403. DOI: 10.1073/pnas.77.1.399Liao C.F., Lin S.H., Chen H.C. et al. CSE1L, a novel microvesicle membrane protein, mediates Ras-triggered microvesicle generation and metastasis of tumor cells. Mol Med 2012;18(1):1269–80. DOI: 10.2119/molmed.2012.00205Clancy J.W., Sedgwick A., Rosse C. et al. Regulated delivery of molecular cargo to invasive tumor-derived microvesicles. Nat Commun 2015;21(6):21. DOI: 10.1038/ncomms7919Zhao X.P., Wang M., Song Y. Membrane microvesicles as mediators for melanoma-fibroblasts communication: Roles of the VCAM-1/VLA-4 axis and the ERK1/2 signal pathway. Cancer Lett 2015;360(2):125–33. DOI: 10.1016/j.canlet.2015.01.032Martı́nez-Lorenzo M.J., Anel A., Alava M.A. et al. The human melanoma cell line MelJuSo secretes bioactive FasL and APO2L/TRAIL on the surface of microvesicles. Possible contribution to tumor counterattack. Cell Res 2004;295(2):315–29. DOI: 10.1016/j.yexcr.2003.12.024Haoran Z., Zhe C., Aijun Z. et al. The role of calcium signaling in melanoma. Int J Mol Sci 2022;23(3):17. DOI: 10.3390/ijms23031010Fox J.E., Austin C.D., Reynolds C.C. et al. Evidence that agonist-induced activation of calpain causes the shedding of procoagulant-containing microvesicles from the membrane of aggregating platelets. Biol Chem 1991;266(20):13289–95. PMID: 2071604Smith P.A., Fitzsimons J.T., Loker J.E. et al. 5-hydroxytryptamine as a possible inhibitory neurotransmitter in the central nervous system of the leech, Haemopis sanguisuga. Comp Biochem Physiol 1975;52(1):65–73. DOI: 10.1016/0306-4492(75)90015-5Yano Y., Shiba E., Kambayashi J. et al. The effects of calpeptin (a calpain specific inhibitor) on agonist induced microparticle formation from the platelet plasma membrane. Thromb Res 1993;71(5):385–96. DOI: 10.1016/0049-3848(93)90163-ISiklos M., BenAissa M., Thatcher G.R. Cysteine proteases as therapeutic targets: Does selectivity matter? A systematic review of calpain and cathepsin inhibitors. Acta Pharm Sin 2015;5(6):506–19. DOI: 10.1016/j.apsb.2015.08.001Letavernier B., Zafrani L., Nassar D. et al. Calpains contribute to vascular repair in rapidly progressive form of glomerulonephritis: potential role of their externalization. Arterioscler Thromb Vasc Biol 2012;32(2):335–42. DOI: 10.1161/ATVBAHA.111.240242Hua T., Robitaille M., Roberts-Thomson S.J. et al. The intersection between cysteine proteases, Ca 2+ signalling and cancer cell apoptosis. Biochim Biophys Mol Cell Res 2023;1870(7):13. DOI: 10.1016/j.bbamcr.2023.119532Youn J.-Y., Wang T., Cai H. An ezrin/calpain/PI3K/AMPK/ eNOSs1179 signaling cascade mediating VEGF-dependent endothelial nitric oxide production. Circ Res 2009;104(1):50–9. DOI: 10.1161/CIRCRESAHA.108.178467Dewitt S., Hallett M. Leukocyte membrane “expansion”: A central mechanism for leukocyte extravasation. J Leukoc Biol 2007;81(5):1160–4. DOI: 10.1189/jlb.1106710Sorimachi H., Hata S., Ono Y. Calpain chronicle – аn enzyme family under multidisciplinary characterization. Proc Jpn Acad Ser B Phys Biol Sci 2011;87(6):287–327. DOI: 10.2183/pjab.87.287Spinozzi S., Albini S., Best H., Richard I. Calpains for dummies: What you need to know about the calpain family. Biochim Biophys Acta Proteins Proteom 2021;1869(5);44. DOI: 10.1016/j.bbapap.2021.140616Shiba E., Kambayashi J.I., Sakon M. et all. Ca 2+ -dependent neutral protease (calpain) activity in breast cancer tissue and estrogen receptor status. Breast Cancer 1996;3(1):13–7. DOI: 10.1007/BF02966957Moretti D., Del Bello B., Cosci E. et al. Novel variants of muscle calpain 3 identified in human melanoma cells: Cisplatin-induced changes in vitro and differential expression in melanocytic lesions. Carcinogenesis 2009;30(6):960–7. DOI: 10.1093/carcin/bgp098Jiang C., Mao Z.G., Kelly A.A.