Abstract
Epithelial-mesenchymal transition (EMT) is a complex process in which epithelial cells acquire the characteristics of invasive mesenchymal cells. EMT has been implicated in cancer progression and metastasis as well as the formation of many tissues and organs during development. Epithelial cells undergoing EMT lose cell-cell adhesion structures and polarity, and rearrange their cytoskeletons. Several oncogenic pathways such as transforming growth factor (TGF)-β, Wnt, and Notch signaling pathways, have been shown to induce EMT. These pathways have activated transcription factors including Snail, Slug, and the ZEB family which work as transcriptional repressors of E-cadherin, thereby making epithelial cells motile and resistant to apoptosis. Mounting evidence shows that EMT is associated with cell invasion and tumor progression. In this review, we summarize the characteristic features of EMT, pathways leading to EMT, and the role of EMT in cell invasion. Three topics are addressed in this review: (1) Definition of EMT, (2) Signaling pathways leading to EMT, (3) Role of EMT in cell invasion. Understanding the role of EMT in cell invasion will provide valuable information for establishing strategies to develop anti-metastatic therapeutics which modulate malignant cellular processes mediated by EMT.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Abbreviations
- EMT:
-
(Epithelial-mesenchymal transition)
- TGF-β:
-
(Transforming growth factor P)
- MMP:
-
(Matrix metalloproteinase)
- ECM:
-
(Extracellular matrix)
- MAPK:
-
(mitogen-activated protein kinase)
- miRNA/miR:
-
(microRNA)
References
Adam, L., Zhong, M., Choi, W., Qi, W., Nicoloso, M., Arora, A., Calin, G., Wang, H., Siefker-Radtke, A., McConkey, D., Bar-Eli, M. and Dinney, C. (2009) miR-200 expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growth factor receptor therapy. Clinical Cancer Research, 15, 5060–5072.
Akiyoshi, S., Inoue, H., Hanai, J., Kusanagi, K., Nemoto, N., Miyazono, K. and Kawabata, M. (1999) c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with smads. J. Biol. Chem., 274, 35269–35277.
Bakin, A.V., Rinehart, C., Tomlinson, A.K. and Arteaga, C.L. (2002) p38 mitogen-activated protein kinase is required for TGF[5-mediated fibroblastic transdifferentiation and cell migration. J.CellSci., 115, 3193–3206.
Bakin, A.V., Tomlinsos, A.K., Bhowmick, N.A., Moses, H.L. and Arteaga, C.L. (2000) Phosphatidylinositol 3-kinase function is required for transforming growth factor-a-mediated epithelial to mesenchymal transition and cell migration. J. Biol. Chem., 275, 36803–36810.
Balkwill, F. (2004) Cancer and the chemokine network. Nat. Rev. Cancer, 4, 540–550.
Batlle, E., Sancho, E., Franci, C., Dominguez, D., Monfar, M., Baulida, J. and Garcia De Herreros, A. (2000) The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat. Cell. Biol, 2, 84–89.
Boyer, B., Valles, A.M. and Edme, N. (2000) Induction and regulation of epithelial-mesenchymal transitions. Biochem. Pharmacol, 60, 1091–1099.
Brabletz, T., Hlubek, E., Spaderna, S., Schmalhofer, O., Hiendlm-eyer, E., Jung, A. and Kirchner T. (2005) Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin. Cells Tissues Organs, 179, 56–65.
Brabletz, T., Jung, A., Reu, S., Porzner, M., Hlubek, F., Kunz-Schughart, L.A., Knuechel, R. and Kirchner, T. (2001) Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc. Natl. Acad.Sci., 98, 10356–10361.
Cano, A., Perez-Moreno, M.A., Rodrigo, I., Locascio, A., Blanco, M.J., del Barrio, M.G, Portillo, F. and Nieto, M.A. (2000) The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat. Cell Biol., 2, 76–83.
Christiansen, J.J. and Rajasekaran, A.K. (2006) Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res., 66, 8319–8326.
Christofori, G. (2006) New signals from the invasive front. Nature, 441, 444–450.
Comijn, J., Berx, G., Vermassen, P., Verschueren, K., van Grunsven, L., Bruyneel, E., Mareel, M., Huylebroeck, D. and van Roy, F. (2001) The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol. Cell, 7, 1267–1278.
