The biological and clinical importance of epithelial–mesenchymal transition in circulating tumor cells

Journal of Cancer Research and Clinical Oncology

Volumn 141, Issue 2, 2015, Pages 189-201

  Liu, Huiying ^a   Zhang, Xiaofeng ^a   Li, Jun ^a   Sun, Bin ^a   Qian, Haihua ^a   Yin, Zhengfeng ^a  

^a SECOND MILITARY MEDICAL UNIVERSITY   (China)

Author keywords

Circulating tumor cells (CTCs); Epithelial mesenchymal transition (EMT); Mesenchymal epithelial transition (MET); Metastasis

Indexed keywords

TUMOR MARKER;

ANIMAL; DRUG RESISTANCE; EPITHELIAL MESENCHYMAL TRANSITION; HUMAN; METASTASIS; NEOPLASMS; PATHOLOGY; TUMOR EMBOLISM;

ANIMALS; DRUG RESISTANCE, NEOPLASM; EPITHELIAL-MESENCHYMAL TRANSITION; HUMANS; NEOPLASM METASTASIS; NEOPLASMS; NEOPLASTIC CELLS, CIRCULATING; TUMOR MARKERS, BIOLOGICAL;

EID: 84924962104     PISSN: 01715216     EISSN: 14321335     Source Type: Journal    
DOI: 10.1007/s00432-014-1752-x     Document Type: Review

References (109)

1. Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer S (2009) Stem cell and epithelial–mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res 11:R46
2. Ansieau S, Bastid J, Doreau A, Morel AP, Bouchet BP, Thomas C, Fauvet F, Puisieux I, Doglioni C, Piccinin S, Maestro R, Voeltzel T, Selmi A, Valsesia-Wittmann S, de Fromentel CC, Puisieux A (2008) Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell 14:79–89
3. Aokage K, Ishii G, Ohtaki Y, Yamaguchi Y, Hishida T, Yoshida J, Nishimura M, Nagai K, Ochiai A (2011) Dynamic molecular changes associated with epithelial–mesenchymal transition and subsequent mesenchymal–epithelial transition in the early phase of metastatic tumor formation. Int J Cancer 128:1585–1595
4. Armstrong AJ, Marengo MS, Oltean S, Kemeny G, Bitting RL, Turnbull JD, Herold CI, Marcom PK, George DJ, Garcia-Blanco MA (2011) Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Mol Cancer Res 9:997–1007
5. Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Abbruzzese JL, Gallick GE, Logsdon CD, McConkey DJ, Choi W (2009) Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res 69:5820–5828
6. Balasubramanian P, Lang JC, Jatana KR, Miller B, Ozer E, Old M, Schuller DE, Agrawal A, Teknos TN, Summers TA Jr, Lustberg MB, Zborowski M, Chalmers JJ (2012) Multiparameter analysis, including EMT markers, on negatively enriched blood samples from patients with squamous cell carcinoma of the head and neck. PLoS ONE 7:e42048
7. Barrallo-Gimeno A, Nieto MA (2005) The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 132:3151–3161
8. Barrière G, Riouallon A, Renaudie J, Tartary M, Rigaud M (2012) Mesenchymal and stemness circulating tumor cells in early breast cancer diagnosis. BMC Cancer 12:114
9. Beasley GM, Riboh JC, Augustine CK, Zager JS, Hochwald SN, Grobmyer SR, Peterson B, Royal R, Ross MI, Tyler DS (2011) Prospective multicenter phase II trial of systemic ADH-1 in combination with melphalan via isolated limb infusion in patients with advanced extremity melanoma. J Clin Oncol 29:1210–1215
10. Bednarz N, Eltze E, Semjonow A, Rink M, Andreas A, Mulder L, Hannemann J, Fisch M, Pantel K, Weier HU, Bielawski KP, Brandt B (2010) BRCA1 loss preexisting in small subpopulations of prostate cancer is associated with advanced disease and metastatic spread to lymph nodes and peripheral blood. Clin Cancer Res 16:3340–3348
11. Bednarz-Knoll N, Alix-Panabières C, Pantel K (2012) Plasticity of disseminating cancer cells in patients with epithelial malignancies. Cancer Metastasis Rev 31:673–687
12. Berezovskaya O, Schimmer AD, Glinskii AB, Pinilla C, Hoffman RM, Reed JC, Glinsky GV (2005) Increased expression of apoptosis inhibitor protein XIAP contributes to anoikis resistance of circulating human prostate cancer metastasis precursor cells. Cancer Res 65:2378–2386
13. Bonnomet A, Syne L, Brysse A, Feyereisen E, Thompson EW, Noël A, Foidart JM, Birembaut P, Polette M, Gilles C (2012) A dynamic in vivo model of epithelial-to-mesenchymal transitions in circulating tumor cells and metastases of breast cancer. Oncogene 31:3741–3753
14. Byers LA, Diao L, Wang J, Saintigny P, Girard L, Peyton M, Shen L, Fan Y, Giri U, Tumula PK, Nilsson MB, Gudikote J, Tran H, Cardnell RJ, Bearss DJ, Warner SL, Foulks JM, Kanner SB, Gandhi V, Krett N, Rosen ST, Kim ES, Herbst RS, Blumenschein GR, Lee JJ, Lippman SM, Ang KK, Mills GB, Hong WK, Weinstein JN, Wistuba II, Coombes KR, Minna JD, Heymach JV (2013) An epithelial–mesenchymal transition gene signature predicts resistance to EGFR and PI3 K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin Cancer Res 19:279–290
15. Chaffer CL, Weinberg RA (2011) A perspective on cancer cell metastasis. Science 331:1559–1564
16. Chaffer CL, Brennan JP, Slavin JL, Blick T, Thompson EW, Williams ED (2006) Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Res 66:11271–11278
17. Chao YL, Shepard CR, Wells A (2010) Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Mol Cancer 9:179
18. Chao Y, Wu Q, Acquafondata M, Dhir R, Wells A (2012) Partial mesenchymal to epithelial reverting transition in breast and prostate cancer metastases. Cancer Microenviron 5:19–28
19. Chui MH (2013) Insights into cancer metastasis from a clinicopathologic perspective: epithelial–mesenchymal transition is not a necessary step. Int J Cancer 132:1487–1495
20. Chunhacha P, Sriuranpong V, Chanvorachote P (2013) Epithelial–mesenchymal transition mediates anoikis resistance and enhances invasion in pleural effusion-derived human lung cancer cells. Oncol Lett 5:1043–1047
