The role of extracellular vesicles in the diagnosis of glioblastoma progression

The article reviews studies highlighting the role of extracellular molecules in non-invasive diagnosis of glioblastoma recurrence. Glioblastoma is the most common malignant tumor of the brain characterized by fatal outcome prognosis. Current treatment of tumor recurrence allows to increase patient survival, improve functional outcome and decrease caregivers» load. The standard method of recurrence diagnosis is neuroimaging which at early stages cannot distinguish between tumor recurrence and post-radiation changes. Currently in oncology, liquid biopsy and marker detection in circulating extracellular vesicles are considered promising approaches allowing to obtain early and differential tumor diagnosis, determine dynamic molecular and genetic status of the tumor, diagnose tumor recurrence at early stages. In this context, the most promising approach to glioblastoma diagnosis is associated with studying of expression of glial fibrillary acidic protein (GFAP), epidermal growth factor receptor (EGFR), its mutant variant EGFRvIII, podoplanin (PDPN) and isocitrate dehydrogenase 1 (IDH1) in extracellular vesicles; for primary glioblastoma diagnosis and early recurrence: studying of microRNA-210, -301a, -222, -123-3p, -21; for control of immunotherapy effectiveness in patients with recurrent forms of glioblastoma after standard treatment: evaluation of СD9+ / GFAP+ / survivin+ exosomes in plasma.

1. Ostrom Q.T., Cioffi G., Gittleman H. et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012–2016. Neurooncology 2019;21(Suppl 5):v1–100. DOI: 10.1093/neuonc/noz150.

2. Chinot O.L., Wick W., Mason W. et al. Bevacizumab plus radiotherapytemozolomide for newly diagnosed glioblastoma. N Engl J Med 2014;370(8):709–22. DOI: 10.1056/NEJMoa1308345.

3. Gilbert M.R., Dignam J.J., Armstrong T.S. et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 2014;370(8):699–708. DOI: 10.1056/NEJMoa1308573.

4. Stupp R., Taillibert S., Kanner A. et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 2017;318(23): 2306–16. DOI: 10.1001/jama.2017.18718.

5. Absalyamova O.V., Kobyakov G.L., Agabekyan G.O. et al. Bevacizumab efficacy in progressive glioblastoma. Own data. Medicinskiy alfavit = Medical Alphabet 2018;2(29):60–5. (In Russ.)

6. Weller M., Le Rhun E., Preusser M. et al. How we treat glioblastoma. ESMO Open 2019;4(Suppl 2):e000520. DOI: 10.1136/esmoopen-2019-000520.

7. Trofimova T.N. Neuroradiology: evaluation of effectiveness of surgery and the combined therapy of gliomas. Prakticheskaya onkologiya = Practical Oncology 2016;17(1):32–40. (In Russ.)

8. Strauss S.B., Meng A., Ebani E.J., Chiang G.C. Imaging glioblastoma posttreatment: progression, pseudoprogression, pseudoresponse, radiation necrosis. Radiol Clin North Am 2019;57(6):1199–216. DOI: 10.1016/j.rcl.2019.07.003.

9. Arevalo O.D., Soto C., Rabiei P. et al. Assessment of glioblastoma response in the era of bevacizumab: longstanding and emergent challenges in the imaging evaluation of pseudoresponse. Front Neurol 2019;10:460. DOI: 10.3389/fneur.2019.00460.

10. Zikou A., Sioka C., Alexiou G.A. et al. Radiation necrosis, pseudoprogression, pseudoresponse, and tumor recurrence: imaging challenges for the evaluation of treated gliomas. Contrast Media Mol Imaging 2018;2018: 6828396. DOI: 10.1155/2018/6828396.

11. Chernov V.I., Zelchan R.V., Medvedeva A.A. Method for radionuclide diagnosing of cerebral tumors. Patent RU2692451C2, 24.06.2019. Application No. 2017134177 dated 02.10.2017. (In Russ.)]

12. MacArthur K.M., Kao G.D., Chandrasekaran S. et al. Detection of brain tumor cells in the peripheral blood by a telomerase promoter-based assay. Cancer Res 2014;74(8):2152–9. DOI: 10.1158/0008-5472.CAN-13-0813.

13. Gao F., Cui Y., Jiang H. et al. Circulating tumor cell is a common property of brain glioma and promotes the monitoring system. Oncotarget 2016;7(44):71330–40. DOI: 10.18632/oncotarget.11114.

