New insights of epithelial-mesenchymal transition in cancer metastasis
Yadi Wu,
Binhua P. Zhou,
Yadi Wu
Departments of Pharmacology and Toxicology, and Sealy Center for Cancer Cell Biology, The University of Texas Medical Branch, Galveston, Texas 77555, USA
Search for more papers by this authorCorresponding Author
Binhua P. Zhou
Departments of Pharmacology and Toxicology, and Sealy Center for Cancer Cell Biology, The University of Texas Medical Branch, Galveston, Texas 77555, USA
*Corresponding author: Tel, 409-747-1963; E-mail, [email protected]Search for more papers by this authorYadi Wu,
Binhua P. Zhou,
Yadi Wu
Departments of Pharmacology and Toxicology, and Sealy Center for Cancer Cell Biology, The University of Texas Medical Branch, Galveston, Texas 77555, USA
Search for more papers by this authorCorresponding Author
Binhua P. Zhou
Departments of Pharmacology and Toxicology, and Sealy Center for Cancer Cell Biology, The University of Texas Medical Branch, Galveston, Texas 77555, USA
*Corresponding author: Tel, 409-747-1963; E-mail, [email protected]Search for more papers by this authorThis work was supported by grants from the John Sealy Memorial Endowment Fund, a pilot award from the ACS (IRG-110376), the Susan G Komen Foundation (KG081310) and NIH (RO1CA125454) (to B.P. Zhou), and the Post-doctoral Fellowships from NIH (T32CA117834) (to Y. Wu)
Abstract
Epithelial-mesenchymal transition (EMT) is a key step during embryonic morphogenesis, heart development, chronic degenerative fibrosis, and cancer metastasis. Several distinct traits have been conveyed by EMT, including cell motility, invasiveness, resistance to apoptosis, and some properties of stem cells. Many signal pathways have contributed to the induction of EMT, such as transforming growth factor-β, Wnt, Hedgehog, Notch, and nuclear factor-κB. Over the last few years, increasing evidence has shown that EMT plays an essential role in tumor progression and metastasis. Understanding the molecular mechanism of EMT has a great effect in unraveling the metastatic cascade and may lead to novel interventions for metastatic disease.
References
- 1 Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002, 2: 563–572.
- 2 Pantel K, Brakenhoff RH. Dissecting the metastatic cascade. Nat Rev Cancer 2004, 4: 448–456.
- 3 MacDonald IC, Groom AC, Chambers AF. Cancer spread and micrometastasis development: quantitative approaches for in vivo models. Bioessays 2002, 24: 885–893.
- 4 Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002, 2: 442–454.
- 5 Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003, 15: 740–746.
- 6 Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 2005, 17: 548–558.
- 7 Grunert S, Jechlinger M, Beug H. Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol 2003, 4: 657–665.
- 8 Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003, 112: 1776–1784.
- 9 Neilson EG. Mechanisms of disease: fibroblasts—a new look at an old problem. Nat Clin Pract Nephrol 2006, 2: 101–108.
- 10 Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 2006, 7: 131–142.
- 11 Tarin D, Thompson EW, Newgreen DF. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 2005, 65: 5996–6001.
- 12 Cardiff RD. Epithelial to mesenchymal transition tumors: fallacious or snail's pace? Clin Cancer Res 2005, 11: 8534–8553.
- 13 Thompson EW, Newgreen DF, Tarin D. Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition? Cancer Res 2005, 65: 5991–5995.
- 14 Kang Y, Massague J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 2004, 118: 277–279.
- 15 Cowin P, Rowlands TM, Hatsell SJ. Cadherins and catenins in breast cancer. Curr Opin Cell Biol 2005, 17: 499–508.
- 16 Junghans D, Haas IG, Kemler R. Mammalian cadherins and protocadherins: about cell death, synapses and processing. Curr Opin Cell Biol 2005, 17: 446–452.
- 17 Blanco MJ, Moreno-Bueno G, Sarrio D, Locascio A, Cano A, Palacios J, Nieto MA. Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 2002, 21: 3241–3246.
- 18 Cheng CW, Wu PE, Yu JC, Huang CS, Yue CT, Wu CW, Shen CY. Mechanisms of inactivation of E-cadherin in breast carcinoma: modification of the two-hit hypothesis of tumor suppressor gene. Oncogene 2001, 20: 3814–3823.
- 19 Behrens J, Lowrick O, Klein-Hitpass L, Birchmeier W. The E-cadherin promoter: functional analysis of a G.C-rich region and an epithelial cell-specific palindromic regulatory element. Proc Natl Acad Sci USA 1991, 88: 11495–11499.
