Transición epitelio mesénquima: de lo molecular a lo fisiológico
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oct 19, 2017
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Resumen
La transición epitelio mesénquima (EMT) es un proceso compuesto de diferentes fases, donde una célula epitelial adquiere un fenotipo mesenquimal. Dentro de los cambios involucrados se encuentran: pérdida de la polaridad celular, adquisición de una capacidad migratoria, capacidad invasora, resistencia a la apoptosis y aumento en la producción de componentes de la matriz extracelular. Todos estos cambios ocurren como una consecuencia de la activación y represión de genes involucrados con rutas de señalización específicas relacionadas con este evento. La EMT está relacionada con procesos fisiológicos y patológicos como el cáncer. Consta de tres fases: una de células no migratorias, células premigratorias y células migratorias; cada una de ellas producto de diferentes señales intra o extracelulares, factores de transcripción (TGF-B, Snail, TWIST, Sox, Slug, ZEB1, entre otras) y proteínas involucradas (E-cadherina, integrina, vimentina, ocludinas y claudinas).
Keywords
transition, epithelial, mesenchymal, physiological, pathological, transcription factorstransición, epitelial, mesenquimal, fisiológicos, patológicos, factores de transcripción
References
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17. Juliano RL. Signal transduction by cell adhesion receptors and the cytoskeleton: functions of integrins, cadherins, selectins, and immunoglobulin-superfamily members. Annu Rev Pharmacol Toxicol. 2002;42:283-323.
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19. Prindull G. Environmental guidance of normal and tumor cell plasticity: epithelial mesenchymal transitions as a paradigm. Blood. 2004;103(8):2892-9.
20. Nieto M. The ins and outs of the epithelial to mesenchymal transition in health and disease. Ann Rev Cell Dev Biol. 2001;27(1):347-76.
21. Ochoa AB, Juárez CI, Rosales MA, Barros P. La vía de señalización Wnt-B-catenina y su relación con cáncer. Cir Cir. 2012;80:389-98.
22. Weinberg RA. The biology of cancer. 2a ed. s. l.:Garland Science; 2013.
23. Xu J, Lamouille S, Derynck R. TGF-β-induced epithelial to mesenchymal transition. Cell Res. 2009;19(2):156-72.
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25. Valcourt U, Kowanetz M, Niimi H, Heldin CH, Moustakas A. TGF-β and the smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell. 2005;16(4):1987-2002.
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30. Niu R, Zhang L, Xi G, et al. Up-regulation of Twist induces angiogenesis and correlates with metastasis in hepatocellular carcinoma. J Exp Clin Cancer Res. 2007;26:385-94.
31. Heerboth S, Housman G, Leary M. EMT and tumor metastasis. Clin Trans Med. 2015;4:6.
32. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 2009;119:1429-37.
33. Van Aelst L, Symons M. Rho family GTPases in epithelial morphogenesis. Genes Dev. 2002;16:1032-54.
34. Tsai J, Yang J. Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev. 2013;27:2192-2206.
35. Radisky DC, Levy DD, Littlepage LE, et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 2005;436:123-7.
36. Zhao X, Yu D, Yang J, Xue K, Liu Y, Jin C. Knockdown of Snail inhibits epithelial-mesenchymal transition of human laryngeal squamous cell carcinoma Hep-2 cells through VDR signaling pathway. Biochem Cell Biol. 2017. doi: 10.1139/bcb-2017-0039
37. Li H, Zhong A, Li S, Meng X, Wang X, Xu F, Lai M. The integrated pathway of TGFβ/Snail with TNFα/NFκB may facilitate the tumor-stroma interaction in the EMT process and colorectal cancer prognosis. Sci Rep. 2017;7(1):4915.
38. Hajra KM, Y-S D, Fearon C, Fearon ER. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res. 2002;2(6);1613-8.
39. Turner FE, Broad S, Khanim FL, Jeanes A, Talma S, Hughes S, Tselepis C, Hotchin NA. Slug regulates integrin expression and cell proliferation in human epidermal keratinocytes. J Biol Chem. 2006;281:21321-31.
40. Gemmill RM, Roche J, Potiron VA, Nasarre P, Mitas M, Coldren CD. Drabkin HA. ZEB1-responsive genes in non-small cell lung cancer. Cancer Lett. 2011;300:66-78.
41. Lazarova D, Bordonaro M. ZEB1 Mediates drug resistance and EMT in p300-deficient CRC. J Cancer. 2017;8:1453-9.
42. Kurahara H, Takao S, Maemura K, Mataki Y, Kuwahata T, Maeda K, et al. Epithelial-mesenchymal transition and mesenchymal-epithelial transition via regulation of ZEB-1 and ZEB-2 expression in pancreatic cancer. J Surg Oncol. 2012;105:655-61.
43. Gao Y, Li W, Liu R, Guo Q, Li J, Bao Y, et al. Norcantharidin inhibits IL-6-induced epithelial‑mesenchymal transition via the JAK2/STAT3/TWIST signaling pathway in hepatocellular carcinoma cells. Oncol Rep. 2017;38(2):1224-32.
