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Epithelial-to-mesenchymal transition in tumor progression

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Abstract

The epithelial-to-mesenchymal transition (EMT) is a biological process in which a non-motile epithelial cell changes to a mesenchymal state with invasive capacities. However, the EMT program is involved in both physiological and pathological processes. Cancer-associated EMT is known to contribute to increase invasiveness and metastasis, resistance to therapies, and generation of cell populations with stem cell-like characteristics and therefore is deeply involved in tumor progression. This process is finely orchestrated by multiple signaling pathways and regulatory transcriptional networks. The hallmark of EMT is the loss of epithelial surface markers, mainly E-cadherin, and the acquisition of mesenchymal phenotype. These events can be mediated by EMT transcription factors which can cooperate with several enzymes to repress the E-cadherin expression and regulate EMT at the epigenetic and post-translational level. A growing body of evidence indicates that cancer cells can reside in various phenotypic states along the EMT spectrum, where cells can jointly retain epithelial traits with mesenchymal ones. This type of phenotypic plasticity endows cancer cells with tumor-initiating potential. The identification of the signaling pathways and modulators that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.

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References

  1. Kalluri R. EMT: when epithelial cells decide to become mesenchymal-like cells. J Clin Invest. 2009. doi:10.1172/JCI39675.

    Google Scholar 

  2. Varga J, De Oliveira T, Greten FR. The architect who never sleeps: tumor-induced plasticity. FEBS Lett. 2014. doi:10.1016/j.febslet.2014.06.019.

    Google Scholar 

  3. Mitra A, Mishra L, Li S. EMT, CTCs and CSCs in tumor relapse and drug-resistance. Oncotarget. 2015. doi:10.18632/oncotarget.4037.

    PubMed  PubMed Central  Google Scholar 

  4. Martin TA, Jiang WG. Loss of tight junction barrier function and its role in cancer metastasis. Biochim Biophys Acta. 2009. doi:10.1016/j.bbamem.2008.11.005.

    PubMed Central  Google Scholar 

  5. Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene. 2010. doi:10.1038/onc.2010.215.

    Google Scholar 

  6. Radisky DC, LaBarge MA. Epithelial–mesenchymal transition and the stem cell phenotype. Cell Stem Cell. 2008. doi:10.1016/j.stem.2008.05.007.

    PubMed  Google Scholar 

  7. De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013. doi:10.1038/nrc3447.

    PubMed  Google Scholar 

  8. Nieto MA, Huang RY, Jackson RA, Thiery JP. Emt: 2016. Cell. 2016;166(1):21–45. doi:10.1016/j.cell.2016.06.028.

    Article  CAS  PubMed  Google Scholar 

  9. Thiery JP, Sleeman JP. Complex networks orchestrate epithelial–mesenchymal transitions. Nat Rev Mol Cell Biol. 2006. doi:10.1038/nrm1835.

    PubMed  Google Scholar 

  10. Moreno-Bueno G, Portillo F, Cano A. Transcriptional regulation of cell polarity in EMT and cancer. Oncogene. 2008. doi:10.1038/onc.2008.346.

    Google Scholar 

  11. Ocana OH, Corcoles R, Fabra A, Moreno-Bueno G, Acloque H, Vega S, et al. Metastatic colonization requires the repression of the epithelial–mesenchymal transition inducer Prrx1. Cancer Cell. 2012. doi:10.1016/j.ccr.2012.10.012.

    PubMed  Google Scholar 

  12. Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J. Spatiotemporal regulation of epithelial–mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell. 2012. doi:10.1016/j.ccr.2012.09.022.

    Google Scholar 

  13. Pattabiraman DR, Weinberg RA. Targeting the epithelial-to-mesenchymal transition: the case for differentiation-based therapy. Cold Spring Harb Symp Quant Biol. 2017. doi:10.1101/sqb.2016.81.030957.

    Google Scholar 

  14. Martin-Belmonte F, Gassama A, Datta A, Yu W, Rescher U, Gerke V, et al. PTEN-mediated apical segregation of phosphoinositides controls epithelial morphogenesis through Cdc42. Cell. 2007. doi:10.1016/j.cell.2006.11.051.

    PubMed  PubMed Central  Google Scholar 

  15. McCaffrey LM, Montalbano J, Mihai C, Macara IG. Loss of the Par3 polarity protein promotes breast tumorigenesis and metastasis. Cancer Cell. 2012. doi:10.1016/j.ccr.2012.10.003.