Conacci-Sorrell, M., Simcha, I., Ben-Yedidia, T., Blechman, J., Savagner, P. and Ben-Ze’ev, A. (2003) Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK. J. Cell Biol, 163, 847–857.
Cordon-Cardo, C. and Prives, C. (1999) At the crossroads of inflammation and tumorigenesis. J. Exp. Med., 190, 1367–1370.
Davies, M., Robinson, M., Smith, E., Huntley, S., Prime, S. and Paterson, I. (2005) Induction of an epithelial to mesenchymal transition in human immortal and malignant keratinocytes by TGF-betal involves MAPK, Smad and AP-1 signalling pathways. J. Cell Biochem., 95, 918–931.
Derynck, R. and Zhang, Y.E. (2003) Smad-dependent and Smad-independent pathways in TGF-b family signalling. Nature, 425, 577–584.
Duong, T.D. and Erickson, C.A. (2004) MMP-2 plays an essential role in producing epithelial-mesenchymal transformations in the avian embryo. Dev. Dyn., 229, 42–53.
Feng, X.H. and Derynck, R. (2005) Specificity and versatility in TGF-beta signaling through Smads. Annu. Rev. Cell Dev. Biol., 21, 659–693.
Ghoul, A., Serova, M., Astorgues-Xerri, L., Bieche, I., Bousquet, G., Varna, M., Vidaud, M., Phillips, E., Weill, S., Benhadji, K.A., Lokiec, E., Cvitkovic, E., Faivre, S. and Raymond, E. (2009) Epithelial-to-mesenchymal transition and resistance to ingenol 3-angelate, a novel protein kinase C modulator, in colon cancer cells. Cancer Res., 69, 4260–4269.
Gotzmann, J., Mikula, M., Eger, A., Schulte-Hermann, R., Fois-ner, R., Beug, H. and Mikulits, W. (2004) Molecular aspects of epithelial cell plasticity: implications for local tumor invasion and metastasis. Mutat. Res., 566, 9–20.
Grande, M., Franzen, A., Karlsson, J.O., Ericson, L.E., Heldin, N.E. and Nilsson, M. (2002) Transforming growth factor-beta and epidermal growth factor synergistically stimulate epithelial to mesenchymal transition (EMT) through a MEK-dependent mechanism in primary cultured pig thyrocytes. J. Cell. Sci., 115, 4227–4236.
Greenburg, G. and Hay, E.D. (1982) Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J. Cell. Biol., 95, 333–339.
Greenburg, G. and Hay, E.D. (1986) Cytodifferentiation and tissue phenotype change during transformation of embryonic lens epithelium to mesenchyme-like cells in vitro. Dev. Biol., 115, 363–379.
Grunert, S., Jechlinger, M. and Beug, H. (2003) Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat. Rev. Mol. Cell. Biol., 4, 657–665.
Hay, E.D. (1968) Organization and fine structure of epithelium and mesenchyme in the developing chick embryo. In Epithelial-Mesenchymal Interactions; 18th Hahnemann Symposium, (eds. R. Fleischmajer, & R. E. Billingham), Williams & Wilkins, Baltimore.
Hay, E.D. (1995) An overview of epithelio-mesenchymal transformation. Acta. Anat., 154, 8–20.
Hay, E.D. (2005) The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev. Dyn., 233, 706–720.
Heldin, C.H., Miyazono, K. and ten Dijke, P. (1997) TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature, 390, 465–471.
Hoot, K.E., Lighthall, J., Han, G., Lu, S.L., Li, A., Ju, W., Kulesz-Martin, M., Bottinger, E. and Wang, X.J. (2008) Keratinocyte-specific Smad2 ablation results in increased epithelial-mesen-chymal transition during skin cancer formation and progression. J. Clin. Invest, 118, 2722–2732.
Huber, M.A., Kraut, N. and Beug, H. (2005) Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr. Opin. Cell. Biol, 17, 548–558.
Humar, B., Blair, V., Charlton, A., More, H., Martin, I. and Guilford, P. (2009) E-cadherin deficiency initiates gastric signet-ring cell carcinoma in mice and man. Cancer Res., 69, 2050–2056.
