THE ROLE AND MECHANISMS OF EPITHELIAL-MESENCHYMAL TRANSITION IN THE PROGRESSION OF MELANOMA

Despite the achievements of modern medicine in the diagnosis and treatment of oncological diseases, skin melanoma remains one of the leading causes of death worldwide: every third case of melanoma ends in death. As you know, one of the main causes of death is the high incidence of melanoma progression. It is important to note that the mechanisms of melanoma progression are diverse and the rapidly developing area of drug therapy for tumors requires a deep understanding of their characteristics. This is primarily due to the fact that these processes lead to the formation of special, minor tumor clones with stem properties. They are highly resistant to therapy. The latter is the mainobstacle to effective treatment of melanoma patients. The epithelial-mesenchymal transition (EMT) plays a leading role in the acquisition of metastatic potential by melanoma cells. An important distinguishing feature of EMT is a change in the level of expression of transmembrane glycoproteins involved in cell adhesion. With EMT, both a decrease in the level of E-cadherin and an increase in the expression of N-cadherin are observed. Such a switch in different classes of adhesion molecules leads to the fact that melanoma cells lose contact with neighboring keratinocytes and begin to interact with fibroblasts and endothelial cells. The key regulator in EMT induction in melanoma is the Notch1 signaling pathway, which accelerates N-cadherin expression when activated. In addition, EMT also regulates many other pathways – RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, Wnt/β-catenin, the dysregulation of which is associated with the development of drug resistance in melanoma. The analysis was carried out in the article of modern literature data on the importance of EMT in carcinogenesis and prognosis of melanoma. The modern mechanisms of EMT, currently known prognostic factors, as well as potential therapeutic targets that affect EMT and, accordingly, inhibit the process of metastasis, are described in detail.

1. Siegel R.L., Miller K.D., Jemal A. Сancer Statistics, 2019. CA Cancer J Clin 2019;69:7.

2. Kaprin A.D., Starinsky V.V., Petrova G.V. Malignant neoplasms in Russia in 2018 (morbidity and mortality). Moscow: FGBU “MNIOI im. P.A. Gertsena” Ministry of Health of Russia, 2019. 250 р. (In Russ.)

3. DeVita V.T., Rosenbergs S.A., Lawrence T.S. Cancer: Principles and Practice of Oncology, 11th edition. Wolters Kluwer, 2018. 1346 р.

4. Nieto M.A., Huang R.Y.J., Jackson R.A., Thiery J.P. EMT: 2016. Cell 2016;166:21–45. DOI: 10.1016/j.cell.2016.06.028.

5. Lambert A.W., Pattabiraman D.R., Weinberg R.A. Emerging Biological Principles of Metastasis. Cell 2017;168:670–91. DOI: 10.1016/j.cell.2016.11.037.

6. Moustakas A., de Herreros A.G. Epithelial-mesenchymal transition in cancer. Mol Oncol 2017;11:715–7. DOI: 10.1002/1878-0261.12094.

7. Jolly M.K., Boareto M., Huang B. et al. Implications of the Hybrid Epithelial/ Mesenchymal Phenotype in Metastasis. Front Oncol 2015;5:155. DOI: 10.3389/fonc.2015.00155.

8. De Craene B., Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 2013;13:97–110. DOI: 10.1038/nrc3447.

9. Sanders D.S., Blessing K., Hassan G.A. et al. Alterations in cadherin and catenin expression during the biological progression of melanocytic tumours. Mol Pathol 1999;52(3):151–7. DOI: 10.1136/mp.52.3.151.

10. Kreizenbeck G.M., Berger A.J., Subtil A. et al. Prognostic significance of cadherin-based adhesion molecules in cutaneous malignant melanoma. Cancer Epidemiol Biomarkers Prev 2008;17(4):949–58. DOI: 10.1158/1055-9965.EPI-07-2729.

11. Micalizzi D.S., Farabaugh S.M., Heide L.F. Epithelial-Mesenchymal Transition in Cancer: Parallels Between Normal Development and Tumor Progression. J Mammary Gland Biol Neoplasia 2020;15(2):117–34. DOI: 10.1007/s10911-010-9178-9.

12. Lamouille S., Xu J., Derynck R. Molecular mechanisms of epithelialmesenchymal transition. Nat Rev Mol Cell Biol 2014;15(3):178–96. DOI: 10.1038/nrm3758.

13. Sistigu A., Di Modugno F., Manic G., Nisticò P. Deciphering the loop of epithelial-mesenchymal transition, inflammatory cytokines and cancer immunoediting. Cytokine & Growth Factor Reviews 2017;36:67–77. DOI: 10.1016/j.cytogfr.2017.05.008.

14. Marcucci F., Stassi G., De Maria R. Epithelial-mesenchymal transition: a new target in anticancer drug discovery. Nat Rev Drug Discov 2016;15:311–25. DOI: 10.1038/nrd.2015.13.