14. Mohammadi H., Shiue K., Grass G.D. et al. Isocitrate dehydrogenase 1 mutant glioblastomas demonstrate a decreased rate of pseudoprogression: a multi-institutional experience. Neurooncol Pract 2020;1(7):185–95. DOI: 10.1093/nop/npz050.

15. García-Romero N., Carrión-Navarro J., Esteban-Rubio S. et al. DNA sequences within glioma-derived extracellular vesicles can cross the intact blood-brain barrier and be detected in peripheral blood of patients. Oncotarget 2017;8(1):1416–28. DOI: 10.18632/oncotarget.13635.

16. Silantyev A.S., Falzone L., Libra M. et al. Current and future trends on diagnosis and prognosis of glioblastoma: from molecular biology to proteomics. Cells 2019;8(8):863. DOI: 10.3390/cells8080863.

17. Yekula A., Muralidharan K., Rosh Z.S. et al. Liquid biopsy strategies to distinguish progression from pseudoprogression and radiation necrosis in glioblastomas. Adv Biosyst 2020;e2000029. DOI: 10.1002/adbi.202000029.

18. Hallal S., Ebrahimkhani S., Shivalingam B. et al. The emerging clinical potential of circulating extracellular vesicles for non-invasive glioma diagnosis and disease monitoring. Brain Tumor Pathol 2019;36(2):29–39. DOI: 10.1007/s10014-019-00335-0.

19. Chen W.W., Balaj L., Liau L.M. et al. Beaming and droplet digital PCR analysis of mutant IDH1 mRNA in glioma patient serum and cerebrospinal fluid extracellular vesicles. Mol Ther Nucleic Acids 2013;2(7): e109. DOI: 10.1038/mtna.2013.28.

20. Figueroa J.M., Skog J., Akers J. et al. Detection of wild-type EGFR amplification and EGFRvIII mutation in CSF-derived extracellular vesicles of glioblastoma patients. Neuro Oncol 2017;19(11):1494–502. DOI: 10.1093/neuonc/nox085.

21. Lane R., Simon T., Vintu M. et al. Cellderived extracellular vesicles can be used as a biomarker reservoir for glioblastoma tumor subtyping. Commun Biol 2019; 2:315. DOI: 10.1038/s42003-019-0560-x.

22. Wang H., Jiang D., Li W. et al. Evaluation of serum extracellular vesicles as noninvasive diagnostic markers of glioma. Theranostics 2019;9(18):5347–58. DOI: 10.7150/thno.33114.

23. Xu R., Rai A., Chen M. et al. Extracellular vesicles in cancer – implications for future improvements in cancer care. Nat Rev Clin Oncol 2018;15(10):617–38. DOI: 10.1038/s41571-018-0036-9.

24. Ciccocioppo F., Lanuti P., Marchisio M., Miscia S. Extracellular vesicles involvement in the modulation of the glioblastoma environment. J Oncol 2020;2020:3961735. DOI: 10.1155/2020/3961735.

25. Yekula A., Yekula A., Muralidharan K. et al. Extracellular vesicles in glioblastoma tumor microenvironment. Front Immunol 2020;10:3137. DOI: 10.3389/fimmu.2019.03137.

26. Skog J., Würdinger T., van Rijn S. et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 2008;10(12):1470–6. DOI: 10.1038/ncb1800.

27. Shao H., Chung J., Lee K. et al. Chipbased analysis of exosomal mRNA mediating drug resistance in glioblastoma. Nat Commun 2015;6:6999. DOI: 10.1038/ncomms7999.

28. Manda S.V., Kataria Y., Tatireddy B.R. et al. Exosomes as a biomarker platform for detecting epidermal growth factor receptor-positive high-grade gliomas. J Neurosurg 2018;128(4):1091–101. DOI: 10.3171/2016.11.JNS161187.

29. Zhang Y., Cruickshanks N., Pahuski M. et al. Noncoding RNAs in glioblastoma. In: Glioblastoma. Ed.: S. Vleeschouwer. Brisbane, QLD, Australia: Codon Publications, 2017. Pp. 95–130. 30. Liu J., Zhao K., Huang N., Zhang N. Circular RNAs and human glioma. Cancer Biol Med 2019;16(1):11–23. DOI: 10.20892/j.issn.2095-3941.2018.0425.

30. Sun J., Li B., Shu C. et al. Functions and clinical significance of circular RNAs in glioma. Mol Cancer 2020;19(1):34. DOI: 10.1186/s12943-019-1121-0.

31. Barbagallo D., Caponnetto A., Cirnigliaro M. et al. CircSMARCA5 inhibits migration of glioblastoma multiforme cells by regulating a molecular axis involving splicing factors SRSF1/SRSF3/PTB. Int J Mol Sci 2018;19(2): 480. DOI: 10.3390/ijms19020480.

