Abstract
Epithelial-mesenchymal transition (EMT) is a differentiation switch between two major cell types, polarized immobile epithelial and contractile and motile mesenchymal/fibroblastic cells. EMT is critical for proper embryonic development and is also relevant to vascular remodeling processes during which endothelial cells generate myoepithelial cells. Similar to all other developmentally relevant differentiation processes, EMT is governed by the concerted action of extracellular polypeptide/morphogenetic factors, transforming growth factor-β (TGF-β) representing one of them. Because of the relevance the EMT process has for tumor cell invasiveness, metastasis, and tissue fibrosis, considerable research effort has recently focused on the mechanism by which TGF-β elicits EMT of normal epithelial and carcinoma cells. Here, we summarize the state of the art with respect to signaling mechanisms and critical effectors of EMT downstream of TGF-β. We also discuss our recent work on this topic and present a wider perspective for the future of this thriving field.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Hay ED. The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev Dyn 2005;233:706–720.
Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003;15:740–746.
Zeisberg M, Kalluri R. The role of epithelial-to-mesenchymal transition in renal fibrosis. J Mol Med 2004;82:175–181.
Tarin D, Thompson EW, Newgreen DF. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 2005;65:5996–6000; Discussion 6000-1.
Barolo S, Posakony JW. Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling. Genes Dev 2002;16:1167–1181.
Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 2005;17:548–558.
Wang W, Goswami S, Sahai E, Wyckoff JB, Segall JE, Condeelis JS. Tumor cells caught in the act of invading: their strategy for enhanced cell motility. Trends Cell Biol 2005;15:138–145.
Nawshad A, LaGamba D, Hay ED. Transforming growth factor β (TGFβ) signalling in palatal growth, apoptosis and epithelial mesenchymal transformation (EMT). Arch Oral Biol 2004;49:675–689.
Person AD, Klewer SE, Runyan RB. Cell biology of cardiac cushion development. Int Rev Cytol 2005;243:287–335.
Desgrosellier JS, Mundell NA, McDonnell MA, Moses HL, Barnett JV. Activin receptor-like kinase 2 and Smad6 regulate epithelial-mesenchymal transformation during cardiac valve formation. Dev Biol 2005;280:201–210.
Cui W, Fowlis DJ, Bryson S, et al. TGFβ1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell 1996;86:531–542.
Portella G, Cumming SA, Liddell J, et al. Transforming growth factor β is essential for spindle cell conversion of mouse skin carcinoma in vivo: implications for tumor invasion. Cell Growth Differ 1998;9:393–404.
Han G, Lu SL, Li AG, et al. Distinct mechanisms of TGF-β1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis. J Clin Invest 2005;115:1714–1723.
Gotzmann J, Huber H, Thallinger C, et al. Hepatocytes convert to a fibroblastoid phenotype through the cooperation of TGF-β1 and Ha-Ras: steps towards invasiveness. J Cell Sci 2002;115:1189–1202.
Janda E, Lehmann K, Killisch I, et al. Ras and TGFβ cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 2002;156:299–313.
Lehmann K, Janda E, Pierreux CE, et al. Reaf induces TGFβ production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. Genes Dev 2000;14:2610–2622.
Oft M, Heider KH, Beug H. TGFβ signaling is necessary for carcinoma cell invasiveness and metastasis. Curr Biol 1998;8:1243–1252.
Valcourt U, Kowanetz M, Niimi H, Heldin C-H, Moustakas A. TGF-β and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell 2005;16:1987–2002.
Akhurst RJ, Derynck R. TGF-β signaling in cancer—a double-edged sword. Trends Cell Biol 2001; 11:S44–S51.
Li Y, Yang J, Dai C, Wu C, Liu Y. Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis. J Clin Invest 2003;112:503–516.
Sato M, Muragaki Y, Saika S, Roberts AB, Ooshima A. Targeted disruption of TGF-β1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J Clin Invest 2003;112:1486–1494.
Brown KA, Aakre ME, Gorska AE, et al. Induction by transforming growth factor-β1 of epithelial to mesenchymal transition is a rare event in vitro. Breast Cancer Res 2004;6:R215–R231.
Kowanetz M, Valcourt U, Bergström R, Heldin C-H, Moustakas A. Id2 and Id3 define the potency of cell proliferation and differentiation responses to transforming growth factor β and bone morphogenetic protein. Mol Cell Biol 2004;24:4241–4254.
Miettinen PJ, Ebner R, Lopez AR, Derynck R. TGF-β induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J Cell Biol 1994;127: 2021–2036.
Saika S, Kono-Saika S, Ohnishi Y, et al. Smad3 signaling is required for epithelial-mesenchymal transition of lens epithelium after injury. Am J Pathol 2004;164:651–663.
Valdes F, Alvarez AM, Locascio A, et al. The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor β in fetal rat hepatocytes. Mol Cancer Res 2002;1:68–78.