    PubMed  PubMed Central  Google Scholar 

  16. Li J, Liu J, Li P, Mao X, Li W, Yang J, et al. Loss of LKB1 disrupts breast epithelial cell polarity and promotes breast cancer metastasis and invasion. J Exp Clin Cancer Res. 2014. doi:10.1186/s13046-014-0070-0.

    Google Scholar 

  17. Huang RY, Guilford P, Thiery JP. Early events in cell adhesion and polarity during epithelial–mesenchymal transition. J Cell Sci. 2012. doi:10.1242/jcs.099697.

    Google Scholar 

  18. Wijnhoven BP, Dinjens WN, Pignatelli M. E-cadherin–catenin cell–cell adhesion complex and human cancer. Br J Surg. 2000. doi:10.1046/j.1365-2168.2000.01513.x.

    PubMed  Google Scholar 

  19. Ghahhari NM, Babashah S. Interplay between microRNAs and WNT/beta-catenin signalling pathway regulates epithelial–mesenchymal transition in cancer. Eur J Cancer. 2015. doi:10.1016/j.ejca.2015.04.021.

    PubMed  Google Scholar 

  20. Goswami MT, Reka AK, Kurapati H, Kaza V, Chen J, Standiford TJ, et al. Regulation of complement-dependent cytotoxicity by TGF-beta-induced epithelial–mesenchymal transition. Oncogene. 2016. doi:10.1038/onc.2015.258.

    PubMed Central  Google Scholar 

  21. Serrano-Gomez SJ, Maziveyi M, Alahari SK. Regulation of epithelial–mesenchymal transition through epigenetic and post-translational modifications. Mol Cancer. 2016. doi:10.1186/s12943-016-0502-x.

    PubMed  PubMed Central  Google Scholar 

  22. Dumont N, Liu B, Defilippis RA, Chang H, Rabban JT, Karnezis AN, et al. Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics. Neoplasia. 2013;15:249–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature. 2004. doi:10.1038/nature03096.

    PubMed  PubMed Central  Google Scholar 

  24. Scheel C, Eaton EN, Li SH, Chaffer CL, Reinhardt F, Kah KJ, et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell. 2011. doi:10.1016/j.cell.2011.04.029.

    PubMed  PubMed Central  Google Scholar 

  25. Smith BN, Bhowmick NA. Role of EMT in metastasis and therapy resistance. J Clin Med. 2016. doi:10.1016/j.celrep.2014.12.032.

    Google Scholar 

  26. Li H, Batth IS, Qu X, Xu L, Song N, Wang R, et al. IGF-IR signaling in epithelial to mesenchymal transition and targeting IGF-IR therapy: overview and new insights. Mol Cancer. 2017. doi:10.1186/s12943-016-0576-5.

    Google Scholar 

  27. Chaffer CL, Marjanovic ND, Lee T, Bell G, Kleer CG, Reinhardt F, et al. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell. 2013. doi:10.1016/j.cell.2013.06.005.

    PubMed  PubMed Central  Google Scholar 

  28. Li HJ, Reinhardt F, Herschman HR, Weinberg RA. Cancer-stimulated mesenchymal stem cells create a carcinoma stem cell niche via prostaglandin E2 signaling. Cancer Discov. 2012. doi:10.1158/2159-8290.CD-12-0101.

    Google Scholar 

  29. Yamamoto M, Taguchi Y, Ito-Kureha T, Semba K, Yamaguchi N, Inoue J. NF-kappaB non-cell-autonomously regulates cancer stem cell populations in the basal-like breast cancer subtype. Nat Commun. 2013. doi:10.1038/ncomms3299.

    Google Scholar 

  30. Gonzalez DM, Medici D. Signaling mechanisms of the epithelial–mesenchymal transition. Sci Signal. 2014. doi:10.1126/scisignal.2005189.

    PubMed  PubMed Central  Google Scholar 

  31. Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, et al. E-cadherin germline mutations in familial gastric cancer. Nature. 1998. doi:10.1038/32918.

    PubMed  Google Scholar 

  32. Pharoah PD, Guilford P, Caldas C. International gastric cancer linkage C. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology. 2001;121:1348–53.

    Article  CAS  PubMed  Google Scholar 

  33. Puisieux A, Brabletz T, Caramel J. Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol. 2014. doi:10.1038/ncb2976.