21. Derksen PW, Liu X, Saridin F, van der Gulden H, Zevenhoven J, Evers B, van Beijnum JR, Griffioen AW, Vink J, Krimpenfort P, Peterse JL, Cardiff RD, Berns A, Jonkers J (2006) Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell 10:437–449
22. DiMeo TA, Anderson K, Phadke P, Fan C, Perou CM, Naber S, Kuperwasser C (2009) A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial–mesenchymal transition in basal-like breast cancer. Cancer Res 69:5364–5373
23. Drake JM, Strohbehn G, Bair TB, Moreland JG, Henry MD (2009) ZEB1 enhances transendothelial migration and represses the epithelial phenotype of prostate cancer cells. Mol Biol Cell 20:2207–2217
24. Duda DG, Duyverman AM, Kohno M, Snuderl M, Steller EJ, Fukumura D, Jain RK (2010) Malignant cells facilitate lung metastasis by bringing their own soil. Proc Natl Acad Sci USA 107:21677–21682
25. Fehm T, Müller V, Aktas B, Janni W, Schneeweiss A, Stickeler E, Lattrich C, Löhberg CR, Solomayer E, Rack B, Riethdorf S, Klein C, Schindlbeck C, Brocker K, Kasimir-Bauer S, Wallwiener D, Pantel K (2010) HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial. Breast Cancer Res Treat 124:403–412
26. Garber K (2008) Epithelial-to-mesenchymal transition is important to metastasis, but questions remain. J Natl Cancer Inst 100(232–233):239
27. Giannoni E, Bianchini F, Masieri L, Serni S, Torre E, Calorini L, Chiarugi P (2010) Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial–mesenchymal transition and cancer stemness. Cancer Res 70:6945–6956
28. Gorges TM, Tinhofer I, Drosch M, Röse L, Zollner TM, Krahn T, von Ahsen O (2012) Circulating tumour cells escape from EpCAM-based detection due to epithelial-to-mesenchymal transition. BMC Cancer 12:178
29. Gradilone A, Naso G, Raimondi C, Cortesi E, Gandini O, Vincenzi B, Saltarelli R, Chiapparino E, Spremberg F, Cristofanilli M, Frati L, Aglianò AM, Gazzaniga P (2011a) Circulating tumor cells (CTCs) in metastatic breast cancer (MBC): prognosis, drug resistance and phenotypic characterization. Ann Oncol 22:86–92
30. Gradilone A, Raimondi C, Nicolazzo C, Petracca A, Gandini O, Vincenzi B, Naso G, Aglianò AM, Cortesi E, Gazzaniga P (2011b) Circulating tumour cells lacking cytokeratin in breast cancer: the importance of being mesenchymal. J Cell Mol Med 15:1066–1070
31. Grunert S, Jechlinger M, Beug H (2003) Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol 4:657–665
32. Han X, Fang X, Lou X, Hua D, Ding W, Foltz G, Hood L, Yuan Y, Lin B (2012) Silencing SOX2 induced mesenchymal–epithelial transition and its expression predicts liver and lymph node metastasis of CRC patients. PLoS ONE 7:e41335
33. Hiscox S, Jiang WG, Obermeier K, Taylor K, Morgan L, Burmi R, Barrow D, Nicholson RI (2006) Tamoxifen resistance in MCF7 cells promotes EMT-like behaviour and involves modulation of beta-catenin phosphorylation. Int J Cancer 118:290–301
34. Hoshino H, Miyoshi N, Nagai K, Tomimaru Y, Nagano H, Sekimoto M, Doki Y, Mori M, Ishii H (2009) Epithelial mesenchymal transition with expression of SNAI1-induced chemoresistance in colorectal cancer. Biochem Biophys Res Commun 390:1061–1065
35. Hou JM, Krebs M, Ward T, Sloane R, Priest L, Hughes A, Clack G, Ranson M, Blackhall F, Dive C (2011) Circulating tumor cells as a window on metastasis biology in lung cancer. Am J Pathol 178:989–996
36. Howard EW, Leung SC, Yuen HF, Chua CW, Lee DT, Chan KW, Wang X, Wong YC (2008) Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer. Clin Exp Metastasis 25:497–508
37. Huber MA, Kraut N, Beug H (2005) Molecular requirements for epithelial–mesenchymal transition during tumor progression. Curr Opin Cell Biol 17:548–558
38. Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED, Thompson EW (2007) Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. J Cell Physiol 213:374–383
39. Kaiser J (2010) Medicine. Cancer's circulation problem. Science 327:1072–1074
40. Kajiyama H, Shibata K, Terauchi M, Yamashita M, Ino K, Nawa A, Kikkawa F (2007) Chemoresistance to paclitaxel induces epithelial–mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells. Int J Oncol 31:277–283
41. Kallergi G, Papadaki MA, Politaki E, Mavroudis D, Georgoulias V, Agelaki S (2011) Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients. Breast Cancer Res 13:R59
42. Kalluri R, Weinberg RA (2009) The basics of epithelial–mesenchymal transition. J Clin Invest 119:1420–1428
43. Kang Y, Pantel K (2013) Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell 23:573–581