44. Doggett K, Turkel N, Willoughby LF, Ellul J, Murray MJ, Richardson HE, Brumby AM. BTB-zinc finger oncogenes are required for Ras and notch-driven tumorigenesis in drosophila. PLoS ONE. 2015;10:e0132987
45. Nobes CD, Hall A. Rho GTPases control polarity, protrusion, and adhesion during cell movement. J Cell Biol. 1999;144(6):1235-44.
46. Hitomi M, Stacey D. Cyclin D1 production in cycling cells depends on Ras in a cell-cycle-specific manner. Curr Biol. 1999;9:1075-84.
47. Zuccarini M, Giuliani P, Buccella S, Di Liberto V, Mudò G, Belluardo N, Carluccio M, et al. Modulation of the TGF-β1-induced epithelial to mesenchymal transition (EMT) mediated by P1 and P2 purine receptors in MDCK cells. Purinergic Signal. 2017;13:1-14.
48. Zhang W, Liu H. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res, 2002;12(1):9-18.
49. DeBerardinis R, Lum J, Hatzivassiliou G, Thompson C. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metabolism, 2008;7:11-20.
50. Poser S. Impey S, Trinh K, Xia Z, Storm DR. SRF-dependent gene expression is required for PI3-kinase-regulated cell proliferation. EMBO J. 2000;19(18):4955-66.
2. Greenburg G, Hay ED. Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J Cell Biol. 1982;95:333-9.
3. Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006;172:973-81.
4. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420-8.
5. Dianbo Y, Chaoliu D, Songlin P. Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res. 2011;9(12):1608-20.
6. Yulong S, Xiqiang C, Daiming F. Roles of epithelial-mesenchymal transition in cancer drug resistance. Curr Cancer Drug Targets. 2013;13(9):915-29.
7. Montenegro MA, Rojas MA. Transformación epitelio-mesenquimática durante el desarrollo embrionario. Rev Chil Anat. 2001;19(3):301-10.
8. Moreno MA, Ramírez J, Medina S. Transición de epitelio-mesénquima y migración celular en células de la cresta neural y células metastásicas de carcinomas: revisión de la literatura. Univ Med. 2016;57(1):83-107.
9. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178-96.
10. Sato R, Semba T, Saya H, Arima Y. Concise review: Stem cells and epithelial-mesenchymal transition in cancer: Biological implications and therapeutic targets. Stem Cells. 2016;34:1997-2007.
11. Royer C, Lu X. Epithelial cell polarity: a major gatekeeper against cancer? Cell Death Differ. 2011;18(9):1470-7.
12. Huang RY, Guilford P, Thiery JP. Early events in cell adhesion
and polarity during epithelial-mesenchymal transition. J Cell Sci. 2012;125:4417-22.
13. Zúñiga L, Freyre S, Navia C, Saavedra S. Adhesión celular: el ensamblaje de la vía al cáncer. Morfolia. 2014;6(2):3-19.
14. Dietmar V. Cadherins in tissue architecture and disease. J Mol Med. 2015;93:5-11.
15. Yamada S, Pokutta S, Drees F, Weis WI, Nelson WJ. Deconstructing the cadherin-catenin-actin complex. Cell. 2005;123:889-901.
16. Yilmaz M, Christofori G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 2009;28(1-2):15-33.
17. Juliano RL. Signal transduction by cell adhesion receptors and the cytoskeleton: functions of integrins, cadherins, selectins, and immunoglobulin-superfamily members. Annu Rev Pharmacol Toxicol. 2002;42:283-323.
18. Zaidel-Bar R, Geiger B. The switchable integrin adhesome. J. Cell Sci. 2010;123:1385-8.
19. Prindull G. Environmental guidance of normal and tumor cell plasticity: epithelial mesenchymal transitions as a paradigm. Blood. 2004;103(8):2892-9.
20. Nieto M. The ins and outs of the epithelial to mesenchymal transition in health and disease. Ann Rev Cell Dev Biol. 2001;27(1):347-76.
21. Ochoa AB, Juárez CI, Rosales MA, Barros P. La vía de señalización Wnt-B-catenina y su relación con cáncer. Cir Cir. 2012;80:389-98.
22. Weinberg RA. The biology of cancer. 2a ed. s. l.:Garland Science; 2013.
23. Xu J, Lamouille S, Derynck R. TGF-β-induced epithelial to mesenchymal transition. Cell Res. 2009;19(2):156-72.
24. Mamuya FA, Duncan MK. aV integrins and TGF-β-induced EMT: a circle of regulation. J Cell Mol Med. 2012;16(3):445-455.
25. Valcourt U, Kowanetz M, Niimi H, Heldin CH, Moustakas A. TGF-β and the smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell. 2005;16(4):1987-2002.
26. Francí C, Takkunen M, Dave N, et al. Expression of Snail protein in tumor-stroma interface. Oncogene. 2006;25:5134-44.