    PubMed  Google Scholar 

  34. Bolos V, Peinado H, Perez-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.

    Article  CAS  PubMed  Google Scholar 

  35. Canel M, Serrels A, Frame MC, Brunton VG. E-cadherin-integrin crosstalk in cancer invasion and metastasis. J Cell Sci. 2013. doi:10.1242/jcs.100115.

    PubMed  Google Scholar 

  36. Vesuna F, van Diest P, Chen JH, Raman V. Twist is a transcriptional repressor of E-cadherin gene expression in breast cancer. Biochem Biophys Res Commun. 2008. doi:10.1016/j.bbrc.2007.11.151.

    PubMed  Google Scholar 

  37. Martinez-Estrada OM, Culleres A, Soriano FX, Peinado H, Bolos V, Martinez FO, et al. The transcription factors Slug and Snail act as repressors of Claudin-1 expression in epithelial cells. Biochem J. 2006. doi:10.1042/BJ20050591.

    PubMed  PubMed Central  Google Scholar 

  38. Ikenouchi J, Matsuda M, Furuse M, Tsukita S. Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail. J Cell Sci. 2003. doi:10.1242/jcs.00389.

    PubMed  Google Scholar 

  39. Ohkubo T, Ozawa M. The transcription factor Snail downregulates the tight junction components independently of E-cadherin downregulation. J Cell Sci. 2004. doi:10.1242/jcs.01004.

    PubMed  Google Scholar 

  40. Jorda M, Olmeda D, Vinyals A, Valero E, Cubillo E, Llorens A, et al. Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor. J Cell Sci. 2005. doi:10.1242/jcs.02465.

    PubMed  Google Scholar 

  41. Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010. doi:10.1016/j.cell.2010.03.015.

    PubMed  PubMed Central  Google Scholar 

  42. Taki M, Verschueren K, Yokoyama K, Nagayama M, Kamata N. Involvement of Ets-1 transcription factor in inducing matrix metalloproteinase-2 expression by epithelial–mesenchymal transition in human squamous carcinoma cells. Int J Oncol. 2006;28:487–96.

    CAS  PubMed  Google Scholar 

  43. Cichon MA, Radisky DC. ROS-induced epithelial–mesenchymal transition in mammary epithelial cells is mediated by NF-kB-dependent activation of Snail. Oncotarget. 2014. doi:10.18632/oncotarget.1940.

    PubMed  PubMed Central  Google Scholar 

  44. Massague J. TGFbeta signalling in context. Nat Rev Mol Cell Biol. 2012. doi:10.1038/nrm3434.

    PubMed  PubMed Central  Google Scholar 

  45. Tsubaki M, Komai M, Fujimoto S, Itoh T, Imano M, Sakamoto K, et al. Activation of NF-kappaB by the RANKL/RANK system up-regulates Snail and twist expressions and induces epithelial-to-mesenchymal transition in mammary tumor cell lines. J Exp Clin Cancer Res. 2013. doi:10.1186/1756-9966-32-62.

    PubMed  PubMed Central  Google Scholar 

  46. Li CW, Xia W, Huo L, Lim SO, Wu Y, Hsu JL, et al. Epithelial–mesenchymal transition induced by TNF-alpha requires NF-kappaB-mediated transcriptional upregulation of Twist1. Cancer Res. 2012. doi:10.1158/0008-5472.CAN-11-3123.

    Google Scholar 

  47. 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;3:718–21.

    Article  CAS  PubMed  Google Scholar 

  48. Stemmer V, de Craene B, Berx G, Behrens J. Snail promotes Wnt target gene expression and interacts with beta-catenin. Oncogene. 2008. doi:10.1038/onc.2008.140.

    PubMed  Google Scholar 

  49. Li B, Huang C. Regulation of EMT by STAT3 in gastrointestinal cancer (Review). Int J Oncol. 2017. doi:10.3892/ijo.2017.3846.

    Google Scholar 

  50. Kouzarides T. Chromatin modifications and their function. Cell. 2007. doi:10.1016/j.cell.2007.11.005.

    Google Scholar 

  51. Yoshiura K, Kanai Y, Ochiai A, Shimoyama Y, Sugimura T, Hirohashi S. Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. Proc Natl Acad Sci USA. 1995;92:7416–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Tamura G, Yin J, Wang S, Fleisher AS, Zou T, Abraham JM, et al. E-cadherin gene promoter hypermethylation in primary human gastric carcinomas. J Natl Cancer Inst. 2000;92:569–73.

