KANSERDE YENİ HEDEF: MİKROVEZİKÜLLER VE EKSOZOMLAR

Son yıllarda hücreler arası haberleşmede ekstrasellüler veziküllerin transferini içeren yeni bir mekanizma öne sürülmüştür. Çoğu kanser hücresi protein, lipit, DNA ve mikroRNA’lardan oluşan ekstrasellüler veziküller (EV’ler) salarak komşu hücre davranışının değişmesine neden olabilmektedir. EV’lerin bir alt tipi olan eksozomlar hücreler arası iletişim sağlayan küresel şekilli, iki lipit tabakalı membran ile çevrili keseciklerdir. Eksozomlar kanser gelişimini, metastaz ve ilaç direncini kontrol etmek için yakın ve uzak çevre kanser hücreleri ile iletişim kurarlar. Eksozomlar hücreler arası iletişimin yanısıra sinyal iletimi, genetik madde aktarımı, bağışıklık yanıtının düzenlenmesi gibi birçok biyolojik işlevde rol oynar. EV’lerin tümör mikro çevresinde ve kanser metastazında alternatif bir haberleşme aracı olduğu ortaya çıkarılmıştır. Eksozomlar çeşitli kanser tedavileri esnasında içeriklerini değiştirebildiklerinden dolayı tedaviyi takip etmede önemli bir rol oynayabilirler. Bu derleme kanser tanı ve tedavisinin hedefi olarak komünikazom (hücreler arası haberleşme) olarak adlandırılan hücreler arasında sinyalleri ileten EV’lerin fonksiyonuna odaklanmaktadır.

Anahtar Kelimeler:

Ekstrasellüler veziküller, eksozom, kanser, tedavi

NEW TARGET MICROVESICLES AND EXOSOMES IN CANCER

In recent years, a new mechanism for intercellular communication has been put forward which involves the intercellular transfer of extracellular vesicles. Most cancer cells release potentially functional biomolecules loaded in extracellular vesicles (EVs) such as DNA, proteins, lipids, and microRNAs. The experiments showed that EVs uptake by tumor cells can alter cellular behavior. Exosomes, a subtype of EVs, are small, lipid bilayer membrane vesicles for intercellular communication. Exosomes communicate with near-by and distant cancer cells that promote cancer development, metastasis, and drug resistance. In addition to intercellular communication, exosomes play a role in many biological processes such as signal transmission, genetic material transfer, and regulation of the immune response. EVs have emerged as an alternative mediator of communication within the tumor microenvironment and cancer metastasis. Because exosomes can change their content during various cancer treatments, they can play an important role in following the treatment. This review focuses on the function of EVs as signal transmitters between cells, called communicasomes (intercellular communication), and the importance of this function in cancer diagnosis and treatment.

Keywords:

