The epigenetics of epithelial-mesenchymal plasticity in cancer

Nature Medicine

Volumn 19, Issue 11, 2013, Pages 1438-1449

  Tam, Wai Leong ^a,b   Weinberg, Robert A ^a,b  

^a WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH   (United States)

^b MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HISTONE DEACETYLASE; HISTONE DEMETHYLASE; TRANSCRIPTION FACTOR;

CANCER CELL; CANCER GROWTH; CARCINOGENESIS; CHROMATIN; CONFORMATIONAL TRANSITION; EPIGENETICS; EPITHELIAL MESENCHYMAL TRANSITION; GENE EXPRESSION; GENE SILENCING; GENE TARGETING; GENETIC REGULATION; HISTONE MODIFICATION; HUMAN; PARACRINE SIGNALING; PHENOTYPE; PHENOTYPIC PLASTICITY; PLASTICITY; PRIORITY JOURNAL; PROTEIN INTERACTION; REGULATORY MECHANISM; REVIEW;

EPIGENESIS, GENETIC; EPITHELIAL-MESENCHYMAL TRANSITION; HISTONES; HUMANS; MODELS, BIOLOGICAL; NEOPLASMS; PHENOTYPE; POLYCOMB-GROUP PROTEINS; SIGNAL TRANSDUCTION; TRANSCRIPTION, GENETIC;

EID: 84887456252     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: 10.1038/nm.3336     Document Type: Review

References (169)

1. Polyak, K. & Weinberg, R.A. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer 9, 265-273 (2009).
2. Thiery, J.P., Acloque, H., Huang, R.Y. & Nieto, M.A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871-890 (2009).
3. Scheel, C. et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 145, 926-940 (2011).
4. Katoh, Y. & Katoh, M. Hedgehog signaling, epithelial-to-mesenchymal transition and miRNA. Int. J. Mol. Med. 22, 271-275 (2008).
5. Moustakas, A. & Heldin, C.H. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci. 98, 1512-1520 (2007).
6. De Craene, B. & Berx, G. Regulatory networks defining EMT during cancer initiation and progression. Nat. Rev. Cancer 13, 97-110 (2013).
7. Zheng, H. & Kang, Y. Multilayer control of the EMT master regulators. Oncogene published online, doi:10.1038/onc.2013.128 (22 April 2013).
8. Mani, S.A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704-715 (2008).
9. Guo, W. et al. Slug and Sox9 cooperatively determine the mammary stem cell state. Cell 148, 1015-1028 (2012).
10. Gregory, P.A. et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol. 10, 593-601 (2008).
11. Peinado, H., Olmeda, D. & Cano, A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat. Rev. Cancer 7, 415-428 (2007).
12. Wellner, U. et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat. Cell Biol. 11, 1487-1495 (2009).
13. Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927-939 (2004).
14. Savagner, P., Yamada, K.M. & Thiery, J.P. The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition. J. Cell Biol. 137, 1403-1419 (1997).
15. Blanco, M.J. et al. Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 21, 3241-3246 (2002).
16. Ocaña, O.H. et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22, 709-724 (2012).
17. Tsai, J.H., Donaher, J.L., Murphy, D.A., Chau, S. & Yang, J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22, 725-736 (2012).
18. Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6-21 (2002).
19. Agger, K., Christensen, J., Cloos, P.A. & Helin, K. The emerging functions of histone demethylases. Curr. Opin. Genet. Dev. 18, 159-168 (2008).
20. Nieto, M.A. The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu. Rev. Cell Dev. Biol. 27, 347-376 (2011).
21. Morel, A.P. et al. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS ONE 3, e2888 (2008).
22. Rhim, A.D. et al. EMT and dissemination precede pancreatic tumor formation. Cell 148, 349-361 (2012).
23. Wang, Z. et al. Activated K-Ras and INK4a/Arf deficiency promote aggressiveness of pancreatic cancer by induction of EMT consistent with cancer stem cell phenotype. J. Cell Physiol. 228, 556-562 (2013).
24. Albino, D. et al. ESE3/EHF controls epithelial cell differentiation and its loss leads to prostate tumors with mesenchymal and stem-like features. Cancer Res. 72, 2889-2900 (2012).
25. Mulholland, D.J. et al. Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Res. 72, 1878-1889 (2012).
26. Morel, A.P. et al. EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors in transgenic mice. PLoS Genet. 8, e1002723 (2012).