Willis BC, Liebler JM, Luby-Phelps K, et al. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-β1: potential role in idiopathic pulmonary fibrosis. Am J Pathol 2005;166:1321–1332.
Zavadil J, Bitzer M, Liang D, et al. Genetic programs of epithelial cell plasticity directed by transforming growth factor-β. Proc Natl Acad Sci USA 2001;98:6686–6691.
Bates RC, Mercurio AM. The epithelial-mesenchymal transition (EMT) and colorectal cancer progression. Cancer Biol Ther 2005;4:365–370.
Piek E, Moustakas A, Kurisaki A, Heldin C-H, ten Dijke P. TGF-β type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells. J Cell Sci 1999;112:4557–4568.
Zeisberg M, Shah AA, Kalluri R. Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. J Biol Chem 2005; 280:8094–8100.
Itoh S, Thorikay M, Kowanetz M, et al. Elucidation of Smad requirement in transforming growth factor-β type I receptor-induced responses. J Biol Chem 2003;278:3751–3761.
Li W, Qiao W, Chen L, et al. Squamous cell carcinoma and mammary abscess formation through squamous metaplasia in Smad4/Dpc4 conditional knockout mice. Development 2003;130:6143–6153.
Oft M, Akhurst RJ, Balmain A. Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat Cell Biol 2002;4:487–494.
Tian F, DaCosta Byfield S, Parks WT, et al. Reduction in Smad2/3 signaling enhances tumorigenesis but suppresses metastasis of breast cancer cell lines. Cancer Res 2003;63:8284–8292.
Tian F, Byfield SD, Parks WT, et al. Smad-binding defective mutant of transforming growth factor β type I receptor enhances tumorigenesis but suppresses metastasis of breast cancer cell lines. Cancer Res 2004;64:4523–4530.
Kurisaki K, Kurisaki A, Valcourt U, et al. Nuclear factor YY1 inhibits transforming growth factorβ-and bone morphogenetic protein-induced cell differentiation. Mol Cell Biol 2003;23:4494–4510.
Takeda M, Mizuide M, Oka M, et al. Interaction with Smad4 is indispensable for suppression of BMP signaling by c-Ski. Mol Biol Cell 2004;15:963–972.
Levy L, Hill CS. Smad4 dependency defines two classes of transforming growth factor β (TGF-β) target genes and distinguishes TGF-β-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses. Mol Cell Biol 2005;25:8108–8125.
Massagué J, Seoane J, Wotton D. Smad transcription factors. Genes Dev 2005;19:2783–2810.
Moustakas A, Heldin C-H. Non-Smad TGF-β signals. J Cell Sci 2005;118:3573–3584.
Huber MA, Azoitei N, Baumann B, et al. NF-kB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 2004;114:569–581.
Shim JH, Xiao C, Paschal AE, et al. TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev 2005;19:2668–2681.
Bakin AV, Rinehart C, Tomlinson AK, Arteaga CL. p38 mitogen-activated protein kinase is required for TGFβ-mediated fibroblastic transdifferentiation and cell migration. J Cell Sci 2002;115:3193–3206.
Bhowmick NA, Ghiassi M, Bakin A, et al. Transforming growth factor-β1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell 2001;12:27–36.
Xie L, Law BK, Chytil AM, Brown KA, Aakre ME, Moses HL. Activation of the Erk pathway is required for TGF-β1-induced EMT in vitro. Neoplasia 2004;6:603–610.
Yu L, Hebert MC, Zhang YE. TGF-β receptor-activated p38 MAP kinase mediates Smad-independent TGF-β responses. EMBO J 2002;21:3749–3759.
Lee YI, Kwon YJ, Joo CK. Integrin-linked kinase function is required for transforming growth factor β-mediated epithelial to mesenchymal transition. Biochem Biophys Res Commun 2004;316:997–1001.
Leung-Hagesteijn C, Hu MC, Mahendra AS, et al. Integrin-linked kinase mediates bone morphogenetic protein 7-dependent renal epithelial cell morphogenesis. Mol Cell Biol 2005;25:3648–3657.
Bates RC, Bellovin DI, Brown C, et al. Transcriptional activation of integrin β6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma. J Clin Invest 2005;115:339–347.
Bhowmick NA, Zent R, Ghiassi M, McDonnell M, Moses HL. Integrin β1 signaling is necessary for transforming growth factor-β activation of p38 MAPK and epithelial plasticity. J Biol Chem 2001;276:46,707–46,713.
Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL. Regulation of the polarity protein Par6 by TGFβ receptors controls epithelial cell plasticity. Science 2005;307:1603–1609.
Tian YC, Phillips AO. Interaction between the transforming growth factor-β type II receptor/Smad pathway and β-catenin during transforming growth factor-β1-mediated adherens junction disassembly. Am J Pathol 2002;160:1619–1628.