- 20 Birchmeier W, Behrens J, Weidner KM, Frixen UH, Schipper J. Dominant and recessive genes involved in tumor cell invasion. Curr Opin Cell Biol 1991, 3: 832–840.
- 21 Giroldi LA, Bringuier PP, De Weijert M, Jansen C, Van Bokhoven A, Schalken JA. Role of E boxes in the repression of E-cadherin expression. Biochem Biophys Res Commun 1997, 241: 453–458.
- 22 Hajra KM, Ji X, Fearon ER. Extinction of E-cadherin expression in breast cancer via a dominant repression pathway acting on proximal promoter elements. Oncogene 1999, 18: 7274–7279.
- 23 Ji X, Woodard AS, Rimm DL, Fearon ER. Transcriptional defects underlie loss of E-cadherin expression in breast cancer. Cell Growth Differ 1997, 8: 773–778.
- 24 Karreth F, Tuveson DA. Twist induces an epithelial-mesenchymal transition to facilitate tumor metastasis. Cancer Biol Ther 2004, 3: 1058–1059.
- 25 Thiery JP, Morgan M. Breast cancer progression with a Twist. Nat Med 2004, 10: 777–778.
- 26 Vernon AE, LaBonne C. Tumor metastasis: a new twist on epithe-lial-mesenchymal transitions. Curr Biol 2004, R719–R721.
- 27 Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004, 117: 927–939.
- 28 Bolós V, Peinado H, Pérez-Moreno MA, Fraga MF, Esteller M, Cano A. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci 2003, 116: 499–511.
- 29 Comijn J, Berx G, Vermassen P, Verschueren K, Van Grunsven L, Bruyneel E, Mareel M et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell 2001, 7: 1267–1278.
- 30 Elloul S, Elstrand MB, Nesland JM, Tropé CG, Kvalheim G, Goldberg I, Reich R et al. Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer 2005, 103: 1631–1643.
- 31 Miyoshi A, Kitajima Y, Sumi K, Sato K, Hagiwara A, Koga Y, Miyazaki K. Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells. Br J Cancer 2004, 90: 1265–1273.
- 32 Perez-Moreno MA, Locascio A, Rodrigo I, Dhondt G, Portillo F, Nieto MA, Cano A. A new role for E12/E47 in the repression of E-cadherin expression and epithelial-mesenchymal transitions. J Biol Chem 2001, 276: 27424–27431.
- 33 Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R, Höfler H et al. Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am J Pathol 2002, 161: 1881–1891.
- 34 Vandewalle C, Comijn J, De Craene B, Vermassen P, Bruyneel E, Andersen H, Tulchinsky E et al. SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell-cell junctions. Nucleic Acids Res 2005, 33: 6566–6578.
- 35 Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 2005, 132: 3151–3161.
- 36 Nieto MA. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 2002, 3: 155–166.
- 37 Carver EA, Jiang R, Lan Y, Oram KF, Gridley T. The mouse snail gene encodes a key regulator of the epithelial-mesenchymal transition. Mol Cell Biol 2001, 21: 8184–8188.
- 38 Batlle E, Sancho E, Francí C, Domínguez D, Monfar M, Baulida J, García De Herreros A. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2000, 2: 84–89.
- 39 Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, Del Barrio MG, Portillo F et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2000, 2: 76–83.
- 40 Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 2004, 6: 931–940.
- 41 Davidson NE, Sukumar S. Of Snail, mice, and women. Cancer Cell 2005, 8: 173–174.
- 42 Moody SE, Perez D, Pan TC, Sarkisian CJ, Portocarrero CP, Sterner CJ, Notorfrancesco KL et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 2005, 8: 197–209.
- 43 Martin TA, Goyal A, Watkins G, Jiang WG. Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer. Ann Surg Oncol 2005, 12: 488–496.
- 44 Parker BS, Argani P, Cook BP, Liangfeng H, Chartrand SD, Zhang M, Saha S et al. Alterations in vascular gene expression in invasivebreast carcinoma. Cancer Res 2004, 64: 7857–7866.
- 45 Gavert N, Ben-Ze'ev A. Epithelial-mesenchymal transition and the invasive potential of tumors. Trends Mol Med 2008, 14: 199–209.
- 46 Li Y, Hively WP, Varmus HE. Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer. Oncogene 2000, 19: 1002–1009.
- 47 Clevers H. Wnt/beta-catenin signaling in development and disease. Cell 2006, 127: 469–480.