27. Carey, L., Winer, E., Viale, G., Cameron, D. & Gianni, L. Triple-negative breast cancer: disease entity or title of convenience? Nat. Rev. Clin. Oncol. 7, 683-692 (2010).
28. Sarrió, D. et al. Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 68, 989-997 (2008).
29. Blick, T. et al. Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44hi/CD24lo/-stem cell phenotype in human breast cancer. J. Mammary Gland Biol. Neoplasia 15, 235-252 (2010).
30. Blick, T. et al. Epithelial mesenchymal transition traits in human breast cancer cell lines. Clin. Exp. Metastasis 25, 629-642 (2008).
31. Trelstad, R.L., Hay, E.D. & Revel, J.D. Cell contact during early morphogenesis in the chick embryo. Dev. Biol. 16, 78-106 (1967).
32. Arnoux, V., Nassour, M., L'Helgoualc'h, A., Hipskind, R.A. & Savagner, P. Erk5 controls Slug expression and keratinocyte activation during wound healing. Mol. Biol. Cell 19, 4738-4749 (2008).
33. Micalizzi, D.S., Farabaugh, S.M. & Ford, H.L. Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. J. Mammary Gland Biol. Neoplasia 15, 117-134 (2010).
34. Bednarz-Knoll, N., Alix-Panabieres, C. & Pantel, K. Plasticity of disseminating cancer cells in patients with epithelial malignancies. Cancer Metastasis Rev. 31, 673-687 (2012).
35. Chao, Y., Wu, Q., Acquafondata, M., Dhir, R. & Wells, A. Partial mesenchymal to epithelial reverting transition in breast and prostate cancer metastases. Cancer Microenviron. 5, 19-28 (2012).
36. Leroy, P. & Mostov, K.E. Slug is required for cell survival during partial epithelial-mesenchymal transition of HGF-induced tubulogenesis. Mol. Biol. Cell 18, 1943-1952 (2007).
37. Theveneau, E. & Mayor, R. Neural crest delamination and migration: from epithelium-to-mesenchyme transition to collective cell migration. Dev. Biol. 366, 34-54 (2012).
38. Gupta, P.B. et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 146, 633-644 (2011).
39. Chaffer, C.L. et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc. Natl. Acad. Sci. USA 108, 7950-7955 (2011).
40. Schwitalla, S. et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152, 25-38 (2013).
41. Frisch, S.M. The epithelial cell default-phenotype hypothesis and its implications for cancer. Bioessays 19, 705-709 (1997).
42. Jechlinger, M. et al. Autocrine PDGFR signaling promotes mammary cancer metastasis. J. Clin. Invest. 116, 1561-1570 (2006).
43. Sparmann, A. & van Lohuizen, M. Polycomb silencers control cell fate, development and cancer. Nat. Rev. Cancer 6, 846-856 (2006).
44. Pietersen, A.M. & van Lohuizen, M. Stem cell regulation by polycomb repressors: postponing commitment. Curr. Opin. Cell Biol. 20, 201-207 (2008).
45. Orlando, V. Polycomb, epigenomes, and control of cell identity. Cell 112, 599-606 (2003).
46. Cedar, H. & Bergman, Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat. Rev. Genet. 10, 295-304 (2009).
47. Bracken, A.P. & Helin, K. Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nat. Rev. Cancer 9, 773-784 (2009).
48. Bracken, A.P., Dietrich, N., Pasini, D., Hansen, K.H. & Helin, K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 20, 1123-1136 (2006).
49. Cao, Q. et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene 27, 7274-7284 (2008).
50. Herranz, N. et al. Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor. Mol. Cell Biol. 28, 4772-4781 (2008).
51. Iliopoulos, D. et al. Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. Mol. Cell 39, 761-772 (2010).
52. Zaret, K.S. & Carroll, J.S. Pioneer transcription factors: establishing competence for gene expression. Genes Dev. 25, 2227-2241 (2011).
53. Wright, M.H. et al. Brca1 breast tumors contain distinct CD44+/CD24-and CD133+ cells with cancer stem cell characteristics. Breast Cancer Res. 10, R10 (2008).
54. Chang, C.J. et al. EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-?-catenin signaling. Cancer Cell 19, 86-100 (2011).
55. Collett, K. et al. Expression of enhancer of zeste homologue 2 is significantly associated with increased tumor cell proliferation and is a marker of aggressive breast cancer. Clin. Cancer Res. 12, 1168-1174 (2006).