-K. et al. Glucose-regulated protein 78 antagonizes cisplatin and adriamycin in human melanoma cells. Carcinogenesis 2009;30(2):197–204. DOI: 10.1093/carcin/bgn220Del Bello B., Moretti D., Gamberucci A. et al. Cross-talk between calpain and caspase-3/-7 in cisplatin-induced apoptosis of melanoma cells: A major role of calpain inhibition in cell death protection and p53 status. Oncogene 2007;26(19):2717–26. DOI: 10.1038/sj.onc.1210079Mandic A., Viktorsson K., Strandberg L. et al. Calpain-mediated bid cleavage and calpain-independent bak modulation: Two Separate pathways in cisplatin-induced apoptosis. Mol Cell Biol 2002;22(9):3003–13. DOI: 10.1128/MCB.22.9.3003-3013.2002Del Bello B., Toscano M., Moretti D. et al. Cisplatin-induced apoptosis inhibits autophagy, which acts as a pro-survival mechanism in human melanoma cells. PLoS One 2013;8(2):14. DOI: 10.1371/journal.pone.0057236Rosenfeldt M.T., Ryan K.M. The multiple roles of autophagy in cancer. Carcinogenesis 2011;32(7):955–63. DOI: 10.1093/carcin/bgr031Colunga A., Bollino D., Schech V. et al. Calpain-dependent clearance of the autophagy protein p62/SQSTM1 is a contributor to ΔPK oncolytic activity in melanoma. Gene Therapy 2014;21(4):371–8. DOI: 10.1038/gt.2014.6Moretti D., Del Bello B., Allavena G. et al. Calpain-3 impairs cell proliferation and stimulates oxidative stress-mediated cell death in melanoma cells. PLoS One 2015;10(2):22. DOI: 10.1371/journal.pone.0117258O’Connell M.P., Fiori J.L., Baugher K.M. et al. Wnt5A activates the calpain-mediated cleavage of filamin A. J Invest Dermatol 2009;129(7):1782–9. DOI: 10.1038/jid.2008.433Salimi R., Bandaru S., Devarakonda S. et al. Blocking the cleavage of filamin a by calpain inhibitor decreases tumor cell growth. Anticancer Res 2018;38(4):2079–85. DOI:10.21873/anticanres.12447Taddei M.L., Giannoni E., Morandi A. et al. Mesenchymal to amoeboid transition is associated with stem-like features of melanoma cells. Cell Commun Signal 2014;1(12):12. DOI: 10.1186/1478-811X-12-24Raimbourg Q., Perez J., Vandermeersch S. et al. The calpain/ calpastatin system has opposing roles in growth and metastatic dissemination of melanoma. PLoS One 2013;8(4):13. DOI: 10.1371/journal.pone.0060469Chen J., Wu Y., Zhang L. et al. Evidence for calpains in cancer metastasis. J Cell Physiol 2019;234(6):8233–40. DOI: 10.1002/jcp.27649Arthur J.S., Elce J.S., Hegadorn C. et al. Disruption of the murine calpain small subunit gene, Capn4: Calpain is essential for embryonic development but not for cell growth and division. Mol Cell Biol 2000;20(12):4474–81. DOI: 10.1128/MCB.20.12.4474-4481.2000Azam M., Andrabi S.S., Sahr K.E. et al. Disruption of the mouse mu-calpain gene reveals an essential role in platelet function. Mol Cell Biol 2001;21(6):2213–20. DOI: 10.1128/MCB.21.6.2213-2220.2001Dutt P., Croall D.E., Arthur J.S. et al. m-Calpain is required for preimplantation embryonic development in mice. BMC Dev Biol 2006;6(3):11. DOI: 10.1186/1471-213X-6-3Chang F., Zhang Y., Mi J. et al. ROCK inhibitor enhances the growth and migration of BRAF‐mutant skin melanoma cells. Cancer Sci 2018;109(11):3428–37. DOI: 10.1111/cas.13786Leary N., Walser S., He Y. et al. Melanoma-derived extracellular vesicles mediate lymphatic remodelling and impair tumour immunity in draining lymph nodes. J Extracell Vesicles 2022;11(2):e12197. DOI: 10.1002/jev2.12197Nishida-Aoki N., Tominaga N., Takeshita F. et al. Disruption of circulating extracellular vesicles as a novel therapeutic strategy against cancer