Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press17810.17650/2313-805X-2018-5-4-94-103REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИWnt-signaling pathway in pathogenesis of glioblastoma multiformeWnt-сигнальный каскад в патогенезе мультиформной глиобластомыhttps://orcid.org/0000-0002-6367-3785VasiletsYu. D.ВасилецЮ. Д.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-0154-8604ArnotskayaN. E.АрноцкаяН. Е.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0001-7588-1066KudryavtsevI. A.КудрявцевИ. А.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

https://orcid.org/0000-0002-0401-9900ShevchenkoV. E.ШевченкоВ. Е.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

Валерий Евгеньевич Шевченко.

115478 Москва, Каширское шоссе, 24

vshev2015@yandex.ruResearch Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaНИИ канцерогенеза, ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России1512201854941030401201904012019Copyright ©; 2018, Vasilets Y.D., Arnotskaya N.E., Kudryavtsev I.A., Shevchenko V.E.Copyright ©; 2018, Василец Ю.Д., Арноцкая Н.Е., Кудрявцев И.А., Шевченко В.Е.2018Vasilets Y.D., Arnotskaya N.E., Kudryavtsev I.A., Shevchenko V.E.Василец Ю.Д., Арноцкая Н.Е., Кудрявцев И.А., Шевченко В.Е.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/178

The Wnt-signaling pathway regulates various biological processes, such as embryonic development, self-renewal, proliferation, differentiation and migration of stem cells. The Wnt-signaling is involved in tumor progression by aberrant activation in stem-like cells, called cancer stem cells, in different kinds of tumor, including multiform glioblastoma. The Wnt-signaling promotes stemness, invasion, metastasis, therapeutic and immune resistance of cancer stem cells in multiform glioblastoma. To summarize, targeting the Wnt-signaling pathway as an oncogenic driver is the future hope for effective therapy of glioblastoma for which current standard therapy is not effective.

In this review, we focused on functions of the Wnt-signaling in cancer stem cells and involvement of the Wnt-signaling pathway in gliomagenesis.

Wnt-сигнальный путь связан с регуляцией различных биологических процессов, таких как эмбриональное развитие, пролиферация, дифференцировка и миграция стволовых клеток. Аберрантная активация Wnt-каскада в опухолевых стволовых клетках вовлечена в онкогенез различных онкологических заболеваний, в том числе мультиформной глиобластомы. Wnt-сигнальный каскад способствует приобретению и поддержанию клетками мультиформной глиобластомы свойств опухолевых стволовых клеток их способности к инвазии, метастазированию, резистентности к терапии и устойчивости к иммунному ответу. Следовательно, фармакологическая модуляция Wnt-сигналинга может представлять особый интерес при лечении мультиформной глиобластомы, для которой текущая стандартная терапия оказывается неэффективной.

В данном обзоре рассмотрена роль Wnt-сигнального каскада в опухолевых стволовых клетках и включение его в глиомагенез.

Wnt-signalingcancer stem cellsmultiform glioblastomaβ-cateninWnt-сигнальный путьопухолевые стволовые клеткимультиформная глиобластомаβ-катенин1. Gulati S., Jakola A.S., Johannesen T.B., Solheim O. Survival and treatment patterns of glioblastoma in the elderly: a population-based study. World Neurosurg 2012;78(5):518—26. DOI: 10.1016/j.wneu.2011.12.008. PMID: 22381305.Gulati S., Jakola A.S., Johannesen T.B., Solheim O. Survival and treatment patterns of glioblastoma in the elderly: a population-based study. World Neurosurg 2012;78(5):518—26. DOI: 10.1016/j.wneu.2011.12.008. PMID: 22381305.2. Stupp R., Mason W.P., Bent M.J. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352(10):987—96. DOI: 10.1056/NEJMoa043330. PMID: 15758009.Stupp R., Mason W.P., Bent M.J. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352(10):987—96. DOI: 10.1056/NEJMoa043330. PMID: 15758009.3. Galli R., Binda E., Orfanelli U. et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 2004;64(19):7011—21. DOI: 10.1158/0008-5472.CAN-04-1364. PMID: 15466194.Galli R., Binda E., Orfanelli U. et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 2004;64(19):7011—21. DOI: 10.1158/0008-5472.CAN-04-1364. PMID: 15466194.4. Rheinbay E., Suva M.L., Gillespie S.M. et al. An aberrant transcription factor network essential for Wnt signaling and stem cell maintenance in glioblastoma. Cell Rep 2013;3(5):1567—79. DOI: 10.1016/j.cel-rep.2013.04.021. PMID: 23707066.Rheinbay E., Suva M.L., Gillespie S.M. et al. An aberrant transcription factor network essential for Wnt signaling and stem cell maintenance in glioblastoma. Cell Rep 2013;3(5):1567—79. DOI: 10.1016/j.cel-rep.2013.04.021. PMID: 23707066.5. McCord M., Mukouyama Y., Gilbert M.R., Jackson S. Targeting WNT signaling for multifaceted glioblastoma therapy. Front Cell Neurosci 2017;11:318. DOI: 10.3389/fncel.2017.00318. PMID: 29081735.McCord M., Mukouyama Y., Gilbert M.R., Jackson S. Targeting WNT signaling for multifaceted glioblastoma therapy. Front Cell Neurosci 2017;11:318. DOI: 10.3389/fncel.2017.00318. PMID: 29081735.6. Nusse R., Varmus H.E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 1982;31(1):99—109. PMID: 6297757.Nusse R., Varmus H.E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 1982;31(1):99—109. PMID: 6297757.7. Tompa M., Kalovits F., Nagy A., Kalman B. Contribution of the Wnt pathway to defining biology of glioblastoma. Neuromolecular Med 2018. DOI: 10.1007/s12017-018-8514-x. PMID: 30259273.Tompa M., Kalovits F., Nagy A., Kalman B. Contribution of the Wnt pathway to defining biology of glioblastoma. Neuromolecular Med 2018. DOI: 10.1007/s12017-018-8514-x. PMID: 30259273.8. Ding D., Lim K.S., Eberhart C.G. Arsenic trioxide inhibits Hedgehog, Notch and stem cell properties in glioblastoma neurospheres. Acta Neuropathol Commun 2014;2:31. DOI: 10.1186/2051-5960-2-31. PMID: 24685274.Ding D., Lim K.S., Eberhart C.G. Arsenic trioxide inhibits Hedgehog, Notch and stem cell properties in glioblastoma neurospheres. Acta Neuropathol Commun 2014;2:31. DOI: 10.1186/2051-5960-2-31. PMID: 24685274.9. Logan C.Y., Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 2004;20:781-810. DOI: 10.1146/annurev.cell-bio.20.010403.113126. PMID: 15473860.Logan C.Y., Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 2004;20:781-810. DOI: 10.1146/annurev.cell-bio.20.010403.113126. PMID: 15473860.10. De Panfilis G., Ferrari D., Santoro S. et al. Cytoplasmic beta-catenin is lacking in a subset of melanoma-associated naevi, but is detectable in naevus-associated melanomas: potential implications for melanoma tumorigenesis? Br J Dermatol 2009;160(3):600-8. DOI: 10.1111/j.1365-2133.2008.09001.x. PMID: 19183173.De Panfilis G., Ferrari D., Santoro S. et al. Cytoplasmic beta-catenin is lacking in a subset of melanoma-associated naevi, but is detectable in naevus-associated melanomas: potential implications for melanoma tumorigenesis? Br J Dermatol 2009;160(3):600-8. DOI: 10.1111/j.1365-2133.2008.09001.x. PMID: 19183173.11. Peifer M., Polakis P. Wnt signaling in oncogenesis and embryogenesis — a look outside the nucleus. Science 2000;287(5458):1606—9. PMID: 10733430.Peifer M., Polakis P. Wnt signaling in oncogenesis and embryogenesis — a look outside the nucleus. Science 2000;287(5458):1606—9. PMID: 10733430.12. Tada M., Concha M. L., Heisenberg C.P. Non-canonical Wnt signalling and regulation of gastrulation movements. Semin Cell Dev Biol 2002;13(3):251—60. PMID: 12137734.Tada M., Concha M. L., Heisenberg C.P. Non-canonical Wnt signalling and regulation of gastrulation movements. Semin Cell Dev Biol 2002;13(3):251—60. PMID: 12137734.13. Nayak L., Bhattacharyya N.P., De R.K. Wnt signal transduction pathways: modules, development and evolution. BMC Syst Biol 2016;10(2):44. DOI: 10.1186/s1291 8-016-0299-7. PMID: 27490822.Nayak L., Bhattacharyya N.P., De R.K. Wnt signal transduction pathways: modules, development and evolution. BMC Syst Biol 2016;10(2):44. DOI: 10.1186/s1291 8-016-0299-7. PMID: 27490822.14. Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov 2014;13(7):513—32. DOI: 10.1038/nrd4233. PMID: 24981364.Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov 2014;13(7):513—32. DOI: 10.1038/nrd4233. PMID: 24981364.15. Willert K., Nusse R. Wnt Proteins. Cold Spring Harb Perspect Biol 2012;4(9):a007864. DOI: 10.1101/cshper-spect.a007864. PMID: 22952392.Willert K., Nusse R. Wnt Proteins. Cold Spring Harb Perspect Biol 2012;4(9):a007864. DOI: 10.1101/cshper-spect.a007864. PMID: 22952392.16. Kikuchi A., Yamamoto H., Sato A., Mat-sumoto S. New insights into the mechanism of Wnt signaling pathway activation. Int Rev Cell Mol Biol 2011;291:21-71. DOI: 10.1016/B978-0-12-386035-4.00002-1. PMID: 22017973.Kikuchi A., Yamamoto H., Sato A., Mat-sumoto S. New insights into the mechanism of Wnt signaling pathway activation. Int Rev Cell Mol Biol 2011;291:21-71. DOI: 10.1016/B978-0-12-386035-4.00002-1. PMID: 22017973.17. Mikels A.J., Nusse R. Wnts as ligands: processing, secretion and reception. Oncogene 2006;25(57):7461—8. DOI: 10.1038/sj.onc.1210053. PMID: 17143290.Mikels A.J., Nusse R. Wnts as ligands: processing, secretion and reception. Oncogene 2006;25(57):7461—8. DOI: 10.1038/sj.onc.1210053. PMID: 17143290.18. Willert K., Nusse R. Beta-catenin: a key mediator of Wnt signaling. Curr Opin Genet Dev 1998;8(1):95—102. PMID: 9529612.Willert K., Nusse R. Beta-catenin: a key mediator of Wnt signaling. Curr Opin Genet Dev 1998;8(1):95—102. PMID: 9529612.19. MacDonald B.T., Tamai K., He X. Wnt/p-catenin signaling: components, mechanisms, and diseases. Dev Cell 2009;17(1):9—26. DOI: 10.1016/j.devcel.2009.06.016. PMID: 19619488.MacDonald B.T., Tamai K., He X. Wnt/p-catenin signaling: components, mechanisms, and diseases. Dev Cell 2009;17(1):9—26. DOI: 10.1016/j.devcel.2009.06.016. PMID: 19619488.20. Baarsma H.A., Konigshoff M., Gosens R. The WNT signaling pathway from ligand secretion to gene transcription: molecular mechanisms and pharmacological targets. Pharmacol Therapeutic 2013;138(1): 66—83. DOI: 10.1016/j.phar-mthera.2013.01.002. PMID: 23328704.Baarsma H.A., Konigshoff M., Gosens R. The WNT signaling pathway from ligand secretion to gene transcription: molecular mechanisms and pharmacological targets. Pharmacol Therapeutic 2013;138(1): 66—83. DOI: 10.1016/j.phar-mthera.2013.01.002. PMID: 23328704.21. Kierulf-Vieira K.S., Sandberg C.J., Grieg Z. et al. Wnt inhibition is dysregu-lated in gliomas and its re-establishment inhibits proliferation and tumor sphere formation. Exp Cell Res 2016;340(1): 53—61. DOI: 10.1016/j.yexcr.2015.12.010. PMID: 26712519.Kierulf-Vieira K.S., Sandberg C.J., Grieg Z. et al. Wnt inhibition is dysregu-lated in gliomas and its re-establishment inhibits proliferation and tumor sphere formation. Exp Cell Res 2016;340(1): 53—61. DOI: 10.1016/j.yexcr.2015.12.010. PMID: 26712519.22. Maher M.T., Mo R., Flozak A.S. et al. p-catenin phosphorylated at serine 45 is spatially uncoupled from p-catenin phosphorylated in the GSK3 domain: implications for signaling. PLoS One 2010;5(4):e10184. DOI: 10.1371/journal.pone.0010184. PMID: 20419129.Maher M.T., Mo R., Flozak A.S. et al. p-catenin phosphorylated at serine 45 is spatially uncoupled from p-catenin phosphorylated in the GSK3 domain: implications for signaling. PLoS One 2010;5(4):e10184. DOI: 10.1371/journal.pone.0010184. PMID: 20419129.23. Latres E., Chiaur D.S., Pagano M. The human F box protein beta-TRCP associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin. Oncogene 1999;18(4):849—54. DOI: 10.1038/sj.onc.1202653. PMID: 10023660.Latres E., Chiaur D.S., Pagano M. The human F box protein beta-TRCP associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin. Oncogene 1999;18(4):849—54. DOI: 10.1038/sj.onc.1202653. PMID: 10023660.24. Hanson A.J., Wallace H.A., Freeman T.J. et al. XIAP mono-ubiquitylates Groucho/ TLE to promote canonical Wnt signaling. Molecular Cell 2012;45(5):619—28. DOI: 10.1016/j.molcel.2011.12.032. PMID: 22304967.Hanson A.J., Wallace H.A., Freeman T.J. et al. XIAP mono-ubiquitylates Groucho/ TLE to promote canonical Wnt signaling. Molecular Cell 2012;45(5):619—28. DOI: 10.1016/j.molcel.2011.12.032. PMID: 22304967.25. Mao J., Wang J., Liu B. et al. Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell 2001;7(4):801 —9. PMID: 11336703.Mao J., Wang J., Liu B. et al. Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell 2001;7(4):801 —9. PMID: 11336703.26. MacDonald B.T., He X. Frizzled and LRP5/6 Receptors for Wnt/p-Catenin Signaling. Cold Spring Harbor Perspect Biol 2012;4(12):a007880. DOI: 10.1101/csh-perspect.a007880. PMID: 23209147.MacDonald B.T., He X. Frizzled and LRP5/6 Receptors for Wnt/p-Catenin Signaling. Cold Spring Harbor Perspect Biol 2012;4(12):a007880. DOI: 10.1101/csh-perspect.a007880. PMID: 23209147.27. Zhang N., Wei P., Gong A. et al. FoxM1 promotes p-catenin nuclear localization and controls wnt target-gene expression and glioma tumorigenesis. Cancer Cell 2011;20(4):427—42. DOI: 10.1016/j.ccr.2011.08.016. PMID: 22014570.Zhang N., Wei P., Gong A. et al. FoxM1 promotes p-catenin nuclear localization and controls wnt target-gene expression and glioma tumorigenesis. Cancer Cell 2011;20(4):427—42. DOI: 10.1016/j.ccr.2011.08.016. PMID: 22014570.28. Arya M., Thrasivoulou C., Henrique R. et al. Targets of Wnt/p-catenin transcription in penile carcinoma. PLoS One 2015;10(4):e0124395. DOI: 10.1371/jour-nal.pone.0124395. PMID: 25901368.Arya M., Thrasivoulou C., Henrique R. et al. Targets of Wnt/p-catenin transcription in penile carcinoma. PLoS One 2015;10(4):e0124395. DOI: 10.1371/jour-nal.pone.0124395. PMID: 25901368.29. Shu W., Guttentag S., Wang Z. et al. Wnt/ p-catenin signaling acts upstream of N-Myc, BMP4, and FGF signaling to regulate proximal-distal patterning in the lung. Develop Biol 2005;283(1):226—39. DOI: 10.1016/j.ydbio.2005.04.014. PMID: 15907834.Shu W., Guttentag S., Wang Z. et al. Wnt/ p-catenin signaling acts upstream of N-Myc, BMP4, and FGF signaling to regulate proximal-distal patterning in the lung. Develop Biol 2005;283(1):226—39. DOI: 10.1016/j.ydbio.2005.04.014. PMID: 15907834.30. Klaus A., Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer 2008;8(5):387—98. DOI: 10.1038/nrc2389. PMID: 18432252.Klaus A., Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer 2008;8(5):387—98. DOI: 10.1038/nrc2389. PMID: 18432252.31. Valenta T., Hausmann G., Basler K. The many faces and functions of p-catenin. EMBO J 2012;31(12):2714—36. DOI: 10.1038/em-boj.2012. PMID: 22617422.Valenta T., Hausmann G., Basler K. The many faces and functions of p-catenin. EMBO J 2012;31(12):2714—36. DOI: 10.1038/em-boj.2012. PMID: 22617422.32. De A. Wnt/Ca2+ signaling pathway: a brief overview. Acta Biochim Biophys Sin 2011;43(10):745—56. DOI: 10.1093/abbs/gmr079. PMID: 21903638.De A. Wnt/Ca2+ signaling pathway: a brief overview. Acta Biochim Biophys Sin 2011;43(10):745—56. DOI: 10.1093/abbs/gmr079. PMID: 21903638.33. Hogan P.G., Chen L., Nardone J., Rao A. Transcriptional regulation by calcium, cal-cineurin, and NFAT. Genes Dev 2003;17(18):2205—32. DOI: 10.1101/gad.1102703. PMID: 12975316.Hogan P.G., Chen L., Nardone J., Rao A. Transcriptional regulation by calcium, cal-cineurin, and NFAT. Genes Dev 2003;17(18):2205—32. DOI: 10.1101/gad.1102703. PMID: 12975316.34. Huang L., Jin Y., Feng S. et al. Role of Wnt/p-catenin, Wnt/c-Jun N-terminal kinase and Wnt/Ca2+ pathways in cisplat-in-induced chemoresistance in ovarian cancer. Exp Ther Med 2016;12(6):3851 —8. DOI: 10.3892/etm.2016.3885. PMID: 28101169.Huang L., Jin Y., Feng S. et al. Role of Wnt/p-catenin, Wnt/c-Jun N-terminal kinase and Wnt/Ca2+ pathways in cisplat-in-induced chemoresistance in ovarian cancer. Exp Ther Med 2016;12(6):3851 —8. DOI: 10.3892/etm.2016.3885. PMID: 28101169.35. Lopez-Escobar B., Cano D.A., Rojas A. et al. The effect of maternal diabetes on the Wnt-PCP pathway during embryogenesis as reflected in the developing mouse eye. Dis Model Mechanism 2015;8(2):157—68. DOI: 10.1242/ dmm.017723. PMID: 25540130.Lopez-Escobar B., Cano D.A., Rojas A. et al. The effect of maternal diabetes on the Wnt-PCP pathway during embryogenesis as reflected in the developing mouse eye. Dis Model Mechanism 2015;8(2):157—68. DOI: 10.1242/ dmm.017723. PMID: 25540130.36. Sparks A.B., Morin PJ., Vogelstein B., Kinzler K.W. Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer Res 1998;58(6):1130—4. PMID: 9515795.Sparks A.B., Morin PJ., Vogelstein B., Kinzler K.W. Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer Res 1998;58(6):1130—4. PMID: 9515795.37. Nikuseva-Martic T., Beros V., Pecina-Slaus N. et al. Genetic changes of CDH1, APC, and CTNNB1 found in human brain tumors. Pathol Res Pract 2007;203(11):779—87. DOI: 10.1016/j.prp.2007.07.009. PMID: 17905526.Nikuseva-Martic T., Beros V., Pecina-Slaus N. et al. Genetic changes of CDH1, APC, and CTNNB1 found in human brain tumors. Pathol Res Pract 2007;203(11):779—87. DOI: 10.1016/j.prp.2007.07.009. PMID: 17905526.38. Galuppo R., Mayanard E., Shah M. et al. Synergistic inhibition of HCC and liver cancer stem cell proliferation by targeting RAS/RAF/MAPK and WNT/p-catenin pathways. Anticancer Res 2014;34(4):1709—13. PMID: 24692700.Galuppo R., Mayanard E., Shah M. et al. Synergistic inhibition of HCC and liver cancer stem cell proliferation by targeting RAS/RAF/MAPK and WNT/p-catenin pathways. Anticancer Res 2014;34(4):1709—13. PMID: 24692700.39. Pasqualucci L., Dominguez-Sola D., Chi-arenza A. et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 2011;471(7337):189—95. DOI: 10.1038/nature09730. PMID: 21390126.Pasqualucci L., Dominguez-Sola D., Chi-arenza A. et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 2011;471(7337):189—95. DOI: 10.1038/nature09730. PMID: 21390126.40. Gotze S., Wolter M., Reifenberger G. et al. Frequent promoter hypermethylation of Wnt pathway inhibitor genes in malignant astrocytic gliomas. Int J Cancer 2010;126(11):2584—93. DOI: 10.1002/ijc.24981. PMID: 19847810.Gotze S., Wolter M., Reifenberger G. et al. Frequent promoter hypermethylation of Wnt pathway inhibitor genes in malignant astrocytic gliomas. Int J Cancer 2010;126(11):2584—93. DOI: 10.1002/ijc.24981. PMID: 19847810.41. Augustin I., Goidts V., Bongers A. et al. The Wnt secretion protein Evi/Gpr177 promotes glioma tumourigenesis. EMBO Mol Med 2012;4(1):38—51. DOI: 10.1002/emmm.201100186. PMID: 22147553.Augustin I., Goidts V., Bongers A. et al. The Wnt secretion protein Evi/Gpr177 promotes glioma tumourigenesis. EMBO Mol Med 2012;4(1):38—51. DOI: 10.1002/emmm.201100186. PMID: 22147553.42. Vassallo I., Zinn P., Lai M. et al. WIF1 reexpression in glioblastoma inhibits migration through attenuation of non-canonical WNT signaling by downregulating the ln-cRNA MALAT1. Oncogene 2016;35(1):12—21. DOI: 10.1038/onc.2015.61. PMID: 25772239.Vassallo I., Zinn P., Lai M. et al. WIF1 reexpression in glioblastoma inhibits migration through attenuation of non-canonical WNT signaling by downregulating the ln-cRNA MALAT1. Oncogene 2016;35(1):12—21. DOI: 10.1038/onc.2015.61. PMID: 25772239.43. Wickstrom M., Dyberg C., Milosevic J. et al. Wnt/p-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance. Nat Commun 2015;6:8904. DOI: 10.1038/ncomms9904. PMID: 26603103.Wickstrom M., Dyberg C., Milosevic J. et al. Wnt/p-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance. Nat Commun 2015;6:8904. DOI: 10.1038/ncomms9904. PMID: 26603103.44. Fong C.Y., Gilan O., Lam E.Y.N. et al. BET inhibitor resistance emerges from leukaemia stem cells. Nature 2015;525(7570):538—42. DOI: 10.1038/nature14888. PMID: 26367796.Fong C.Y., Gilan O., Lam E.Y.N. et al. BET inhibitor resistance emerges from leukaemia stem cells. Nature 2015;525(7570):538—42. DOI: 10.1038/nature14888. PMID: 26367796.45. Jun S., Jung Y.S., Suh H.N. et al. LIG4 mediates Wnt signalling-induced radioresistance. Nat Commun 2016;7:10994. DOI: 10.1038/ncomms10994. PMID: 27009971.Jun S., Jung Y.S., Suh H.N. et al. LIG4 mediates Wnt signalling-induced radioresistance. Nat Commun 2016;7:10994. DOI: 10.1038/ncomms10994. PMID: 27009971.46. Hong Y., Manoharan I., Suryawanshi A. et al. p-catenin promotes T regulatory cell responses in tumors by inducing vitamin A metabolism in dendritic cells. Cancer Res 2015;75(4):656—65. DOI: 10.1158/0008-5472.CAN-14-2377. PMID: 25568183.Hong Y., Manoharan I., Suryawanshi A. et al. p-catenin promotes T regulatory cell responses in tumors by inducing vitamin A metabolism in dendritic cells. Cancer Res 2015;75(4):656—65. DOI: 10.1158/0008-5472.CAN-14-2377. PMID: 25568183.47. Kaler P., Augenlicht L., Klampfer L. Macrophage-derived IL-1 p stimulates Wnt signaling and growth of colon cancer cells; a crosstalk interrupted by vitamin D3. Oncogene 2009;28(44):3892—902. DOI: 10.1038/onc.2009.247. PMID: 19701245.Kaler P., Augenlicht L., Klampfer L. Macrophage-derived IL-1 p stimulates Wnt signaling and growth of colon cancer cells; a crosstalk interrupted by vitamin D3. Oncogene 2009;28(44):3892—902. DOI: 10.1038/onc.2009.247. PMID: 19701245.48. Liu Z., Rebowe R.E., Wang Z. et al. KIF3a promotes proliferation and invasion via Wnt signaling in advanced prostate cancer. Mol Cancer Res 2.014;12(4):491—503. DOI: 10.1158/1541-7786.MCR-13-0418. PMID: 24413182.Liu Z., Rebowe R.E., Wang Z. et al. KIF3a promotes proliferation and invasion via Wnt signaling in advanced prostate cancer. Mol