15. Moriyama M., Osawa M., Mak S.S. et al. Notch signaling via Hes1 transcription factor maintains survival of melanoblasts and melanocyte stem cells. J Cell Biol 2006;173:333–9. DOI: 1083/jcb.200509084.

16. Chulkova S.V., Markina I.G., Chernysheva O.A. et al. The role of stem tumor cells in the development of drug resistance of melanoma. Rossiyskiy bioterapevticheskiy zhurnal = Russian Journal of Biotherapy 2019;18(2):6–14. (In Russ.).

17. Kaushik G., Venugopal A., Ramamoorthy P. et al. Honokiol inhibits melanoma stem cells by targeting notch signaling. Mol Carcinog 2015;54(12):1710–21. DOI: 10.1002/mc.22242.

18. Hsu M.Y., Meier F.E., Nesbit M. et al. E-cadherin expression in melanoma cells restores keratinocyte-mediated growth control and down-regulates expression of invasion-related adhesion receptors. Am J Pathol 2000;156(5):1515–25. DOI: 10.1016/S0002-9440(10)65023-7.

19. Li G., Satyamoorthy K., Herlyn M. N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells. Cancer Res 2001; 61(9):3819–25. PMID: 11325858.

20. Kim J.E., Leung E., Baguley B.C., Finlay G.J. Heterogeneity of expression of epithelial-mesenchymal transition markers in melanocytes and melanoma cell lines. Front Genet 2013;4:97. DOI: 10.3389/fgene.2013.00097.

21. Mikesh L.M., Kumar M., Erdag G. et al. Evaluation of molecular markers of mesenchymal phenotype in melanoma. Melanoma Res 2010;20(6):485–95. DOI: 10.1097/CMR.0b013e32833fafb4.

22. Barrallo-Gimeno A., Nieto M.A. The SNAIL genes as inducers of cell movement and survival: implications in development and cancer. Development 2005;132(14):3151–61. DOI: 10.1242/dev.01907.

23. Sakamoto K., Imanishi Y., Tomita T. et al. Overexpression of SIP1 and downregulation of E-cadherin predict delayed neck metastasis in stage I/II oral tongue squamous cell carcinoma after partial glossectomy. Ann Surg Oncol 2012;19(2):612–9. DOI: 10.1245/s10434-011-2052-1.

24. Hazan R.B., Phillips G.R., Qiao R.F. et al. Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis. J Cell Biol 2000;148(4):779–90. DOI: 10.1083/jcb.148.4.779.

25. Silye R., Karayiannakis A.J., Syrigos K.N. et al. E-cadherin/catenin complex in benign and malignant melanocytic lesions. J Pathol 1998;186(4): 350–5. DOI: 10.1002/(SICI)1096-9896(199812)186:4<350::AIDPATH181>3.0.CO;2-K.

26. Valencak J., Kittler H., Schmid K. et al. Prognostic relevance of hypoxia inducible factor-1alpha expression in patients with melanoma. Clin Exp Dermatol 2009;34(8):e962–4. DOI: 10.1111/j.1365-2230.2009.03706.x.

27. Massoumi R., Kuphal S., Hellerbrand C. et al. Down-regulation of CYLD expression by SNAIL promotes tumor progression in malignant melanoma. J Exp Med 2009;206(1):221–32. DOI: 10.1084/jem.20082044.

28. Mitchell B., Leone D.A., Feller J.K. et al. BRAF and epithelial-mesenchymal transition in primary cutaneous melanoma: a role for SNAIL and E-cadherin? Hum Pathol 2016;52:19–27. DOI: 10.1016/j.humpath.2015.12.030.

29. Guo Q., Zhao Y., Chen J. et al. BRAF-activated long non-coding RNA contributes to colorectal cancer migration by inducing epithelialmesenchymal transition. Oncol Lett 2014;8(2):869–75. DOI: 10.3892/ol.2014.2154.

30. Tucci M.G., Lucarini G., Brancorsini D. et al. Involvement of E-cadherin, betacatenin, Cdc42 and CXCR4 in the progression and prognosis of cutaneous melanoma. Br J Dermatol 2007;157(6):1212–6. DOI: 10.1111/j.1365-2133.2007.08246.x.

31. Bachmann I.M., Straume O., Puntervoll H.E. et al. Importance of P-cadherin, beta-catenin, and Wnt5a/frizzled for progression of melanocytic tumors and prognosis in cutaneous melanoma. Clin Cancer Res 2005;11(24 Pt 1):8606–14. DOI: 10.1158/1078-0432.CCR-05-0011.

32. Yan Sh., Holderness B.M., Li Zh. et al. Epithelial-Mesenchymal Expression Phenotype of Primary Melanoma and Matched Metastases and Relationship with Overall Survival. Anticancer Res 2016;36(12):6449–56. DOI: 10.21873/anticanres.11243. PMID: 27919967.

33. Nishizawa A., Nakanishi Y., Yoshimura K. et al. Clinicopathologic significance of dysadherin expression in cutaneous malignant melanoma: immunohistochemical analysis of 115 patients. Cancer 2005;103(8):1693–700. DOI: 10.1002/cncr.20984.