    Article  CAS  PubMed  Google Scholar 

  53. Lombaerts M, van Wezel T, Philippo K, Dierssen JW, Zimmerman RM, Oosting J, et al. E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines. Br J Cancer. 2006. doi:10.1038/sj.bjc.6602996.

    PubMed  PubMed Central  Google Scholar 

  54. McDonald OG, Wu H, Timp W, Doi A, Feinberg AP. Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition. Nat Struct Mol Biol. 2011. doi:10.1038/nsmb.2084.

    PubMed  PubMed Central  Google Scholar 

  55. Ateeq B, Unterberger A, Szyf M, Rabbani SA. Pharmacological inhibition of DNA methylation induces proinvasive and prometastatic genes in vitro and in vivo. Neoplasia. 2008;10:266–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. McMahon S, Charbonneau M, Grandmont S, Richard DE, Dubois CM. Transforming growth factor beta1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression. J Biol Chem. 2006. doi:10.1074/jbc.M604507200.

    Google Scholar 

  57. Saitoh M. Epithelial–mesenchymal transition is regulated at post-transcriptional levels by transforming growth factor-beta signaling during tumor progression. Cancer Sci. 2015. doi:10.1111/cas.12630.

    Google Scholar 

  58. Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, et al. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial–mesenchymal transition. Nat Cell Biol. 2004. doi:10.1038/ncb1173.

    Google Scholar 

  59. Mahmood MQ, Ward C, Muller HK, Sohal SS, Walters EH. Epithelial mesenchymal transition (EMT) and non-small cell lung cancer (NSCLC): a mutual association with airway disease. Med Oncol. 2017. doi:10.1007/s12032-017-0900-y.

    PubMed  Google Scholar 

  60. Lu Z, Jiang G, Blume-Jensen P, Hunter T. Epidermal growth factor-induced tumor cell invasion and metastasis initiated by dephosphorylation and downregulation of focal adhesion kinase. Mol Cell Biol. 2001. doi:10.1128/MCB.21.12.4016-4031.2001.

    Google Scholar 

  61. Guo F, Parker Kerrigan BC, Yang D, Hu L, Shmulevich I, Sood AK, et al. Post-transcriptional regulatory network of epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions. J Hematol Oncol. 2014. doi:10.1186/1756-8722-7-19.

    Google Scholar 

  62. Braun J, Hoang-Vu C, Dralle H, Huttelmaier S. Downregulation of microRNAs directs the EMT and invasive potential of anaplastic thyroid carcinomas. Oncogene. 2010. doi:10.1038/onc.2010.169.

    PubMed  Google Scholar 

  63. Hill L, Browne G, Tulchinsky E. ZEB/miR-200 feedback loop: at the crossroads of signal transduction in cancer. Int J Cancer. 2013. doi:10.1002/ijc.27708.

    Google Scholar 

  64. Schubert J, Brabletz T. p53 Spreads out further: suppression of EMT and stemness by activating miR-200c expression. Cell Res. 2011. doi:10.1038/cr.2011.62.

    PubMed  PubMed Central  Google Scholar 

  65. Brabletz T. MiR-34 and SNAIL: another double-negative feedback loop controlling cellular plasticity/EMT governed by p53. Cell Cycle. 2012. doi:10.4161/cc.11.2.18900.

    PubMed Central  Google Scholar 

  66. Cha YH, Kim NH, Park C, Lee I, Kim HS, Yook JI. MiRNA-34 intrinsically links p53 tumor suppressor and Wnt signaling. Cell Cycle. 2012. doi:10.4161/cc.19618.

    Google Scholar 

  67. Zhao X, Dou W, He L, Liang S, Tie J, Liu C, et al. MicroRNA-7 functions as an anti-metastatic microRNA in gastric cancer by targeting insulin-like growth factor-1 receptor. Oncogene. 2013. doi:10.1038/onc.2012.156.

    Google Scholar 

  68. Musumeci M, Coppola V, Addario A, Patrizii M, Maugeri-Sacca M, Memeo L, et al. Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer. Oncogene. 2011. doi:10.1038/onc.2011.140.