56. Kleer, C.G. et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl. Acad. Sci. USA 100, 11606-11611 (2003).
57. Puppe, J. et al. BRCA1-deficient mammary tumor cells are dependent on EZH2 expression and sensitive to Polycomb Repressive Complex 2-inhibitor 3-deazaneplanocin A. Breast Cancer Res. 11, R63 (2009).
58. Onder, T.T. et al. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 68, 3645-3654 (2008).
59. Mills, A.A. Throwing the cancer switch: reciprocal roles of polycomb and trithorax proteins. Nat. Rev. Cancer 10, 669-682 (2010).
60. Molofsky, A.V. et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962-967 (2003).
61. Iwama, A. et al. Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity 21, 843-851 (2004).
62. Sangiorgi, E. & Capecchi, M.R. Bmi1 is expressed in vivo in intestinal stem cells. Nat. Genet. 40, 915-920 (2008).
63. Sangiorgi, E. & Capecchi, M.R. Bmi1 lineage tracing identifies a self-renewing pancreatic acinar cell subpopulation capable of maintaining pancreatic organ homeostasis. Proc. Natl. Acad. Sci. USA 106, 7101-7106 (2009).
64. Lobo, N.A., Shimono, Y., Qian, D. & Clarke, M.F. The biology of cancer stem cells. Annu. Rev. Cell Dev. Biol. 23, 675-699 (2007).
65. Valk-Lingbeek, M.E., Bruggeman, S.W. & van Lohuizen, M. Stem cells and cancer; the polycomb connection. Cell 118, 409-418 (2004).
66. Pardal, R., Molofsky, A.V., He, S. & Morrison, S.J. Stem cell self-renewal and cancer cell proliferation are regulated by common networks that balance the activation of proto-oncogenes and tumor suppressors. Cold Spring Harb. Symp. Quant. Biol. 70, 177-185 (2005).
67. Park, I.K., Morrison, S.J. & Clarke, M.F. Bmi1, stem cells, and senescence regulation. J. Clin. Invest. 113, 175-179 (2004).
68. Song, L.B. et al. The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. J. Clin. Invest. 119, 3626-3636 (2009).
69. Martin, A. & Cano, A. Tumorigenesis: Twist1 links EMT to self-renewal. Nat. Cell Biol. 12, 924-925 (2010).
70. Yang, M.H. et al. Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat. Cell Biol. 12, 982-992 (2010).
71. Peinado, H., Ballestar, E., Esteller, M. & Cano, A. Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol. Cell Biol. 24, 306-319 (2004).
72. von Burstin, J. et al. E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex. Gastroenterology 137, 361-371, 371.e1-5 (2009).
73. Lin, Y. et al. The SNAG domain of Snail1 functions as a molecular hook for recruiting lysine-specific demethylase 1. EMBO J. 29, 1803-1816 (2010).
74. Fu, J. et al. The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis. Cell Res. 21, 275-289 (2011).
75. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941-953 (2004).
76. Harris, W.J. et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell 21, 473-487 (2012).
77. Lim, S. et al. Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology. Carcinogenesis 31, 512-520 (2010).
78. Lin, T., Ponn, A., Hu, X., Law, B.K. & Lu, J. Requirement of the histone demethylase LSD1 in Snai1-mediated transcriptional repression during epithelial-mesenchymal transition. Oncogene 29, 4896-4904 (2010).
79. Schenk, T. et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat. Med. 18, 605-611 (2012).
80. Wang, Y. et al. LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell 138, 660-672 (2009).
81. Metzger, E. et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436-439 (2005).
82. Bernstein, B.E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315-326 (2006).
83. Chaffer, C.L. et al. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell 154, 61-74 (2013).
84. Maruyama, R. et al. Epigenetic regulation of cell type-specific expression patterns in the human mammary epithelium. PLoS Genet. 7, e1001369 (2011).
85. Vallés, A.M. et al. Acidic fibroblast growth factor is a modulator of epithelial plasticity in a rat bladder carcinoma cell line. Proc. Natl. Acad. Sci. USA 87, 1124-1128 (1990).
86. Dong, C. et al. G9a interacts with Snail and is critical for Snail-mediated E-cadherin repression in human breast cancer. J. Clin. Invest. 122, 1469-1486 (2012).