Cancer Res 2.014;12(4):491—503. DOI: 10.1158/1541-7786.MCR-13-0418. PMID: 24413182.49. Kwon M., Lee S.J., Wang Y. et al. Fila-min A interacting protein 1-like inhibits WNT signaling and MMP expression to suppress cancer cell invasion and metastasis. Int J Cancer 2014;135(1):48—60. DOI: 10.1002/ijc.28662. PMID: 24327474.Kwon M., Lee S.J., Wang Y. et al. Fila-min A interacting protein 1-like inhibits WNT signaling and MMP expression to suppress cancer cell invasion and metastasis. Int J Cancer 2014;135(1):48—60. DOI: 10.1002/ijc.28662. PMID: 24327474.50. Qiang L., Yang Y., Ma YJ. et al. Isolation and characterization of cancer stem like Jmj cells in human glioblastoma cell lines. Cancer Lett 2009;279(1):13—21. DOI: 10.1016/j.canlet.2009.01.016. PMID: 19232461.Qiang L., Yang Y., Ma YJ. et al. Isolation and characterization of cancer stem like Jmj cells in human glioblastoma cell lines. Cancer Lett 2009;279(1):13—21. DOI: 10.1016/j.canlet.2009.01.016. PMID: 19232461.51. Schhle R., Dictus C., Campos B. et al. Pos tential canonical Wnt pathway activation in high-grade astrocytomas. Sci World J 2012;2012:697313. DOI: 10.1100/2012/697313. PMID: 22919349.Schhle R., Dictus C., Campos B. et al. Pos tential canonical Wnt pathway activation in high-grade astrocytomas. Sci World J 2012;2012:697313. DOI: 10.1100/2012/697313. PMID: 22919349.52. Kaur N., Chettiar S., Rathod S. et al. Wnt3a mediated activation of Wnt/p-catenin signaling promotes tumor progression in glioblastoma. Mol Cell Neurosci 2013;54:44-57. DOI: 10.1016/j.mcn.2013.01.001. PMID: 23337036.Kaur N., Chettiar S., Rathod S. et al. Wnt3a mediated activation of Wnt/p-catenin signaling promotes tumor progression in glioblastoma. Mol Cell Neurosci 2013;54:44-57. DOI: 10.1016/j.mcn.2013.01.001. PMID: 23337036.53. Phillips H.S., Kharbanda S., Chen R. et al. Molecular subclasses of high grade glioma ® predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 2006;9: 157-73. DOI: 10.1016/j.ccr.2006.02.019. PMID: 16530701.Phillips H.S., Kharbanda S., Chen R. et al. Molecular subclasses of high grade glioma ® predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 2006;9: 157-73. DOI: 10.1016/j.ccr.2006.02.019. PMID: 16530701.54. Chen L., Huang K., Han L. et al. b-catenin/TCF-4 complex transcriptionally regulates AKT1 in glioma. Int J Oncol 2011;39(4):883—90. DOI: 10.3892/ijo.2011.1104. PMID: 21720709.Chen L., Huang K., Han L. et al. b-catenin/TCF-4 complex transcriptionally regulates AKT1 in glioma. Int J Oncol 2011;39(4):883—90. DOI: 10.3892/ijo.2011.1104. PMID: 21720709.55. Gong A., Huang S. FoxM1 and Wnt/b-catenin signaling in glioma stem cells. Cancer Res 2012;72:5658-62. DOI: 10.1158/0008-5472.CAN-12-0953. PMID: 23139209.Gong A., Huang S. FoxM1 and Wnt/b-catenin signaling in glioma stem cells. Cancer Res 2012;72:5658-62. DOI: 10.1158/0008-5472.CAN-12-0953. PMID: 23139209.56. Zheng H., Ying H., Wiedemeyer R. et al. PLAGL2 regulates Wnt signaling to impede differentiation in neural stem cells and gliomas. Cancer Cell 2010;17(5): 497—509. DOI: 10.1016/j.ccr.2010.03.020. PMID: 20478531.Zheng H., Ying H., Wiedemeyer R. et al. PLAGL2 regulates Wnt signaling to impede differentiation in neural stem cells and gliomas. Cancer Cell 2010;17(5): 497—509. DOI: 10.1016/j.ccr.2010.03.020. PMID: 20478531.57. Jin X., Jeon H.Y., Joo K.M. et al. Frizzled 4 regulates stemness and invasiveness of migrating glioma cells established by serial intracranial transplantation. Cancer Res 2011;71(8):3066—75. DOI: 10.1158/0008-5472.CAN-10-1495. PMID: 21363911.Jin X., Jeon H.Y., Joo K.M. et al. Frizzled 4 regulates stemness and invasiveness of migrating glioma cells established by serial intracranial transplantation. Cancer Res 2011;71(8):3066—75. DOI: 10.1158/0008-5472.CAN-10-1495. PMID: 21363911.58. Kamino M., Kishida M., Kibe T. et al. Wnt-5a signaling is correlated with infiltrative activity in human glioma by inducing cellular migration and MMP-2. Cancer Sci 2011;102(3):540—8. DOI: 10.1111/j.1349-7006.2010.01815.x. PMID: 21205070.Kamino M., Kishida M., Kibe T. et al. Wnt-5a signaling is correlated with infiltrative activity in human glioma by inducing cellular migration and MMP-2. Cancer Sci 2011;102(3):540—8. DOI: 10.1111/j.1349-7006.2010.01815.x. PMID: 21205070.59. Florian