Illman, S.A., Lehti, K., Keski-Oja, J. and Lohi, 1(2006) Epilysin (MMP-28) induces TGF-beta mediated epithelial to mesenchymal transition in lung carcinoma cells. J. Cell Sci., 119, 3856–3865.
Jones, L.E., Humphreys, M.J., Campbell, E., Neoptolemos, IP. and Boyd, M.T. (2004) Comprehensive analysis of matrix met-alloproteinase and tissue inhibitor expression in pancreatic cancer: increased expression of matrix metalloproteinase-7 predicts poor survival. Clin. Cancer Res., 10, 2832–2845.
Ju, W., Ogawa, A., Heyer, J., Nierhof, D., Yu, L., Kucherlapati, R., Shafritz, D.A. and Bottinger, E.P. (2006) Deletion of Smad2 in mouse liver reveals novel functions in hepatocyte growth and differentiation. Mol. Cell. Biol, 26, 654–667.
Kalluri, R. and Neilson, E.G. (2003) Epithelial-mesenchymal transition and its implications for fibrosis. J. Clin. Invest., 112, 1776–1784.
Kang, Y. and Massague, J. (2004) Epithelial-mesenchymal transitions: twist in development and metastasis. Cell, 118, 277–279.
Kim, E.S., Kim, M.S. and Moon, A. (2005) Transforming growth factor (TGF)-beta in conjunction with H-ras activation promotes malignant progression of MCF10A breast epithelial cells. Cytokine, 29, 84–91.
Kim, M.S., Lee, E.J., Kim, H.R. and Moon, A. (2003) p38 kinase is a key signaling molecule for H-Ras-induced cell motility and invasive phenotype in human breast epithelial cells. Cancer Res., 63, 5454–5461.
Kim, M.A., Lee, H.S., Lee, H.E., Kim, J.H., Yang, H.K. and Kim, W.H. (2009) Prognostic importance of epithelial-mesenchy-mal-related protein expression in gastric carcinoma. Histopa-thology, 54, 442–451.
Lamouille, S. and Derynck, R. (2007) Cell size and invasion in TGF-P-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J. Cell Biol., 178, 437–451.
Larue, L. and Bellacosa, A. (2005) Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3’kinase/AKT pathways. Oncogene, 24, 7443–7454.
Lee, M.K., Pardoux, C., Hall, M.C., Lee, PS., Warburton, D., Qing, J., Smith, S.M. and Derynck, R. (2007) TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA. EMBOJ., 26, 3957–3967.
Lehmann, K., Janda, E., Pierreux, C.E., Rytomaa, M., Schulze, A., McMahon, M., Hill, C.S., Beug, H. and Downward, J. (2000) Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. Genes Dev, 14, 2610–2622.
Lewis-Tuffin, L.J., Rodriguez, F., Giannini, C., Scheithauer, B., Necela, B.M., Sarkaria, J.N. and Anastasiadis, P.Z. (2010) Mis-regulated e-cadherin expression associated with an aggressive brain tumor phenotype. PLoS One., 5, el3665.
Lien, S.C., Usami, S., Chien, S. and Chiu, J.J. (2006) Phosphatidylinositol 3-kinase/Akt pathway is involved in transforming growth factor-betal-induced phenotypic modulation of 10T1/2 cells to smooth muscle cells. Cell Signal, 18, 1270–1278.
Lin, C.C., Chiang, L.L., Lin, C.H., Shih, C.H., Liao, Y.T., Hsu, M.J. and Chen, B.C. (2007) Transforming growth factor-betal stimulates heme oxygenase-1 expression via the PI3K/Akt and NF-kappaB pathways in human lung epithelial cells. Eur. J. Pharmacol, 560, 101–109.
Liu, D., Nakano, J., Ishikawa, S., Yokomise, H., Ueno, M., Kadota, K., Urushihara, M. and Huang, C.L. (2007) Overex-pression of matrix metalloproteinase-7 (MMP-7) correlates with tumor proliferation, and a poor prognosis in non-small cell lung cancer. Lung Cancer, 58, 384–391.
Massague, J. and Chen, Y.G (2000) Controlling TGF-beta signaling. Genes Dev., 14, 627–644.