Extracellular vesicles, exosome, cancer, therapy,

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1. Ariazi J, Benowitz A, De Biasi V, Den Boer ML, Cherqui S, Cui H, et al. Tunneling nanotubes and gap junctions-their role in long-range intercellular communication during development, health, and disease conditions. Front Mol Neurosci 2017;10:333. [CrossRef]
2. Lee Y, El Andaloussi S, Wood MJ. Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum Mol Genet 2012;15;21(R1): R125-34. [CrossRef] 3. Yoon YJ, Kim OY, Gho YS. Extracellular vesicles as emerging intercellular communicasomes. BMB Rep 2014;47(10):531-9. [CrossRef]
4. Zhao H, Achreja A, Iessi E, Logozzi M, Mizzoni D, Di Raimo R, et al. The key role of extracellular vesicles in the metastatic process. Biochim Biophys Acta 2018;1869(1):64-77. [CrossRef]
5. Abak A, Abhari A, Rahimzadeh S. Exosomes in cancer: small vesicular transporters for cancer progression and metastasis, biomarkers in cancer therapeutics. Peer J 2018 29;6:e4763. [CrossRef]
6. Jeppesen DK, Fenix AM, Franklin JL, Higginbotham JN, Zhang Q, Zimmerman LJ, et al. Reassessment of exosome composition. Cell 2019;177(2):428-45. [CrossRef]
7. Zhang X, Yuan X, Shi H, Wu L, Qian H, Xu W. Exosomes in cancer: small particle, big player. J Hematol Oncol 2015;8:83. [CrossRef]
8. Zomer A, Maynard C, Verweij FJ, Kamermans A, Schäfer R, Beerling E, et al. In Vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell 2015;161(5):1046-57. [CrossRef]
9. Andre F, Schartz NE, Movassagh M, Flament C, Pautier P, Morice P, et al. Malignant effusions and immunogenic tumour-derived exosomes. Lancet 2002;27;360(9329):295- 305. [CrossRef]
10. Lässer C, Eldh M, Lötvall J. Isolation and characterization of RNA-containing exosomes. J Vis Exp 2012;(59):e3037. [CrossRef]
11. Yoshioka Y, Kosaka N, Konishi Y, Ohta H, Okamoto H, Sonoda H, et al. Ultra-sensitive liquid biopsy of circulating extracellular vesicles using ExoScreen. Nat Commun 2014;5:3591. [CrossRef]
12. Choi DS, Kim DK, Kim YK, Gho YS. Proteomics of extracellular vesicles:Exosomes and ectosomes. Mass Spectrom Rev 2015;34(4):474-90. [CrossRef]
13. Keerthikumar S, Chisanga D, Ariyaratne D, Al Saffar H, Anand S, Zhao K, et al. ExoCarta: A Web- Based Compendium of Exosomal Cargo. J Mol Biol 2016;428(4):688-92. [CrossRef]
14. Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 2018;7(1):1535750. [CrossRef]
15. Trams EG, Lauter CJ, Salem N Jr, Heine U. Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. Biochim Biophys Acta 1981;645(1):63-70. [CrossRef]
16. Azmi AS, Bao B, Sarkar FH. Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review. Cancer Metastasis Rev 2013;32(3-4):623-42. [CrossRef]
17. Zhang G, Yang P. A novel cell-cell communication mechanism in the nervous system: exosomes. J Neurosci Res 2018;96(1):45-52. [CrossRef]
18. Tian T, Zhu YL, Hu FH, Wang YY, Huang NP, Xiao ZD. Dynamics of exosome internalization and trafficking. J Cell Physiol 2013;228:1487-95. [CrossRef]
19. Wei Y, Wang D, Jin F, Bian Z, Li L, Liang H, et al. Pyruvate kinase type M2 promotes tumour cell exosome release via phosphorylating synaptosome-associated protein 23. Nat Commun 2017;8:14041. [CrossRef]
20. Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, De Milito A, et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem 2009;284(49):34211-22. [CrossRef]
21. Sinha S, Hoshino D, Hong NH, Kirkbride KC, Grega-Larson NE, Seiki M, et al. Cortactin promotes exosome secretion by controlling branched actin dynamics. J Cell Biol 2016;214(2):197-213. [CrossRef]
22. Zhang Y, Liu F, Yuan Y, Jin C, Chang C, Zhu Y, et al. Inflammasome-derived exosomes activate NF-κB signaling in macrophages. J Proteome Res 2017;16(1):170-8. [CrossRef]
23. Samanta S, Rajasingh S, Drosos N, Zhou Z, Dawn B, Rajasingh J. Exosomes: new molecular targets of diseases. Acta Pharmacol Sin 2018; 39(4):501-13. [CrossRef]
24. Kim MS, Haney MJ, Zhao Y, Mahajan V, Deygen I, Klyachko NL, et al. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine 2016;12(3):655-64. [CrossRef]
25. Christianson HC, Svensson KJ, van Kuppevelt TH, Li JP, Belting M. Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity. Proc Natl Acad Sci U S A 2013;110(43):17380-5. [CrossRef]