M.C., Nattamai K.J., Dorr K. et al. A canonical to non-canonical-Wnt signalling switch in haematopoietic stem-cell ageing. Nature 2013;503(7476):392—6. DOI: 10.1038/nature12631. PMID: 24141946.Florian M.C., Nattamai K.J., Dorr K. et al. A canonical to non-canonical-Wnt signalling switch in haematopoietic stem-cell ageing. Nature 2013;503(7476):392—6. DOI: 10.1038/nature12631. PMID: 24141946.60. Yu J.M., Jun E.S., Jung J.S. et al. Role of Wnt5a in the proliferation of humangli-oblastoma cells. Cancer Lett 2007;257(2):172—81. DOI: 10.1016/j.can-let.2007.07.011. PMID: 17709179.Yu J.M., Jun E.S., Jung J.S. et al. Role of Wnt5a in the proliferation of humangli-oblastoma cells. Cancer Lett 2007;257(2):172—81. DOI: 10.1016/j.can-let.2007.07.011. PMID: 17709179.61. Wu M., Guan J., Li C. et al. Aberrantly activated Cox-2 and Wnt signaling interact to maintain cancer stem cells in glioblastoma. Oncotarget 2017;8(47):82217—30. DOI: 10.18632/oncotarget.19283. PMID: 29137258.Wu M., Guan J., Li C. et al. Aberrantly activated Cox-2 and Wnt signaling interact to maintain cancer stem cells in glioblastoma. Oncotarget 2017;8(47):82217—30. DOI: 10.18632/oncotarget.19283. PMID: 29137258.62. Gao L., Chen B., Li J. et al. Wnt/p-catenin signaling pathway inhibits the proliferation and apoptosis of U87 glioma cells via different mechanisms. PLoS One 2017;12(8):e0181346. DOI: 10.1371/journal.pone.0181346. PMID: 28837560.Gao L., Chen B., Li J. et al. Wnt/p-catenin signaling pathway inhibits the proliferation and apoptosis of U87 glioma cells via different mechanisms. PLoS One 2017;12(8):e0181346. DOI: 10.1371/journal.pone.0181346. PMID: 28837560.63. Velpula K.K., Dasani V.R., Tsung A.J. et al. Regulation of glioblastoma progression by cord blood stem cells is mediated by down-regulation of cyclin D1. PLoS One 2011;6(3):e18017. DOI: 10.1371/journal.pone.0018017. PMID: 21455311.Velpula K.K., Dasani V.R., Tsung A.J. et al. Regulation of glioblastoma progression by cord blood stem cells is mediated by down-regulation of cyclin D1. PLoS One 2011;6(3):e18017. DOI: 10.1371/journal.pone.0018017. PMID: 21455311.64. Wang J., Wang H., Li Z. et al. c-Myc is required for maintenance of glioma cancer stem cells. PLoS One 2008;3(11):e3769. DOI: 10.1371/journal.pone.0003769. PMID: 19020659.Wang J., Wang H., Li Z. et al. c-Myc is required for maintenance of glioma cancer stem cells. PLoS One 2008;3(11):e3769. DOI: 10.1371/journal.pone.0003769. PMID: 19020659.65. Niu C.S., Li D.X., Liu Y.H. et al. Expression of NANOG in human gliomas and its relationship with undifferentiated glioma cells. Oncol Rep 2011;26(3):593—601. DOI: 10.3892/or.2011.1308. PMID: 21573506.Niu C.S., Li D.X., Liu Y.H. et al. Expression of NANOG in human gliomas and its relationship with undifferentiated glioma cells. Oncol Rep 2011;26(3):593—601. DOI: 10.3892/or.2011.1308. PMID: 21573506.66. Rome C., Arsaut J., Taris C. MMP-7 (matrilysin) expression in human brain tumors. Mol Carcinog 2007;46(6):446—52. DOI: 10.1002/mc.20293. PMID: 17219436.Rome C., Arsaut J., Taris C. MMP-7 (matrilysin) expression in human brain tumors. Mol Carcinog 2007;46(6):446—52. DOI: 10.1002/mc.20293. PMID: 17219436.67. Ben-Porath I., Thomson M.W., Carey V.J. et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 2008;40(5):499—507. DOI: 10.1038/ng.127. PMID: 18443585.Ben-Porath I., Thomson M.W., Carey V.J. et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 2008;40(5):499—507. DOI: 10.1038/ng.127. PMID: 18443585.68. Lin J.J., Zhao T.Z., Cai W.K. et al. Inhibition of histamine receptor 3 suppresses glioblastoma tumor growth, invasion, and epithelial-to-mesenchymal transition. Oncotarget 2015;6(19):17107—20. DOI: 10.18632/oncotarget.3672. PMID: 25940798.Lin J.J., Zhao T.Z., Cai W.K. et al. Inhibition of histamine receptor 3 suppresses glioblastoma tumor growth, invasion, and epithelial-to-mesenchymal transition. Oncotarget 2015;6(19):17107—20. DOI: 10.18632/oncotarget.3672. PMID: 25940798.69. Siebzehnrubl F.A., Silver D.J., Tugerti-mur B. et al. The ZEB1 pathway links glioblastoma initiation, invasion and chemore-sistance. EMBO Mol Med 2013;5(8):1196—212. DOI: 10.1002/emmm.201302827. PMID: 23818228.Siebzehnrubl F.A., Silver D.J., Tugerti-mur B. et al. The ZEB1 pathway links glioblastoma