McConkey, D.J., Choi, W., Marquis, L., Martin, F., Williams, M.B., Shah, J., Svatek, R., Das, A., Adam, L., Kamat, A., Sief-ker-Radtke, A. and Dinney, C. (2009) Role of epithelial-to-mesenchymal transition (EMT) in drug sensitivity and metastasis in bladder cancer. Cancer Metastasis Rev., 28, 335–344.
McGuire, J.K., Li, Q. and Parks, WC. (2003) Matrilysin (matrix metalloproteinase-7) mediates E-cadherin ectodomain shedding in injured lung epithelium. Am. J. Pathol, 162, 1831–1843.
Micalizzi, D.S., Farabaugh, S.M. and Ford, H.L. (2010) Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. J. Mammary Gland Biol. Neoplasia, 15, 117–134.
Morgia, G., Falsaperla, M., Malaponte, G., Madonia, M., Indelicate, M., Travali, S. and Mazzarino, M.C. (2005) Matrix metal-loproteinases as diagnostic (MMP-13) and prognostic (MMP-2, MMP-9) markers of prostate cancer. Urol Res., 33, 44–50.
Moustakas, A. and Heldin, C.H. (2005) Non-Smad TGF-beta signals. J. Cell Sci., 118, 3573–3584.
Moustakas, A. and Heldin, C.H. (2007) Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and caner progression. Cancer Sci., 98, 1512–1520.
Nawshad, A., Lagamba, D., Polad, A. and Hay, E.D. (2005) Transforming growth factor-beta signaling during epithelial-mesenchymal transformation: implications for embryogenesis and tumor metastasis. Cells Tissues Organs, 179, 11–23.
Nawshad, A., Medici, D., Liu, C.C. and Hay, E.D. (2007) TGFbeta3 inhibits E-cadherin gene expression in palate medial-edge epithelial cells through a Smad2-Smad4-LEF1 transcription complex. J. Cell. Sci., 120, 1646–1653.
Nishihara, A., Hanai, J.I., Okamoto, N., Yanagisawa, J., Kato, S., Miyazono, K. and Kawabata, M. (1998) Role of p300, a transcriptional coactivator, in signalling of TGF-beta. Genes Cells, 3,613-623.
Noel, A., Boulay, A., Kebers, F., Kannan, R., Hajitou, A., Calberg-Bacq, C.M., Basset, P., Rio, M.C. and Foidart, J.M. (2000) Demonstration in vivo that stromelysin-3 functions through its proteolytic activity. Oncogene,19, 1605-1612.
Oft, M., Heider, K.H. and Beug, H. (1998) TGFbeta signaling is necessary for carcinoma cell invasiveness and metastasis. Curr. Biol, 8, 1243–1252.
Peinado, H., Olmeda, D. and Cano, A. (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nature Reviews Cancer, 7, 415–428.
Perez-Moreno, M., Jamora, C. and Fuchs, E. (2003) Sticky business: orchestrating cellular signals at adherens junctions. Cell, 112, 535–548.
Piek, E., Moustakas, A., Kurisaki, A., Heldin, C.H. and Ten Dijke, P. (1999) TGF-P type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells. J. CellSci., 112, 4557–4568.
Platten, M., Wick, W. and Weller, M. (2001) Malignant glioma biology: role for TGF-beta in growth, motility, angiogenesis, and immune escape. Microsc. Res. Tech., 52, 401–410.
Pon, Y.L., Zhou, H.Y., Cheung, A.N., Ngan, H.Y. and Wong, A.S. (2008) p70 S6 kinase promotes epithelial to mesenchymal transition through snail induction in ovarian cancer cells. Cancer Res., 68, 6524–6532.
Radisky, E.S. and Radisky, D.C. (2010) Matrix metalloproteinase-induced epithelial-mesenchymal transition in breast cancer. J. Mammary GlandBiol. Neoplasia., 15, 201–212.
Radisky, D.C, Levy, D.D., Littlepage, L.E., Liu, H., Nelson, CM., Fata, IE., Leake, D., Godden, E.L., Albertson, D.G, Nieto, M.A., Werb, Z. and Bissell, MJ. (2005) Raclb and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature, 436, 123–127.