32. Duan X.B., Liu D.L., Wang Y., Chen Z.Q. Circular RNA hsa_ circ_0074362 promotes glioma cell proliferation, migration, and invasion by attenuating the inhibition of mir-1236-3p on HOXB7 expression. DNA Cell Biol 2018;37:917–24. DOI: 10.1089/dna.2018.4311.

33. Wang R.J., Zhang S., Chen X.Y. et al. EIF4A3-induced circular RNA MMP9 (circMMP9) acts as a sponge of miR-124 and promotes glioblastoma multiforme cell tumorigenesis. Mol Cancer 2018;17:166. DOI: 10.1186/s12943-018-0911-0.

34. Wang Y., Sui X., Zhao H. et al. Decreased circular RNA hsa_circ_0001649 predicts unfavorable prognosis in glioma and exerts oncogenic properties in vitro and in vivo. Gene 2018;676:117–22. DOI: 10.1016/j.gene.2018.07.037.

35. Barbagallo D., Caponnetto A., Brex D. et al. CircSMARCA5 regulates VEGFA mRNA splicing and angiogenesis in glioblastoma multiforme through the binding of SRSF1. Cancers (Basel) 2019;11(2):194. DOI: 10.3390/cancers11020194.

36. Jin P., Huang Y., Zhu P. et al. CircRNA circHIPK3 serves as a prognostic marker to promote glioma progression by regulating miR-654/IGF2BP3 signaling. Biochem Biophys Res Commun 2018;503(3):1570–4. DOI: 10.1016/j.bbrc.2018.07.081.

37. Zhang M., Huang N., Yang X. et al. A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis. Oncogene 2018;37(13):1805–14. DOI: 10.1038/s41388-017-0019-9.

38. Yang M., Li G., Fan L. et al. Circular RNA circ_0034642 elevates BATF3 expression and promotes cell proliferation and invasion through miR-1205 in glioma. Biochem Biophys Res Commun 2019;508(3):980–5. DOI: 10.1016/j.bbrc.2018.12.052.

39. Lei B., Huang Y., Zhou Z. et al. Circular RNA hsa_circ_0076248 promotes oncogenesis of glioma by sponging miR-181a to modulate SIRT1 expression. J Cell Biochem 2019;120(4):6698–708. DOI: 10.1002/jcb.27966.

40. Ding C., Yi X., Wu X. et al. Exosomemediated transfer of circRNA CircNFIX enhances temozolomide resistance in glioma. Cancer Lett 2020;479:1–12. DOI: 10.1016/j.canlet.2020.03.002.

41. Chen W., Xu X.K., Li J.L. et al. MALAT1 is a prognostic factor in glioblastoma multiforme and induces chemoresistance to temozolomide through suppressing miR-203 and promoting thymidylate synthase expression. Oncotarget 2017;8(14):22783–99. DOI: 10.18632/oncotarget.15199.

42. Shen J., Hodges T.R., Song R. et al. Serum HOTAIR and GAS5 levels as predictors of survival in patients with glioblastoma. Mol Carcinog 2018;57(1): 137–41. DOI: 10.1002/mc.22739.

43. Tan S.K., Pastori C., Penas C. et al. Serum long noncoding RNA HOTAIR as a novel diagnostic and prognostic biomarker in glioblastoma multiforme. Mol Cancer 2018;17(1):74. DOI: 10.1186/s12943-018-0822-0.

44. Xie J., Wang X., Liu S. et al. LncRNA SAMMSON overexpression distinguished glioblastoma patients from patients with diffuse neurosarcoidosis. Neuroreport 2019;30(12):817–21. DOI: 10.1097/WNR.0000000000001278.

45. Zhang Z., Yin J., Lu C. et al. Exosomal transfer of long non-coding RNA SBF2- AS1 enhances chemoresistance to temozolomide in glioblastoma. J Exp Clin Cancer Res 2019;38(1):166. DOI: 10.1186/s13046-019-1139-6.

46. Manterola L., Guruceaga E., Gállego Pérez-Larraya J. et al. A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool. Neuro Oncol 2014;16(4):520–7. DOI: 10.1093/neuonc/not218.

47. Ebrahimkhani S., Vafaee F., Hallal S. et al. Deep sequencing of circulating exosomal microRNA allows non-invasive glioblastoma diagnosis. NPJ Precis Oncol 2018;2:28. DOI: 10.1038/s41698-018-0071-0.