metastasis. Mol Ther 2017;25(1):181–91. DOI: 10.1016/j.ymthe.2016.10.009Santos M.F., Rappa G., Fontana S. et al. Anti-human CD9 fab fragment antibody blocks the extracellular vesicle-mediated increase in malignancy of colon cancer cells. Cells 2022;11(16):2474. DOI: 10.3390/cells11162474Gobbo J., Marcion G., Cordonnier M. et al. Restoring anticancer immune response by targeting tumor-derived exosomes with a HSP70 peptide aptamer. J Natl Cancer Inst 2016;108(3). DOI: 10.1093/jnci/djv330Chanteloup G., Cordonnier M., Isambert N. et al. Monitoring HSP70 exosomes in cancer patients’ follow up: A clinical prospective pilot study. J Extracell Vesicles 2020;9(1): 1766192. DOI: 10.1080/20013078.2020.1766192Sojka D.R., Abramowicz A., Adamiec-Organiściok M. et al. Heat shock protein A2 is a novel extracellular vesicle-associated protein. Sci Rep 2023;13(1):4734. DOI: 10.1038/s41598-023-31962-5Sariano P.A., Mizenko R.R., Shirure V.S. et al. Convection and extracellular matrix binding control interstitial transport of extracellular vesicles. J Extracell Vesicles 2023;12(4):e12323. DOI: 10.1002/jev2.12323Surman M., Stępień E., Przybyło M. Melanoma-derived extracellular vesicles: Focus on their proteome. Proteomes 2019;7(2):21. DOI: 10.3390/proteomes7020021Maguire C.A., Balaj L., Sivaraman S. et al. Microvesicle-associated AAV vector as a novel gene delivery system. Mol Ther 2012;20(5):960–71. DOI: 10.1038/mt.2011.303Atai N.A., Balaj L., van Veen H. et al. Heparin blocks transfer of extracellular vesicles between donor and recipient cells. J Neurooncol 2013;115(3):343–51. DOI: 10.1007/s11060-013-1235-yGamperl H., Plattfaut C., Freund A. et al. Extracellular vesicles from malignant effusions induce tumor cell migration: inhibitory effect of LMWH tinzaparin. Cell Biol Int 2016;40(10):1050–61. DOI: 10.1002/cbin.10645Manandhar S., Park J., Kothandan V.K. et al. Properties of heparinoids premixed with tumor-derived extracellular vesicles. Bioconjug Chem 2018;29(11):3757–67. DOI: 10.1021/acs.bioconjchem.8b00637Kuroda H., Tachikawa M., Yagi Y. et al. Cluster of differentiation 46 is the major receptor in human blood–brain barrier endothelial cells for uptake of exosomes derived from brain-metastatic melanoma cells (SK-Mel-28). Mol Pharm 2019;16(1):292–304. DOI: 10.1021/acs.molpharmaceut.8b00985Ukrainskaya V.M., Rubtsov Y.P., Knorre V.D. et al. Vesicles secreted by tumor cells and their role in the regulation of antitumor immunity. Acta Naturae 2019;11(4):33–41. (In Russ.). DOI: 10.32607/20758251-2019-11-4-33-41Украинская В.М., Рубцов Ю.П., Кнорре В.Д. и др. Везикулы, секретируемые опухолевыми клетками, и их роль в регуляции противоопухолевого иммунитета. Acta Naturae 2019;11(4):33–41. DOI: 10.32607/20758251-2019-11-4-33-41Cardeñes B., Clares I., Bezos T. et al. ALCAM/CD166 is involved in the binding and uptake of cancer-derived extracellular vesicles. Int J Mol Sci 2022;23(10):5753. DOI: 10.3390/ijms23105753Kowal J., Tkach M., Théry C. Biogenesis and secretion of exosomes. Curr Opin Cell Biol 2014;2(1):116–25. DOI: 10.1016/j.ceb.2014.05.004Willms E., Cabañas C., Mäger I. et al. Extracellular vesicle heterogeneity: subpopulations, isolation techniques, and diverse functions in cancer progression. Front Immunol 2018;9:738. DOI: 10.3389/fimmu.2018.00738Nazarenko I., Rana S., Baumann A. et al. Surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res 2010;70(4):1668–78. DOI: 10.1158/0008-5472.CAN-09-2470Reyes R., Cardeñes B., Machado-Pineda Y., Cabañas C. Tetra spanin CD9: A key regulator of cell adhesion in the immune system. Front Immunol 2018;9:863. DOI: 10.3389/fimmu.2018.00863