Reiss, M. and Barcellos-Hoff, M.H. (1997) Transforming growth factor-beta in breast cancer: a working hypothesis. Breast Cancer Res. Treat., 45, 91–95.
Roger, L., Jullien, L., Gire, V. and Roux, P. (2010) Gain of oncogenic function of p53 mutants regulates E-cadherin expression uncoupled from cell invasion in colon cancer cells. J. Cell Sci., 123, 1295–1305.
Saika, S., Kono-Saika, S., Ohnishi, Y., Sato, M., Muragaki, Y., Ooshima, A., Flanders, K.C, Yoo, J., Anzano, M., Liu, C.Y., Kao, W.W and Roberts, A.B. (2004) Smad3 signaling is required for epithelial-mesenchymal transition of lens epithelium after injury. Am. J. Pathol., 164, 651–663.
Santibanez, IF. (2006) JNK mediates TGF-betal-induced epithelial mesenchymal transdifferentiation of mouse transformed keratinocytes. FEBSLett, 580, 5385–5391.
Sarbassove, D.D., Ali, S.M., and Sabatini, D.M. (2005) Growing roles for the mTOR pathway. Curr. Opin. Cell Biol., 17, 596–603.
Sato, M., Muragaki, Y, Saika, S., Roberts, A.B. and Ooshima, A. (2003) Targeted disruption of TGF-pi/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J. Clin. Invest., 112, 1486–1494.
Schilling, S.H., Hjelemeland, A.B., Rich, J.N. and Wang, X.F. (2008) TGF-P Family (eds. Derynck, R., and Miyazono, K.). Cold Spring Harbor Laboratory Pres, New York, pp. 45–78.
Snoek-van Beurden, PA. and Von den Hoff, J.W. (2005) Zymo-graphic techniques for the analysis of matrix metalloprotein-ases and their inhibitors. Biotechniques, 38, 73–83.
Somiari, S.B., Somiari, R.I., Heckman, CM., Olsen, C.H., Jordan, R.M., Russell, S.J. and Shriver, CD. (2006) Circulating MMP2 and MMP9 in breast cancer potential role in classification of patients into low risk, high risk, benign disease and breast cancer categories. Int. J. Cancer, 119, 1403–1411.
Song, H., Ki, S.H., Kim, S.G and Moon, A. (2006) Activating transcription factor 2 mediates matrix metalloproteinase-2 transcriptional activation induced by p38 in breast epithelial cells. Cancer Res., 66, 10487–10496.
Song, W., Jackson, K. and McGuire, P.G (2000) Degradation of type IV collagen by matrix metalloproteinases is an important step in the epithelial-mesenchymal transformation of the endocardial cushions. Dev Biol, 227, 606–617.
Taki, M., Kamata, N., Yokoyama, K., Fujimoto, R., Tsutsumi, S. and Nagayama, M. (2003) Down-regulation of Wnt-4 and up-regulation of Wnt-5a expression by epithelial-mesenchymal transition in human squamous carcinoma cells. Cancer Sci., 94, 593–597.
Takkunen, M., Grenman, R, Hukkanen, M., Korhonen, M., Garcia de Herreros, A. and Virtanen, I. (2006) Snail-dependent and -independent epithelial-mesenchymal transition in oral squamous carcinoma cells. J. Histochem. Cytochem., 54, 1263–1275.
Tavares, A.L., Mercado-Pimentel, M.E., Runyan, R.B. and Kitten, GT. (2006) TGF-P-mediated RhoA expression is necessary for epithelial-mesenchymal transition in the embryonic chick heart. Dev. Dyn., 235, 1589–1598.
Thiery, J.P (2002) Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer, 2, 442–454.
Thiery, J.P. (2003) Epithelial-mesenchymal transitions in development and pathologies. Curr. Opin. Cell. Biol., 15, 740–746.
Thiery, J.P. and Morgan, M. (2004) Breast cancer progression with a Twist. Nat. Med, 10, 777–778.
Timmerman, L.A., Grego-Bessa, J., Raya, A., Bertran, E., Perez-Pomares, J.M., Diez, J., Aranda, S., Palomo, S., McCormick, F., Izpisiia-Belmonte, J.C and de la Pompa, J.L. (2004) Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev, 18, 99–115.