    PubMed  Google Scholar 

  69. McCubrey JA, Fitzgerald TL, Yang LV, Lertpiriyapong K, Steelman LS, Abrams SL, et al. Roles of GSK-3 and microRNAs on epithelial mesenchymal transition and cancer stem cells. Oncotarget. 2016. doi:10.18632/oncotarget.13991.

    Google Scholar 

  70. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell. 2008. doi:10.1016/j.cell.2008.03.027.

    PubMed  PubMed Central  Google Scholar 

  71. Rasheed ZA, Yang J, Wang Q, Kowalski J, Freed I, Murter C, et al. Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. J Natl Cancer Inst. 2010. doi:10.1093/jnci/djp535.

    PubMed  PubMed Central  Google Scholar 

  72. Kong D, Banerjee S, Ahmad A, Li Y, Wang Z, Sethi S, et al. Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS ONE. 2010. doi:10.1371/journal.pone.0012445.

    Google Scholar 

  73. Hwang WL, Yang MH, Tsai ML, Lan HY, Su SH, Chang SC, et al. SNAIL regulates interleukin-8 expression, stem cell-like activity, and tumorigenicity of human colorectal carcinoma cells. Gastroenterology. 2011. doi:10.1053/j.gastro.2011.04.008.

    Google Scholar 

  74. Fan F, Samuel S, Evans KW, Lu J, Xia L, Zhou Y, et al. Overexpression of Snail induces epithelial–mesenchymal transition and a cancer stem cell-like phenotype in human colorectal cancer cells. Cancer Med. 2012. doi:10.1002/cam4.4.

    Google Scholar 

  75. Long H, Xiang T, Qi W, Huang J, Chen J, He L, et al. CD133+ ovarian cancer stem-like cells promote non-stem cancer cell metastasis via CCL5 induced epithelial–mesenchymal transition. Oncotarget. 2015. doi:10.18632/oncotarget.3462.

    Google Scholar 

  76. Kurrey NK, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD, Doiphode RY, et al. Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells. 2009. doi:10.1002/stem.154.

    PubMed  Google Scholar 

  77. Zhou D, Kannappan V, Chen X, Li J, Leng X, Zhang J, et al. RBP2 induces stem-like cancer cells by promoting EMT and is a prognostic marker for renal cell carcinoma. Exp Mol Med. 2016. doi:10.1038/emm.2016.37.

    PubMed  PubMed Central  Google Scholar 

  78. Celia-Terrassa T, Meca-Cortes O, Mateo F, Martinez de Paz A, Rubio N, Arnal-Estape A, et al. Epithelial–mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells. J Clin Invest. 2012. doi:10.1172/JCI59218.

    PubMed  PubMed Central  Google Scholar 

  79. Xie G, Ji A, Yuan Q, Jin Z, Yuan Y, Ren C, et al. Tumour-initiating capacity is independent of epithelial–mesenchymal transition status in breast cancer cell lines. Br J Cancer. 2014. doi:10.1038/bjc.2014.153.

    Google Scholar 

  80. Grosse-Wilde A, Fouquier d’Herouel A, McIntosh E, Ertaylan G, Skupin A, Kuestner RE, et al. Stemness of the hybrid epithelial/mesenchymal state in breast cancer and its association with poor survival. PLoS ONE. 2015. doi:10.1371/journal.pone.0126522.

    PubMed  PubMed Central  Google Scholar 

  81. Jolly MK, Jia D, Boareto M, Mani SA, Pienta KJ, Ben-Jacob E, et al. Coupling the modules of EMT and stemness: a tunable ‘stemness window’ model. Oncotarget. 2015. doi:10.18632/oncotarget.4629.

    Google Scholar 

  82. Andriani F, Bertolini G, Facchinetti F, Baldoli E, Moro M, Casalini P, et al. Conversion to stem-cell state in response to microenvironmental cues is regulated by balance between epithelial and mesenchymal features in lung cancer cells. Mol Oncol. 2016. doi:10.1016/j.molonc.2015.10.002.

    PubMed  Google Scholar 

  83. Chaffer CL, San Juan BP, Lim E, Weinberg RA. EMT, cell plasticity and metastasis. Cancer Metastasis Rev. 2016. doi:10.1007/s10555-016-9648-7.