34. Chulkova S.V., Markina I.G., Antipova A.S. et al. Role of stem tumor cells in carcinogenesis and prognosis of melanoma. Vestnik Rossiyskogo nauchnogo centra rentgenoradiologii = Bulletin of the Russian scientific center of roentgenology and radiology 2018;18(4):100–6. (In Russ.).

35. Ding Q., Miyazaki Y., Tsukasa K. et al. CD133 facilitates epithelial-mesenchymal transition through interaction with the ERK pathway in pancreatic cancer metastasis. Mol Cancer 2014; 13:15. DOI: 10.1186/1476-4598-13-15.

36. Moon Y., Kim D., Sohn H., Lim W. Effect of CD133 overexpression on the epithelial-to-mesenchymal transition in oral cancer cell lines. Clin Exp Metastasis 2016;33(5):487–96. DOI: 10.1007/s10585-016-9793-y.

37. Lo J.F., Yu C.C., Chiou S.H. et al. The epithelial-mesenchymal transition mediator S100A4 maintains cancerinitiating cells in head and neck cancers. Cancer Res 2011;71(5):1912–23. DOI: 10.1158/0008-5472.CAN-10-2350.

38. Morel A.P., Lièvre M., Thomas C. et al. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One 2008;3(8):e2888. DOI: 10.1371/journal.pone.0002888.

39. Mani S.A., Guo W., Liao M.J. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008;133(4):704–15. DOI: 10.1016/j.cell.2008.03.027.

40. Kumar D., Kumar S., Gorain M. et al. Notch1-MAPK signaling axis regulates CD133+ cancer stem cell-mediated melanoma growth and angiogenesis. J Invest Dermatol 2016;136(12):2462–74. DOI: 10.1016/j.jid.2016.07.024.

41. Yao J., Caballero O.L., Huang Y. et al. Altered expression and splicing of ESRP1 in malignant melanoma correlates with epithelial-mesenchymal status and tumor-associated immune cytolytic activity. Cancer Immunol Res 2016;4(6):552–61. DOI: 10.1158/2326-6066.cir-15-0255.

42. Richard G., Puisieux A., Caramel J. Antagonistic functions of EMT-inducers in melanoma development: implications for cancer cell plasticity. Cancer Cell Microenviron 2014;1(1):e61. DOI: 10.14800/ccm.61.

43. Wels C., Joshi S., Koefinger P. et al. Transcriptional activation of ZEB1 by Slug leads to cooperative regulation of the epithelial-mesenchymal transition-like phenotype in melanoma. J Invest Dermatol 2011;131(9):1877–85. DOI: 10.1038/jid.2011.142.

44. Zhao F., He X., Wang Y. et al. Decrease of ZEB1 expression inhibits the B16F10 cancer stem-like properties. Biosci Trends 2015;9(5):325–34. DOI: 10.5582/bst.2015.01106.

45. Asnaghi L., Gezgin G., Tripathy A. et al. EMT-associated factors promote invasive properties of uveal melanoma cells. Mol Vis 2015;21:919–29. PMID: 26321866.

46. Perrot C.Y., Gilbert C., Marsaud V. et al. GLI2 cooperates with ZEB1 for transcriptional repression of CDH1 expression in human melanoma cells. Pigment Cell Melanoma Res 2013;26(6): 861–73. DOI: 10.1111/pcmr.12149.

47. Hui C.C., Angers S. Gli proteins in development and disease. Annu Rev Cell Dev Biol 2011;27:513–37. DOI: 10.1146/annurevcellbio-092910-154048.

48. Denecker G., Vandamme N., Akay O. et al. Identification of a ZEB2-MITFZEB1 transcriptional network that controls melanogenesis and melanoma progression. Cell Death Differ 2014;21(8):1250–61. DOI: 10.1038/cdd.2014.44.

49. Tian L., Li L., Xing W. et al. IRGM1 enhances B16 melanoma cell metastasis through PI3K-Rac1 mediated epithelial mesenchymal transition. Sci Rep 2015;5:12357. DOI: 10.1038/srep12357.

50. Taddei 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;12:24. DOI: 10.1186/1478-811X-12-24.

51. Schlegel N.C., von Planta A., Widmer D.S. et al. PI3K signalling is required for a TGFβ-induced epithelial-mesenchymal-like transition (EMT-like) in human melanoma cells. Exp Dermatol 2015;24(1):22–8. DOI: 10.1371/journal.pone.0049419.

52. Cantelli G., Orgaz J.L., RodriguezHernandez I. et al. TGF-β-induced transcription sustains amoeboid melanoma migration and dissemination. Curr Biol 2015;25(22):2899–914. DOI: 10.1016/j.cub.2015.09.054.

53. Peppicelli S., Bianchini F., Torre E., Calorini L. Contribution of acidic melanoma cells undergoing epithelialto-mesenchymal transition to aggressiveness of non-acidic melanoma cells. Clin Exp Metastasis 2014;31(4):423–33. DOI: 10.1007/s10585-014-9637-6.