- 48 Yook JI, Li XY, Ota I, Fearon ER, Weiss SJ. Wnt-dependent regulation of the E-cadherin repressor snail. J Biol Chem 2005, 280: 11740–11748.
- 49 Yook JI, Li XY, Ota I, Hu C, Kim HS, Kim NH, Cha SY et al. A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol 2006, 8: 1398–1406.
- 50 Zavadil J, Bottinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 2005, 24: 5764–5774.
- 51 Valcourt U, Kowanetz M, Niimi H, Heldin CH, Moustakas A. TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell 2005, 16: 1987–2002.
- 52 Zavadil J, Cermak L, Soto-Nieves N, Bottinger EP. Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. Embo J 2004, 23: 1155–1165.
- 53 Buijs JT, Henriquez NV, Van Overveld PG, Van Der Horst G, Ten Dijke P, Van Der Pluijm G. TGF-beta and BMP7 interactions in tumour progression and bone metastasis. Clin Exp Metastasis 2007, 24: 609–617.
- 54 Hooper JE, Scott MP. Communicating with Hedgehogs. Nat Rev Mol Cell Biol 2005, 6: 306–317.
- 55 Jacob L, Lum L. Deconstructing the hedgehog pathway in development and disease. Science 2007, 318: 66–68.
- 56 Li X, Deng W, Lobo-Ruppert SM, Ruppert JM. Gli1 acts through Snail and E-cadherin to promote nuclear signaling by beta-catenin. Oncogene 2007, 26: 4489–4498.
- 57 Li X, Deng W, Nail CD, Bailey SK, Kraus MH, Ruppert JM, Lobo-Ruppert SM. Snail induction is an early response to Gli1 that determines the efficiency of epithelial transformation. Oncogene 2006, 25: 609–621.
- 58 Fiaschi M, Rozell B, Bergstrom A, Toftgard R, Kleman MI. Targeted expression of GLI1 in the mammary gland disrupts pregnancy-induced maturation and causes lactation failure. J Biol Chem 2007, 282: 36090–36101.
- 59 Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M, Karikari C et al. Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res 2007, 67: 2187–2196.
- 60 Timmerman LA, Grego-Bessa J, Raya A, Bertrán E, Pérez-Pomares JM, Díez J, Aranda S et al. Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. Genes Dev 2004, 18: 99–115.
- 61 Grego-Bessa J, Diez J, Timmerman L, De La Pompa JL. Notch and epithelial-mesenchyme transition in development and tumor progression: another turn of the screw. Cell Cycle 2004, 3: 718–721.
- 62 Leong KG, Niessen K, Kulic I, Raouf A, Eaves C, Pollet I, Karsan A. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J Exp Med 2007, 204: 2935–2948.
- 63 Sahlgren C, Gustafsson MV, Jin S, Poellinger L, Lendahl U. Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA 2008, 105: 6392–6397.
- 64 Huber MA, Azoitei N, Baumann B, Grünert S, Sommer A, Pehamberger H, Kraut N et al. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 2004, 114: 569–581.
- 65 Bachelder RE, Yoon SO, Franci C, De Herreros AG, Mercurio AM. Glycogen synthase kinase-3 is an endogenous inhibitor of Snail transcription: implications for the epithelial-mesenchymal transition. J Cell Biol 2005, 168: 29–33.
- 66 Julien S, Puig I, Caretti E, Bonaventure J, Nelles L, Van Roy F, Dargemont C et al. Activation of NF-kappaB by Akt upregulates Snail expression and induces epithelium mesenchyme transition. Oncogene 2007, 26: 7445–7456.
- 67 Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 2005, 307: 1603–1609.
- 68 Wang X, Nie J, Zhou Q, Liu W, Zhu F, Chen W, Mao H et al. Downregulation of Par-3 expression and disruption of Par complex integrity by TGF-beta during the process of epithelial to mesenchymal transition in rat proximal epithelial cells. Biochim Biophys Acta 2008, 1782: 51–59.
- 69 Whiteman EL, Liu CJ, Fearon ER, Margolis B. The transcription factor snail represses Crumbs3 expression and disrupts apico-basal polarity complexes. Oncogene 2008, 27: 3875–3879.
- 70 Aigner K, Dampier B, Descovich L, Mikula M, Sultan A, Schreiber M, Mikulits W et al. The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene 2007, 26: 6979–6988.
- 71 Spaderna S, Schmalhofer O, Wahlbuhl M, Dimmler A, Bauer K, Sultan A, Hlubek F et al. The transcriptional repressor ZEB1 promotes metastasis and loss of cell polarity in cancer. Cancer Res 2008, 68: 537–544.