    PubMed  Google Scholar 

  84. Gregory PA, Bracken CP, Smith E, Bert AG, Wright JA, Roslan S, et al. An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial–mesenchymal transition. Mol Biol Cell. 2011. doi:10.1091/mbc.E11-02-0103.

    PubMed  PubMed Central  Google Scholar 

  85. Gunasinghe NP, Wells A, Thompson EW, Hugo HJ. Mesenchymal–epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer. Cancer Metastasis Rev. 2012. doi:10.1007/s10555-012-9377-5.

    PubMed  Google Scholar 

  86. Stankic M, Pavlovic S, Chin Y, Brogi E, Padua D, Norton L, et al. TGF-beta-Id1 signaling opposes Twist1 and promotes metastatic colonization via a mesenchymal-to-epithelial transition. Cell Rep. 2013. doi:10.1016/j.celrep.2013.11.014.

    PubMed  PubMed Central  Google Scholar 

  87. Schmidt JM, Panzilius E, Bartsch HS, Irmler M, Beckers J, Kari V, et al. Stem-cell-like properties and epithelial plasticity arise as stable traits after transient Twist1 activation. Cell Rep. 2015. doi:10.1016/j.celrep.2014.12.032.

    Google Scholar 

  88. Hong T, Watanabe K, Ta CH, Villarreal-Ponce A, Nie Q, Dai X. An Ovol2-Zeb1 mutual inhibitory circuit governs bidirectional and multi-step transition between epithelial and mesenchymal states. PLoS Comput Biol. 2015. doi:10.1371/journal.pcbi.1004569.

    PubMed  PubMed Central  Google Scholar 

  89. Schliekelman MJ, Taguchi A, Zhu J, Dai X, Rodriguez J, Celiktas M, et al. Molecular portraits of epithelial, mesenchymal, and hybrid States in lung adenocarcinoma and their relevance to survival. Cancer Res. 2015. doi:10.1158/0008-5472.CAN-14-2535.

    PubMed  PubMed Central  Google Scholar 

  90. Grigore AD, Jolly MK, Jia D, Farach-Carson MC, Levine H. Tumor budding: the name is EMT. Partial EMT. J Clin Med. 2016. doi:10.3390/jcm5050051.

    PubMed  PubMed Central  Google Scholar 

  91. Clark AG, Vignjevic DM. Modes of cancer cell invasion and the role of the microenvironment. Curr Opin Cell Biol. 2015. doi:10.1016/j.ceb.2015.06.004.

    PubMed  Google Scholar 

  92. Bonnomet A, Syne L, Brysse A, Feyereisen E, Thompson EW, Noel A, et al. A dynamic in vivo model of epithelial-to-mesenchymal transitions in circulating tumor cells and metastases of breast cancer. Oncogene. 2012. doi:10.1038/onc.2011.540.

    PubMed  Google Scholar 

  93. Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci USA. 2009. doi:10.1073/pnas.0905718106.

    PubMed  PubMed Central  Google Scholar 

  94. Moitra K. Overcoming multidrug resistance in cancer stem cells. Biomed Res Int. 2015. doi:10.1155/2015/635745.

    PubMed  PubMed Central  Google Scholar 

  95. Pattabiraman DR, Bierie B, Kober KI, Thiru P, Krall JA, Zill C, et al. Activation of PKA leads to mesenchymal-to-epithelial transition and loss of tumor-initiating ability. Science. 2016. doi:10.1126/science.aad3680.

    PubMed  PubMed Central  Google Scholar 

  96. Yoshida T, Ozawa Y, Kimura T, Sato Y, Kuznetsov G, Xu S, et al. Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial–mesenchymal transition (EMT) to mesenchymal–epithelial transition (MET) states. Br J Cancer. 2014. doi:10.1038/bjc.2014.80.

    Google Scholar 

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All the authors gave substantial contributions to the conception and design of the study, data acquisition, and interpretation. They all revised the manuscript and approved the final version.

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  1. Laboratory of Translational Oncology, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Avda de Córdoba s/n, 28041, Madrid, Spain

    Elena Prieto-García, C. Vanesa Díaz-García, Inmaculada García-Ruiz & M. Teresa Agulló-Ortuño

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  1. Elena Prieto-García
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Prieto-García, E., Díaz-García, C.V., García-Ruiz, I. et al. Epithelial-to-mesenchymal transition in tumor progression. Med Oncol 34, 122 (2017). https://doi.org/10.1007/s12032-017-0980-8

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