initiation, invasion and chemore-sistance. EMBO Mol Med 2013;5(8):1196—212. DOI: 10.1002/emmm.201302827. PMID: 23818228.70. Myung J.K., Choi S.A., Kim S.K. et al. SNAIL plays an oncogenic role in glioblastoma by promoting epithelial mesenchymal transition. Int J Clin Exp Pathol 2014;7(5):1977—87. PMID: 24966907.Myung J.K., Choi S.A., Kim S.K. et al. SNAIL plays an oncogenic role in glioblastoma by promoting epithelial mesenchymal transition. Int J Clin Exp Pathol 2014;7(5):1977—87. PMID: 24966907.71. Krossa S., Schmitt A.D., Hattermann K. et al. Down regulation of Akirin-2 increases chemosensitivity in human glioblastomas more efficiently than Twist-1. Onco-target 2015;6(25):21029—45. DOI: 10.18632/oncotarget.3763. PMID: 26036627.Krossa S., Schmitt A.D., Hattermann K. et al. Down regulation of Akirin-2 increases chemosensitivity in human glioblastomas more efficiently than Twist-1. Onco-target 2015;6(25):21029—45. DOI: 10.18632/oncotarget.3763. PMID: 26036627.72. Sharma V., Dixit D., Koul N. et al. Ras regulates interleukin-1 p-induced HIF-1a transcriptional activity in glioblastoma. J Mol Med (Berl) 2011;89(2):123—36. DOI: 10.1007/s00109-010-0683-5. PMID: 20865400.Sharma V., Dixit D., Koul N. et al. Ras regulates interleukin-1 p-induced HIF-1a transcriptional activity in glioblastoma. J Mol Med (Berl) 2011;89(2):123—36. DOI: 10.1007/s00109-010-0683-5. PMID: 20865400.73. Pyko I.V., Nakada M., Sabit H. et al. Glycogen synthase kinase 3p inhibition sensitizes human glioblastoma cells to temo-zolomide by affecting O6-methylguanine DNA methyltransferase promoter meth-ylation via c-Myc signaling. Carcinogenesis 2013;34(10):2206—17. DOI: 10.1093/carcin/bgt182. PMID: 23715499.Pyko I.V., Nakada M., Sabit H. et al. Glycogen synthase kinase 3p inhibition sensitizes human glioblastoma cells to temo-zolomide by affecting O6-methylguanine DNA methyltransferase promoter meth-ylation via c-Myc signaling. Carcinogenesis 2013;34(10):2206—17. DOI: 10.1093/carcin/bgt182. PMID: 23715499.74. Warrier S., Balu S.K., Kumar A.P. et al. Wnt antagonist, secreted frizzled-related protein 4 (sFRP4), increases chemotherapeutic response of glioma stem-like cells. Oncol Res 2013;21(2):93—102. DOI: 10.3727/096504013X13786659070154. PMID: 24406045.Warrier S., Balu S.K., Kumar A.P. et al. Wnt antagonist, secreted frizzled-related protein 4 (sFRP4), increases chemotherapeutic response of glioma stem-like cells. Oncol Res 2013;21(2):93—102. DOI: 10.3727/096504013X13786659070154. PMID: 24406045.75. Kahlert U.D., Suwala A.K., Koch K. et al. Pharmacological WNT inhibition reduces proliferation, survival and clonogenicity of glioblastoma cells. J Neuropathol Exp Neurol 2015;74(9):889—900. DOI: 10.1097/NEN.0000000000000227. PMID: 2622250.Kahlert U.D., Suwala A.K., Koch K. et al. Pharmacological WNT inhibition reduces proliferation, survival and clonogenicity of glioblastoma cells. J Neuropathol Exp Neurol 2015;74(9):889—900. DOI: 10.1097/NEN.0000000000000227. PMID: 2622250.76. Dong Z., Zhou L., Han N. et al. Wnt/p-catenin pathway involvement in ionizing radiation-induced invasion of U87 glioblastoma cells. Strahlenther Onkol 2015;191(8):672—80. DOI: 10.1007/s00066-015-0858-7. PMID: 26072169.Dong Z., Zhou L., Han N. et al. Wnt/p-catenin pathway involvement in ionizing radiation-induced invasion of U87 glioblastoma cells. Strahlenther Onkol 2015;191(8):672—80. DOI: 10.1007/s00066-015-0858-7. PMID: 26072169.77. Dijksterhuis J.P., Arthofer E., Marinescu V.D. et al. High levels of WNT-5A in human glioma correlate with increased presence of tumor-associated microglia/monocytes. Exp Cell Res 2015;339(2):280—8. DOI: 10.1016/j.yexcr.2015.10.022. PMID: 26511503.Dijksterhuis J.P., Arthofer E., Marinescu V.D. et al. High levels of WNT-5A in human glioma correlate with increased presence of tumor-associated microglia/monocytes. Exp Cell Res 2015;339(2):280—8. DOI: 10.1016/j.yexcr.2015.10.022. PMID: 26511503.78. Lee Y., Lee J.K., Ahn S.H. et al. WNT signaling in glioblastoma and therapeutic opportunities. Lab Invest 2016;96(2):137—50. DOI: 10.1038/labinvest.2015.140. PMID: 26641068.Lee Y., Lee J.K., Ahn S.H. et al. WNT signaling in glioblastoma and therapeutic opportunities. Lab Invest 2016;96(2):137—50. DOI: 10.1038/labinvest.2015.140. PMID: 26641068.