LaGamba D, Nawshad A, Hay ED. Microarray analysis of gene expression during epithelial-mesenchymal transformation. Dev Dyn 2005;234:132–142.
Xie L, Law BK, Aakre ME, et al. Transforming growth factor β-regulated gene expression in a mouse mammary gland epithelial cell line. Breast Cancer Res 2003;5:R187–R198.
Jechlinger M, Grunert S, Tamir IH, et al. Expression profiling of epithelial plasticity in tumor progression. Oncogene 2003;22:7155–7169.
Kang Y, Siegel PM, Shu W, et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 2003;3:537–549.
Kondo M, Cubillo E, Tobiume K, et al. A role for Id in the regulation of TGF-β-induced epithelial-mesenchymal transdifferentiation. Cell Death Differ 2004;11:1092–1101.
Saika S, Ikeda Y, Yamanaka O, et al. Adenoviral gene transfer of BMP-7, Id2, or Id3 suppresses injury-induced epithelial-to-mesenchymal transition of lens epithelium in mice. Am J Physiol Cell Physiol 2006;290:C282–C289.
Siegel PM, Massagué J. Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer. Nat Rev Cancer 2003;3:807–820.
Pardali K, Kowanetz M, Heldin C-H, Moustakas A. Smad pathway-specific transcriptional regulation of the cell cycle inhibitor p21WAF1/Cip1. J Cell Physiol 2005;204:260–272.
Perk J, Iavarone A, Benezra R. Id family of helix-loop-helix proteins in cancer. Nat Rev Cancer 2005;5:603–614.
Peinado H, Portillo F, Cano A. Transcriptional regulation of cadherins during development and carcinogenesis. Int J Dev Biol 2004;48:365–375.
Comijn J, Berx G, Vermassen P, et al. The two-handed E box binding zinc finger protein SIP1 down-regulates E-cadherin and induces invasion. Mol Cell 2001;7:1267–1278.
Martinez-Alvarez C, Blanco MJ, Perez R, et al. Snail family members and cell survival in physiological and pathological cleft palates. Dev Biol 2004;265:207–218.
Romano LA, Runyan RB. Slug is an essential target of TGFβ2 signaling in the developing chicken heart. Dev Biol 2000;223:91–102.
Peinado H, Quintanilla M, Cano A. Transforming growth factor β-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transition. J Biol Chem 2003;278: 21,113–21,123.
Eger A, Stockinger A, Park J, et al. β-Catenin and TGFβ signalling cooperate to maintain a mesenchymal phenotype after FosER-induced epithelial to mesenchymal transition. Oncogene 2004;23:2672–2680.
Yang J, Mani SA, Donaher JL, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004;117:927–939.
Zavadil J, Cermak L, Soto-Nieves N, Böttinger EP. Integration of TGF-β/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J 2004;23:1155–1165.
Shen X, Li J, Hu PP, Waddell D, Zhang J, Wang X-F. The activity of guagine exchange factor NET1 is essential for transforming growth factor-β-mediated stress fiber formation. J Biol Chem 2001;276: 15,362–15,368.
Bakin AV, Safina A, Rinehart C, Daroqui C, Darbary H, Helfman DM. A critical role of tropomyosins in TGF-β regulation of the actin cytoskeleton and cell motility in epithelial cells. Mol Biol Cell 2004;15:4682–4694.
Michl P, Ramjaun AR, Pardo OE, et al. CUTL1 is a target of TGFβ signaling that enhances cancer cell motility and invasiveness. Cancer Cell 2005;7:521–532.
Prunier C, Howe PH. Disabled-2 (Dab2) is required for transforming growth factor β-induced epithelial to mesenchymal transition (EMT). J Biol Chem 2005;280:17,540–17,548.
Yingling JM, Blanchard KL, Sawyer JS. Development of TGF-β signalling inhibitors for cancer therapy. Nat Rev Drug Discov 2004;3:1011–1022.
Wang S, Wilkes MC, Leof EB, Hirschberg R. Imatinib mesylate blocks a non-Smad TGF-β pathway and reduces renal fibrogenesis in vivo. FASEB J 2005;19:1–11.
Moody SE, Perez D, Pan TC, et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 2005;8:197–209.
Author information
Authors and Affiliations
Rights and permissions
Copyright information
© 2008 Humana Press
About this chapter
Cite this chapter
Thuault, S., Valcourt, U., Kowanetz, M., Moustakas, A. (2008). TGF-β and Smad Signaling in Transcriptome Reprogramming During EMT. In: Transforming Growth Factor-β in Cancer Therapy, Volume I. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-292-2_16
Download citation
DOI: https://doi.org/10.1007/978-1-59745-292-2_16
Publisher Name: Humana Press
Print ISBN: 978-1-58829-714-3
Online ISBN: 978-1-59745-292-2
eBook Packages: MedicineMedicine (R0)