87. Dong, C. et al. Interaction with Suv39H1 is critical for Snail-mediated E-cadherin repression in breast cancer. Oncogene 32, 1351-1362 (2013).
88. Ke, X.S. et al. Global profiling of histone and DNA methylation reveals epigenetic-based regulation of gene expression during epithelial to mesenchymal transition in prostate cells. BMC Genomics 11, 669 (2010).
89. Bert, S.A. et al. Regional activation of the cancer genome by long-range epigenetic remodeling. Cancer Cell 23, 9-22 (2013).
90. Zouridis, H. et al. Methylation subtypes and large-scale epigenetic alterations in gastric cancer. Sci. Transl. Med. 4, 156ra140 (2012).
91. Coolen, M.W. et al. Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity. Nat. Cell Biol. 12, 235-246 (2010).
92. Easwaran, H. & Baylin, S.B. Epigenetic abnormalities in cancer find a "home on the range". Cancer Cell 23, 1-3 (2013).
93. Creighton, C.J. et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc. Natl. Acad. Sci. USA 106, 13820-13825 (2009).
94. Li, X. et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J. Natl. Cancer Inst. 100, 672-679 (2008).
95. Singh, A. & Settleman, J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29, 4741-4751 (2010).
96. Diehn, M. et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780-783 (2009).
97. Ceppi, P. et al. Loss of miR-200c expression induces an aggressive, invasive, and chemoresistant phenotype in non-small cell lung cancer. Mol. Cancer Res. 8, 1207-1216 (2010).
98. Vrba, L. et al. Role for DNA methylation in the regulation of miR-200c and miR-141 expression in normal and cancer cells. PLoS ONE 5, e8697 (2010).
99. Eades, G. et al. miR-200a regulates SIRT1 expression and epithelial to mesenchymal transition (EMT)-like transformation in mammary epithelial cells. J. Biol. Chem. 286, 25992-26002 (2011).
100. Tryndyak, V.P., Beland, F.A. & Pogribny, I.P. E-cadherin transcriptional down-regulation by epigenetic and microRNA-200 family alterations is related to mesenchymal and drug-resistant phenotypes in human breast cancer cells. Int. J. Cancer 126, 2575-2583 (2010).
101. Daskalakis, M. et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2?-deoxycytidine (decitabine) treatment. Blood 100, 2957-2964 (2002).
102. Petti, M.C. et al. Complete remission through blast cell differentiation in PLZF/RAR?-positive acute promyelocytic leukemia: in vitro and in vivo studies. Blood 100, 1065-1067 (2002).
103. Shaker, S., Bernstein, M., Momparler, L.F. & Momparler, R.L. Preclinical evaluation of antineoplastic activity of inhibitors of DNA methylation (5-aza-2?-deoxycytidine) and histone deacetylation (trichostatin A, depsipeptide) in combination against myeloid leukemic cells. Leuk. Res. 27, 437-444 (2003).
104. Cameron, E.E., Bachman, K.E., Myohanen, S., Herman, J.G. & Baylin, S.B. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat. Genet. 21, 103-107 (1999).
105. Lengauer, C. Cancer. An unstable liaison. Science 300, 442-443 (2003).
106. Gaudet, F. et al. Induction of tumors in mice by genomic hypomethylation. Science 300, 489-492 (2003).
107. Eden, A., Gaudet, F., Waghmare, A. & Jaenisch, R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300, 455 (2003).
108. Yang, A.S., Estecio, M.R., Garcia-Manero, G., Kantarjian, H.M. & Issa, J.P. Comment on "Chromosomal instability and tumors promoted by DNA hypomethylation" and "Induction of tumors in nice by genomic hypomethylation". Science 302, 1153 (2003).
109. Bruzzese, F. et al. HDAC inhibitor vorinostat enhances the antitumor effect of gefitinib in squamous cell carcinoma of head and neck by modulating ErbB receptor expression and reverting EMT. J. Cell. Physiol. 226, 2378-2390 (2011).
110. Lei, W. et al. Histone deacetylase 1 is required for transforming growth factor-?1-induced epithelial-mesenchymal transition. Int. J. Biochem. Cell Biol. 42, 1489-1497 (2010).
111. Kaimori, A. et al. Histone deacetylase inhibition suppresses the transforming growth factor ?1-induced epithelial-to-mesenchymal transition in hepatocytes. Hepatology 52, 1033-1045 (2010).