- 72 Martin SS, Ridgeway AG, Pinkas J, Lu Y, Reginato MJ, Koh EY, Michelman M et al. A cytoskeleton-based functional genetic screen identifies Bcl-xL as an enhancer of metastasis, but not primary tumor growth. Oncogene 2004, 23: 4641–4645.
- 73 Wang X, Belguise K, Kersual N, Kirsch KH, Mineva ND, Galtier F, Chalbos D et al. Oestrogen signalling inhibits invasive phenotype by repressing Re1B and its target BCL2. Nat Cell Biol 2007, 9: 470–478.
- 74 McLean GW, Komiyama NH, Serrels B, Asano H, Reynolds L, Conti F, Hodivala-Dilke K et al. Specific deletion of focal adhesion kinase suppresses tumor formation and blocks malignant progression. Genes 2004, 18: 2998–3003.
- 75 Cheung M, Chaboissier MC, Mynett A, Hirst E, Schedl A, Briscoe J. The transcriptional control of trunk neural crest induction, survival, and delamination. Dev Cell 2005, 8: 179–192.
- 76 Inoue A, Seidel MG, Wu W, Kamizono S, Ferrando AA, Bronson RT, Iwasaki H et al. Slug, a highly conserved zinc finger transcriptional repressor, protects hematopoietic progenitor cells from radiation-induced apoptosis in vivo. Cancer Cell 2002, 2: 279–288.
- 77 Wu WS, Heinrichs S, Xu D, Garrison SP, Zambetti GP, Adams JM, Look AT. Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma. Cell 2005, 123: 641–653.
- 78 Zilfou JT, Spector MS, Lowe SW. Slugging it out: fine tuning the p53-PUMA death connection. Cell 2005, 123: 545–548.
- 79 Kajita M, McClinic KN, Wade PA. Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress. Mol Cell Biol 2004, 24: 7559–7566.
- 80 Vega S, Morales AV, Ocaña OH, Valdés F, Fabregat I, Nieto MA. Snail blocks the cell cycle and confers resistance to cell death. Genes 2004, 18: 1131–1143.
- 81 Zohn IE, Li Y, Skolnik EY, Anderson KV, Han J, Niswander L. p38 and a p38-interacting protein are critical for downregulation of E-cadherin during mouse gastrulation. Cell 2006, 125: 957–969.
- 82 Puisieux A, Valsesia-Wittmann S, Ansieau S. A twist for survival and cancer progression. Br J Cancer 2006, 94: 13–17.
- 83 Debies MT, Gestl SA, Mathers JL, Mikse OR, Leonard TL, Moody SE, Chodosh LA et al. Tumor escape in a Wnt1-dependent mouse breast cancer model is enabled by p19Arf/p53 pathway lesions but not p16 Ink4a loss. J Clin Invest 2008, 118: 51–63.
- 84 Liu Y, El-Naggar S, Darling DS, Higashi Y, Dean DC. Zeb1 links epithelial-mesenchymal transition and cellular senescence. Development 2008, 135: 579–588.
- 85 Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008, 133: 704–715.
- 86 Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N, Kutok JL et al. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc Natl Acad Sci USA 2007, 104: 10069–10074.
- 87 Eastham AM, Spencer H, Soncin F, Ritson S, Merry CL, Stern PL, Ward CM. Epithelial-mesenchymal transition events during human embryonic stem cell differentiation. Cancer Res 2007, 67: 11254–11262.
- 88 Stadler BM, Ruohola-Baker H. Small RNAs: keeping stem cells in line. Cell 2008, 132: 563–536.
- 89 Stefani G, Slack FJ. Small non-coding RNAs in animal development. Nat Rev Mol Cell Biol 2008, 9: 219–230.
- 90 Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 2007, 449: 682–688.
- 91 Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, Brabletz T. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep 2008, 9: 582–589.
- 92 Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 2008, 10: 593–601.
- 93 Korpal M, Lee ES, Hu G, Kang Y. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem 2008, 283: 14910–14914.
- 94 Park SM, Gaur AB, Lengyel E, Peter ME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 2008, 22: 894–907.
- 95 Zavadil J, Narasimhan M, Blumenberg M, Schneider RJ. Transforming growth factor-beta and microRNA: mRNA regulatory networks in epithelial plasticity. Cells Tissues Organs 2007, 185: 157–161.
- 96 Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, Allgayer H. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, in-travasation and metastasis in colorectal cancer. Oncogene 2008, 27: 2128–2136.
- 97 Zhu S, Si ML, Wu H, Mo YY. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 TPM1). J Biol Chem 2007, 282: 14328–14336.