48. Santangelo A., Imbruce P., Gardenghi B. et al. A microRNA signature from serum exosomes of patients with glioma as complementary diagnostic biomarker. J Neurooncol 2018;136(1):51–62. DOI: 10.1007/s11060-017-2639-x.

49. Akers J.C., Ramakrishnan V., Kim R. et al. MiR-21 in the extracellular vesicles (EVs) of cerebrospinal fluid (CSF): a platform for glioblastoma biomarker development. PLoS One 2013;8(10): e78115. DOI: 10.1371/journal.pone.0078115.

50. Shi R., Wang P.Y., Li X.Y. et al. Exosomal levels of miRNA-21 from cerebrospinal fluids associated with poor prognosis and tumor recurrence of glioma patients. Oncotarget 2015;6(29):26971–81. DOI: 10.18632/oncotarget.4699.

51. Lan F., Qing Q., Pan Q. et al. Serum exosomal miR- 301a as a potential diagnostic and prognostic biomarker for human glioma. Cell Oncol (Dordr) 2018;41:25–33. DOI: 10.1007/s13402-017-0355-3.

52. Lan F., Yue X., Xia T. Exosomal microRNA-210 is a potentially noninvasive biomarker for the diagnosis and prognosis of glioma. Oncol Lett 2020;19(3):1967–74. DOI: 10.3892/ol.2020.11249.

53. Shao H., Chung J., Balaj L. et al. Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy. Nat Med 2012;18(12): 1835–40. DOI: 10.1038/nm.2994.

54. Malek A., Samsonov R.V., Chiesi A. Development of cancer diagnostics and monitoring methods based on analysis of tumor-derived exosomes. Rossijskiy bioterapevticheskiy zhurnal = Russian Journal of Biotherapy 2015;14(4):9–18. (In Russ.) DOI: 10.17650/1726-9784-2015-14-4-9-18.

55. Koch C.J., Lustig R.A., Yang X.Y. et al. Microvesicles as a biomarker for tumor progression versus treatment effect in radiation/temozolomide-treated glioblastoma patients. Transl Oncol 2014;7(6):752–8. DOI: 10.1016/j.tranon.2014.10.004.

56. André-Grégoire G., Bidere N., Gavard J. Temozolomide affects extracellular vesicles released by glioblastoma cells. Biochimie 2018;155:11–5. DOI: 10.1016/j.biochi.2018.02.007.

57. Osti D., Del Bene M., Rappa G. et al. Clinical significance of extracellular vesicles in plasma from glioblastoma patients. Clin Cancer Res 2019;25(1):266–76. DOI: 10.1158/1078-0432.CCR-18-1941.

58. Simon T., Pinioti S., Schellenberger P. et al. Shedding of bevacizumab in tumour cellsderived extracellular vesicles as a new therapeutic escape mechanism in glioblastoma. Mol Cancer 2018;17(1):132. DOI: 10.1186/s12943-018-0878-x.

59. Sheybani N.D., Batts A.J., Mathew A.S. et al. Focused ultrasound hyperthermia augments release of glioma-derived extracellular vesicles with differential immunomodulatory capacity. Theranostics 2020;10(16):7436–47. DOI: 10.7150/thno.46534.

60. Brennan K., Martin K., FitzGerald S.P. et al. A comparison of methods for the isolation and separation of extracellular vesicles from protein and lipid particles in human serum. Sci Rep 2020;10(1):1039. DOI: 10.1038/s41598-020-57497-7.

61. Galbo P.M. Jr, Ciesielski M.J., Figel S. et al. Circulating CD9+/ GFAP+/survivin+ exosomes in malignant glioma patients following survivin vaccination. Oncotarget 2017;8(70):114722–35. DOI: 10.18632/oncotarget.21773.

62. Zhu L., Oh J.M., Gangadaran P. et al. Targeting and therapy of glioblastoma in a mouse model using exosomes derived from natural killer cells. Front Immunol 2018;9:824. DOI: 10.3389/fimmu.2018.00824.

63. Melzer C., Rehn V., Yang Y. et al. Taxolloaded MSC-derived exosomes provide a therapeutic vehicle to target metastatic breast cancer and other carcinoma cells. Cancers (Basel) 2019;11(6):E798. DOI: 10.3390/cancers11060798.

64. Altanerova U., Babincova M., Babinec P. et al. Human mesenchymal stem cellderived iron oxide exosomes allow targeted ablation of tumor cells via magnetic hyperthermia. Int J Nanomedicine 2017;12:7923–36. DOI: 10.2147/IJN.S145096.