112. Jiang, G.M. et al. Histone deacetylase inhibitor induction of epithelial-mesenchymal transitions via up-regulation of Snail facilitates cancer progression. Biochim. Biophys. Acta 1833, 663-671 (2013).
113. Kong, D. et al. Histone deacetylase inhibitors induce epithelial-to-mesenchymal transition in prostate cancer cells. PLoS ONE 7, e45045 (2012).
114. Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067-1073 (2010).
115. Delmore, J.E. et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904-917 (2011).
116. Whyte, W.A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307-319 (2013).
117. Lovén, J. et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320-334 (2013).
118. Daigle, S.R. et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20, 53-65 (2011).
119. Knutson, S.K. et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat. Chem. Biol. 8, 890-896 (2012).
120. Finn, R.S. et al. Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/"triple-negative" breast cancer cell lines growing in vitro. Breast Cancer Res. Treat. 105, 319-326 (2007).
121. Tam, W.L. et al. Protein kinase C ? is a central signaling node and therapeutic target for breast cancer stem cells. Cancer Cell 24, 347-364 (2013).
122. Bonde, A.K., Tischler, V., Kumar, S., Soltermann, A. & Schwendener, R.A. Intratumoral macrophages contribute to epithelial-mesenchymal transition in solid tumors. BMC Cancer 12, 35 (2012).
123. Gao, M.Q. et al. Stromal fibroblasts from the interface zone of human breast carcinomas induce an epithelial-mesenchymal transition-like state in breast cancer cells in vitro. J. Cell Sci. 123, 3507-3514 (2010).
124. van Zijl, F. et al. Hepatic tumor-stroma crosstalk guides epithelial to mesenchymal transition at the tumor edge. Oncogene 28, 4022-4033 (2009).
125. Li, H.J., Reinhardt, F., Herschman, H.R. & Weinberg, R.A. Cancer-stimulated mesenchymal stem cells create a carcinoma stem-cell niche via Prostaglandin E2 signaling. Cancer Discov. 2, 840-855 (2012).
126. Wyckoff, J.B. et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 67, 2649-2656 (2007).
127. Yu, M. et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339, 580-584 (2013).
128. Brabletz, T. To differentiate or not-routes towards metastasis. Nat. Rev. Cancer 12, 425-436 (2012).
129. Brabletz, S. & Brabletz, T. The ZEB/miR-200 feedback loop-a motor of cellular plasticity in development and cancer? EMBO Rep. 11, 670-677 (2010).
130. Bracken, C.P. et al. A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 68, 7846-7854 (2008).
131. Chang, C.J. et al. p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat. Cell Biol. 13, 317-323 (2011).
132. Acloque, H., Adams, M.S., Fishwick, K., Bronner-Fraser, M. & Nieto, M.A. Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J. Clin. Invest. 119, 1438-1449 (2009).
133. Thiery, J.P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2, 442-454 (2002).
134. Zavadil, J. & Bottinger, E.P. TGF-? and epithelial-to-mesenchymal transitions. Oncogene 24, 5764-5774 (2005).
135. Taylor, M.A., Parvani, J.G. & Schiemann, W.P. The pathophysiology of epithelial-mesenchymal transition induced by transforming growth factor-? in normal and malignant mammary epithelial cells. J. Mammary Gland Biol. Neoplasia 15, 169-190 (2010).
136. Han, G. et al. Distinct mechanisms of TGF-?1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis. J. Clin. Invest. 115, 1714-1723 (2005).
137. Lehmann, K. et al. Raf induces TGF? production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. Genes Dev. 14, 2610-2622 (2000).
138. Oft, M., Heider, K.H. & Beug, H. TGF? signaling is necessary for carcinoma cell invasiveness and metastasis. Curr. Biol. 8, 1243-1252 (1998).
139. Xi, Q. et al. A poised chromatin platform for TGF-? access to master regulators. Cell 147, 1511-1524 (2011).
140. McDonald, O.G., Wu, H., Timp, W., Doi, A. & Feinberg, A.P. Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition. Nat. Struct. Mol. Biol. 18, 867-874 (2011).
141. Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 12, 468-476 (2010).
142. Moon, R.T., Kohn, A.D., De Ferrari, G.V. & Kaykas, A. WNT and ?-catenin signalling: diseases and therapies. Nat. Rev. Genet. 5, 691-701 (2004).