26. Hannafon BN, Trigoso YD, Calloway CL, Zhao YD, Lum DH, Welm AL, et al. Plasma exosome microRNAs are indicative of breast cancer. Breast Cancer Res 2016;18(1):90. [CrossRef]
27. Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal-Bengtson B, et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci U S A 2016;113(8):E968-77. [CrossRef]
28. Baran J, Baj-Krzyworzeka M, Weglarczyk K, Szatanek R, Zembala M, Barbasz J, et al. Circulating tumour-derived microvesicles in plasma of gastric cancer patients. Cancer Immunol Immunother 2010;59 (6):841-50. [CrossRef]
29. Becker A, Thakur BK, Weiss JM, Kim HS, Peinado H, Lyden D. Extracellular vesicles in cancer: Cell-to-cell mediators of metastasis. Cancer Cell 2016;30(6):836-48. [CrossRef]
30. Cai Z, Yang F, Yu L, Yu Z, Jiang L, Wang Q, et al. Activated T cell exosomes promote tumor invasion via Fas signaling pathway. J Immunol 2012;15;188(12):5954-61. [CrossRef]
31. Higginbotham JN, Demory Beckler M, Gephart JD, Franklin JL, Bogatcheva G, Kremers GJ, et al. Amphiregulin exosomes increase cancer cell invasion. Curr Biol 2011;21(9):779-86. [CrossRef]
32. Brinton TL, Sloane HS, Kester M, Kelly KA. Formation and role of exosomes in cancer. Cell Mol Life Sci 2015;72(4): 659- 71. [CrossRef]
33. Mashouri L, Yousefi H, Aref AR, Ahadi AM, Molaei F, Alahari SK. Exosomes: composition, biogenesis, and mechanisms in cancer metastasis and drug resistance. Mol Cancer 2019;18(1):75. [CrossRef]
34. Melo SA, Sugimoto H, O’Connell JT, Kato N, Villanueva A, Vidal A, et al. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 2014;26(5):707-21. [CrossRef]
35. Bach DH, Hong JY, Park HJ, Lee SK. The role of exosomes and miRNAs in drug-resistance of cancer cells. Int J Cancer 2017;141(2):220-30. [CrossRef]
36. Sun Z, Shi K, Yang S, Liu J, Zhou Q, Wang G, et al. Effect of exosomal miRNA on cancer biology and clinical applications. Mol Cancer 2018;17(1):147. [CrossRef]
37. Huang T, Deng CX. Current progresses of exosomes as cancer diagnostic and prognostic biomarkers. Int J BiolSci 2019;15(1):1-11. [CrossRef]
38. Vaksman O, Tropé C, Davidson B, Reich R. Exosomederived miRNAs and ovarian carcinoma progression. Carcinogenesis 2014;35(9):2113-20. [CrossRef]
39. Liu Q, Yu Z, Yuan S, Xie W, Li C, Hu Z, et al. Circulating exosomal microRNAs as prognostic biomarkers for non-smallcell lung cancer. Oncotarget 2017;8(8):13048-58. [CrossRef]
40. Xue X, Liu Y, Wang Y, Meng M, Wang K, Zang X, et al. MiR-21 and MiR-155 promote non-small cell lung cancer progression by downregulating SOCS1, SOCS6, and PTEN. Oncotarget 2016;7(51):84508-19. [CrossRef]
41. Liu X, Jiang T, Li X, Zhao C, Li J, Zhou F, et al. Exosomes transmit T790M mutation-induced resistance in EGFRmutant NSCLC by activating PI3K/AKT signalling pathway. J Cell Mol Med 2020;24(2):1529-40. [CrossRef]
42. Lan J, Sun L, Xu F, Liu L, Hu F, Song D, et al. M2 Macrophagederived exosomes promote cell migration and invasion in colon cancer. Cancer Res 2019;79(1):146-58. [CrossRef]
43. Wu Y, Deng W, McGinley EC, Klinke DJ 2nd. Melanoma exosomes deliver a complex biological payload that upregulates PTPN11 to suppress T lymphocyte function. Pigment Cell Melanoma Res 2017;30(2):203-18. [CrossRef]
44. Dai S, Wei D, Wu Z, Zhou X, Wei X, Huang H, 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. [CrossRef]
45. Besse B, Charrier M, Lapierre V, Dansin E, Lantz O, Planchard D, et al. Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. Oncoimmunology 2015;5(4):e1071008. [CrossRef]
46. Ciravolo V, Huber V, Ghedini GC, Venturelli E, Bianchi F, Campiglio M, et al. Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy. J Cell Physiol 2012;227(2):658-67. [CrossRef]
47. Taylor DD, Gercel-Taylor C. MicroRNA signatures of tumorderived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 2008;110(1):13-21. [CrossRef]
48. Balaj L, Lessard R, Dai L, Cho YJ, Pomeroy SL, Breakefield XO, et al. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat Commun 2011;2:180. [CrossRef] 4
9. Park ES, Kim SJ, Kim SW, Yoon SL, Leem SH, Kim SB, et al. Cross-species hybridization of microarrays for studying tumor transcriptome of brain metastasis. Proc Natl Acad Sci USA 2011;108(42):17456-61. [CrossRef]
50. Zhang L, Zhang S, Yao J, Lowery FJ, Zhang Q, Huang WC, et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 2015;527(7576):100-4. [CrossRef]