27. Postigo A. Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway. EMBO J. 2003;22(10):2443-52.
28. Moustakas A, Heldin CH. Mechanisms of TGFβ-induced epithelial-mesenchymal transition. J Clin Med 2016;5(7):63.
29. Bilder D, Perrimon N. Localization of apical epithelial determinants by the basolateral PDZ protein Scribble. Nature. 1999;403:676-80.
30. Niu R, Zhang L, Xi G, et al. Up-regulation of Twist induces angiogenesis and correlates with metastasis in hepatocellular carcinoma. J Exp Clin Cancer Res. 2007;26:385-94.
31. Heerboth S, Housman G, Leary M. EMT and tumor metastasis. Clin Trans Med. 2015;4:6.
32. Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 2009;119:1429-37.
33. Van Aelst L, Symons M. Rho family GTPases in epithelial morphogenesis. Genes Dev. 2002;16:1032-54.
34. Tsai J, Yang J. Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev. 2013;27:2192-2206.
35. Radisky DC, Levy DD, Littlepage LE, et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 2005;436:123-7.
36. Zhao X, Yu D, Yang J, Xue K, Liu Y, Jin C. Knockdown of Snail inhibits epithelial-mesenchymal transition of human laryngeal squamous cell carcinoma Hep-2 cells through VDR signaling pathway. Biochem Cell Biol. 2017. doi: 10.1139/bcb-2017-0039
37. Li H, Zhong A, Li S, Meng X, Wang X, Xu F, Lai M. The integrated pathway of TGFβ/Snail with TNFα/NFκB may facilitate the tumor-stroma interaction in the EMT process and colorectal cancer prognosis. Sci Rep. 2017;7(1):4915.
38. Hajra KM, Y-S D, Fearon C, Fearon ER. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res. 2002;2(6);1613-8.
39. Turner FE, Broad S, Khanim FL, Jeanes A, Talma S, Hughes S, Tselepis C, Hotchin NA. Slug regulates integrin expression and cell proliferation in human epidermal keratinocytes. J Biol Chem. 2006;281:21321-31.
40. Gemmill RM, Roche J, Potiron VA, Nasarre P, Mitas M, Coldren CD. Drabkin HA. ZEB1-responsive genes in non-small cell lung cancer. Cancer Lett. 2011;300:66-78.
41. Lazarova D, Bordonaro M. ZEB1 Mediates drug resistance and EMT in p300-deficient CRC. J Cancer. 2017;8:1453-9.
42. Kurahara H, Takao S, Maemura K, Mataki Y, Kuwahata T, Maeda K, et al. Epithelial-mesenchymal transition and mesenchymal-epithelial transition via regulation of ZEB-1 and ZEB-2 expression in pancreatic cancer. J Surg Oncol. 2012;105:655-61.
43. Gao Y, Li W, Liu R, Guo Q, Li J, Bao Y, et al. Norcantharidin inhibits IL-6-induced epithelial‑mesenchymal transition via the JAK2/STAT3/TWIST signaling pathway in hepatocellular carcinoma cells. Oncol Rep. 2017;38(2):1224-32.
44. Doggett K, Turkel N, Willoughby LF, Ellul J, Murray MJ, Richardson HE, Brumby AM. BTB-zinc finger oncogenes are required for Ras and notch-driven tumorigenesis in drosophila. PLoS ONE. 2015;10:e0132987
45. Nobes CD, Hall A. Rho GTPases control polarity, protrusion, and adhesion during cell movement. J Cell Biol. 1999;144(6):1235-44.
46. Hitomi M, Stacey D. Cyclin D1 production in cycling cells depends on Ras in a cell-cycle-specific manner. Curr Biol. 1999;9:1075-84.
47. Zuccarini M, Giuliani P, Buccella S, Di Liberto V, Mudò G, Belluardo N, Carluccio M, et al. Modulation of the TGF-β1-induced epithelial to mesenchymal transition (EMT) mediated by P1 and P2 purine receptors in MDCK cells. Purinergic Signal. 2017;13:1-14.
48. Zhang W, Liu H. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res, 2002;12(1):9-18.
49. DeBerardinis R, Lum J, Hatzivassiliou G, Thompson C. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metabolism, 2008;7:11-20.
50. Poser S. Impey S, Trinh K, Xia Z, Storm DR. SRF-dependent gene expression is required for PI3-kinase-regulated cell proliferation. EMBO J. 2000;19(18):4955-66.
Cómo citar
Troncoso, D., Madariaga Perpiñan, I., Aldana Mancera, S. A., Herreño Pachón, A. M., Chaparro Ramírez, V. P., Molina Camargo, M. L., Rey Vargas, L., Ramírez Rodríguez, A. C., Montoya Estupiñan, C. F., Valderrama Álvarez, A., Cañas Arboleda, A., & Rojas Moreno, A. P. (2017). Transición epitelio mesénquima: de lo molecular a lo fisiológico. Universitas Medica, 58(4). https://doi.org/10.11144/Javeriana.umed58-4.temm
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