143. Taketo, M.M. Shutting down Wnt signal-activated cancer. Nat. Genet. 36, 320-322 (2004).
144. Liu, B.Y., McDermott, S.P., Khwaja, S.S. & Alexander, C.M. The transforming activity of Wnt effectors correlates with their ability to induce the accumulation of mammary progenitor cells. Proc. Natl. Acad. Sci. USA 101, 4158-4163 (2004).
145. Mohamed, O.A., Clarke, H.J. & Dufort, D. ?-catenin signaling marks the prospective site of primitive streak formation in the mouse embryo. Dev. Dyn. 231, 416-424 (2004).
146. Kemler, R. et al. Stabilization of ?-catenin in the mouse zygote leads to premature epithelial-mesenchymal transition in the epiblast. Development 131, 5817-5824 (2004).
147. Kim, K., Lu, Z. & Hay, E.D. Direct evidence for a role of ?-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biol. Int. 26, 463-476 (2002).
148. Reya, T. & Clevers, H. Wnt signalling in stem cells and cancer. Nature 434, 843-850 (2005).
149. Yook, J.I. et al. A Wnt-Axin2-GSK3? cascade regulates Snail1 activity in breast cancer cells. Nat. Cell Biol. 8, 1398-1406 (2006).
150. Gilles, C. et al. Transactivation of vimentin by ?-catenin in human breast cancer cells. Cancer Res. 63, 2658-2664 (2003).
151. Kong, D. et al. Platelet-derived growth factor-D overexpression contributes to epithelial-mesenchymal transition of PC3 prostate cancer cells. Stem Cells 26, 1425-1435 (2008).
152. Brabletz, S. et al. The ZEB1/miR-200 feedback loop controls Notch signalling in cancer cells. EMBO J. 30, 770-782 (2011).
153. Thomson, S. et al. A systems view of epithelial-mesenchymal transition signaling states. Clin. Exp. Metastasis 28, 137-155 (2011).
154. Hardy, K.M., Booth, B.W., Hendrix, M.J., Salomon, D.S. & Strizzi, L. ErbB/EGF signaling and EMT in mammary development and breast cancer. J. Mammary Gland Biol. Neoplasia 15, 191-199 (2010).
155. Sakai, D. et al. Regulation of Slug transcription in embryonic ectoderm by ?-catenin-Lef/Tcf and BMP-Smad signaling. Dev. Growth Differ. 47, 471-482 (2005).
156. Sánchez-Tilló, E. et al. ?-catenin/TCF4 complex induces the epithelial-to-mesenchymal transition (EMT)-activator ZEB1 to regulate tumor invasiveness. Proc. Natl. Acad. Sci. USA 108, 19204-19209 (2011).
157. Kim, T. et al. p53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEB1 and ZEB2. J. Exp. Med. 208, 875-883 (2011).
158. Korpal, M., Lee, E.S., 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. 283, 14910-14914 (2008).
159. Park, S.M., Gaur, A.B., Lengyel, E. & Peter, M.E. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 22, 894-907 (2008).
160. Davalos, V. et al. Dynamic epigenetic regulation of the microRNA-200 family mediates epithelial and mesenchymal transitions in human tumorigenesis. Oncogene 31, 2062-2074 (2012).
161. Neves, R. et al. Role of DNA methylation in miR-200c/141 cluster silencing in invasive breast cancer cells. BMC Res. Notes 3, 219 (2010).
162. Wiklund, E.D. et al. Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer. Int. J. Cancer 128, 1327-1334 (2011).
163. Tellez, C.S. et al. EMT and stem cell-like properties associated with miR-205 and miR-200 epigenetic silencing are early manifestations during carcinogen-induced transformation of human lung epithelial cells. Cancer Res. 71, 3087-3097 (2011).
164. Kasinski, A.L. & Slack, F.J. Epigenetics and genetics. MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy. Nat. Rev. Cancer 11, 849-864 (2011).
165. Kong, Y.W., Ferland-McCollough, D., Jackson, T.J. & Bushell, M. microRNAs in cancer management. Lancet Oncol. 13, e249-e258 (2012).
166. Rinn, J.L. & Chang, H.Y. Genome regulation by long noncoding RNAs. Annu. Rev. Biochem. 81, 145-166 (2012).
167. Prensner, J.R. & Chinnaiyan, A.M. The emergence of lncRNAs in cancer biology. Cancer Discov. 1, 391-407 (2011).
168. Gupta, R.A. et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071-1076 (2010).
169. Rinn, J.L. et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311-1323 (2007)