Trelstad, R.L., Hay, E.D. and Revel, J.D. (1967) Cell contact during early morphogenesis in the chick embryo. Dev. Biol., 16, 78–106.
Trimboli, A.J., Fukino, K., de Bruin, A., Wei, G., Shen, L., Tanner, S.M., Creasap, N., Rosol, T.J., Robinson, M.L., Eng, C., Ostrowski, M.C and Leone, G. (2008) Direct evidence for epithelial-mesenchymal transitions in breast cancer. Cancer Res., 68, 937–945.
Uttamsingh, S., Bao, X., Nguyen, K.T., Bhanot, M., Gong, J., Chan, J.L., Liu, E, Chu, T.T. and Wang, L.H. (2008) Synergistic effect between EGF and TGF-betal in inducing oncogenic properties of intestinal epithelial cells. Oncogene, 27, 2626–2634.
Valcourt, U., Kowanetz, M., Niimi, H., Heldin, C.H. and Moustakas, A. (2005) TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol. Biol. Cell, 16, 1987–2002.
Voulgari, A. and Pintzas, A. (2009) Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim. Biophys. Acta., 1796, 75–90.
Vuoriluoto, K., Haugen, H., Kiviluoto, S., Mpindi, J.P., Nevo, J., Gjerdrum, C., Tiron, C., Lorens, L.B. and Ivaska, I. (2010) Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene, Epub ahead of print.
Wang, Z., Banerjee, S., Li, Y., Rahman, K.M., Zhang, Y. and Sarkar, F.H. (2006) Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells. Cancer Res., 66, 2778–2784.
Wick, W., Platten, M. and Weller, M. (2001) Glioma cell invasion: regulation of metalloproteinase activity by TGF-beta. J. NeurooncoL, 53, 177–185.
Xie, L., Law, B.K., Chytil, A.M., Brown, K.A., Aakre, M.E. and Moses, H.L. (2004) Activation of the Erk pathway is required for TGF-betal-induced EMT in vitro. Neoplasia, 6, 603–610.
Xu, I., Lamouille, S. and Derynck, R. (2009) TGF-beta-induced epithelial to mesenchymal transition. Cell Res., 19, 156–172.
Yee, D.S., Tang, Y., Li, X., Liu, Z., Guo, Y., Ghaffar, S., McQueen, R., Atreya, D., Xie, I., Simoneau, A.R., Hoang, B.H. and Zi, X. (2010) The Wnt inhibitory factor 1 restoration in prostate cancer cells was associated with reduced tumor growth, decreased capacity of cell migration and invasion and a reversal of epithelial to mesenchymal transition. Mol. Cancer, 9, 162.
Yi, J.Y., Shin, I. and Arteaga, C.L. (2005) Type I transforming growth factor beta receptor binds to and activates phosphati-dylinositol 3-kinase. J. Biol. Chem., 280, 10870–10876.
Yook, I.I., Li, X.Y, Ota, I., Fearon, E.R and Weiss, S.I. (2005) Wnt-dependent regulation of the E-cadherin repressor snail. J. Biol. Chem., 280, 11740–11748.
Yu, L., Hebert, M.C. and Zhang, Y.E. (2002) TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses. EMBOJ., 21, 3749–3759.
Zavadil, I. and Bottinger, E.R (2005) TGF-beta and epithelial-to-mesenchymal transitions. Oncogene, 24, 5764–5774.
Zavadil, I., Cermak, L., Soto-Nieves, N. and Bottinger, E.R (2004) Integration of TGF-beta/Smad and Jagged 1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J., 23, 1155–1165.
Zavadil, I., Narasimhan, M., Blumenberg, M. and Schneider, R.I (2007) Transforming growth factor-beta and microRNA: mRNA regulatory networks in epithelial plasticity. Cells Tissues Organs, 185, 157–161.
Zhou, B.P., Deng, I., Xia, W., Xu, I., Li, Y.M., Gunduz, M. and Hung, M.C. (2004) Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat. Cell Biol, 6, 931–940.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Son, H., Moon, A. Epithelial-mesenchymal Transition and Cell Invasion. Toxicol Res. 26, 245–252 (2010). https://doi.org/10.5487/TR.2010.26.4.245
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.5487/TR.2010.26.4.245