44. Kasimir-Bauer S, Hoffmann O, Wallwiener D, Kimmig R, Fehm T (2012) Expression of stem cell and epithelial–mesenchymal transition markers in primary breast cancer patients with circulating tumor cells. Breast Cancer Res 14:R15
45. Khoja L, Backen A, Sloane R, Menasce L, Ryder D, Krebs M, Board R, Clack G, Hughes A, Blackhall F, Valle JW, Dive C (2011) A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarker. Br J Cancer 106:508–516
46. Königsberg R, Obermayr E, Bises G, Pfeiler G, Gneist M, Wrba F, de Santis M, Zeillinger R, Hudec M, Dittrich C (2011) Detection of EpCAM positive and negative circulating tumor cells in metastatic breast cancer patients. Acta Oncol 50:700–710
47. Kowalski PJ, Rubin MA, Kleer CG (2003) E-cadherin expression in primary carcinomas of the breast and its distant metastases. Breast Cancer Res 5:R217–R222
48. Książkiewicz M, Markiewicz A, Zaczek AJ (2012) Epithelial–mesenchymal transition: a hallmark in metastasis formation linking circulating tumor cells and cancer stem cells. Pathobiology 79:195–208
49. Larson CJ, Moreno JG, Pienta KJ, Gross S, Repollet M, O’hara SM, Russell T, Terstappen LW (2004) Apoptosis of circulating tumor cells in prostate cancer patients. Cytom A 62:46–53
50. Lecharpentier A, Vielh P, Perez-Moreno P, Planchard D, Soria JC, Farace F (2011) Detection of circulating tumour cells with a hybrid (epithelial/mesenchymal) phenotype in patients with metastatic non-small cell lung cancer. Br J Cancer 105:1338–1341
51. Ledford H (2011) Cancer theory faces doubts. Nature 472:273
52. Li QQ, Xu JD, Wang WJ, Cao XX, Chen Q, Tang F, Chen ZQ, Liu XP, Xu ZD (2009) Twist1-mediated adriamycin-induced epithelial–mesenchymal transition relates to multidrug resistance and invasive potential in breast cancer cells. Clin Cancer Res 15:2657–2665
53. Li YM, Xu SC, Li J, Han KQ, Pi HF, Zheng L, Zuo GH, Huang XB, Li HY, Zhao HZ, Yu ZP, Zhou Z, Liang P (2013) Epithelial–mesenchymal transition markers expressed in circulating tumor cells in hepatocellular carcinoma patients with different stages of disease. Cell Death Dis 4:e831
54. Li J, Chen L, Zhang Y, Zhang XF, Liu HY, Sun B, Zhao LL, Ge NJ, Qian HY, Yang YY, Wu MC, Yin ZF (2014) Detection of circulating tumor cells in hepatocellular carcinoma using antibodies against asialoglycoprotein receptor, carbamoyl phosphate synthetase 1 and pan-cytokeratin. PLoS ONE 9:e96185
55. Lu S, Yu G, Zhu Y, Archer MC (2005) Cyclooxygenase-2 overexpression in MCF-10F human breast epithelial cells inhibits proliferation, apoptosis and differentiation, and causes partial transformation. Int J Cancer 116:847–852
56. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA (2008) The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715
57. Markou A, Strati A, Malamos N, Georgoulias V, Lianidou ES (2011) Molecular characterization of circulating tumor cells in breast cancer by a liquid bead array hybridization assay. Clin Chem 57:421–430
58. Mego M, De Giorgi U, Dawood S, Wang X, Valero V, Andreopoulou E, Handy B, Ueno NT, Reuben JM, Cristofanilli M (2011) Characterization of metastatic breast cancer patients with nondetectable circulating tumor cells. Int J Cancer 129:417–423
59. Mego M, Mani SA, Lee BN, Li C, Evans KW, Cohen EN, Gao H, Jackson SA, Giordano A, Hortobagyi GN, Cristofanilli M, Lucci A, Reuben JM (2012) Expression of epithelial–mesenchymal transition-inducing transcription factors in primary breast cancer: the effect of neoadjuvant therapy. Inter J Cancer 130:808–816
60. Miles FL, Pruitt FL, van Golen KL, Cooper CR (2008) Stepping out of the flow: capillary extravasation in cancer metastasis. Clin Exp Metastasis 25:305–324
61. Min AL, Choi JY, Woo HY, Kim JD, Kwon JH, Bae SH, Yoon SK, Shin SH, Chung YJ, Jung CK (2009) High expression of Snail mRNA in blood from hepatocellular carcinoma patients with extra-hepatic metastasis. Clin Exp Metastasis 26:759–767
62. Mostert B, Kraan J, Sieuwerts AM, van der Spoel P, Bolt-de Vries J, Prager-van der Smissen WJ, Smid M, Timmermans AM, Martens JW, Gratama JW, Foekens JA, Sleijfer S (2012) CD49f-based selection of circulating tumor cells (CTCs) improves detection across breast cancer subtypes. Cancer Lett 319:49–55
63. Nel I, Baba HA, Ertle J, Weber F, Sitek B, Eisenacher M, Meyer HE, Schlaak JF, Hoffmann AC (2013) Individual profiling of circulating tumor cell composition and therapeutic outcome in patients with hepatocellular carcinoma. Transl Oncol 6:420–428
64. Ocaña OH, Córcoles R, Fabra A, Moreno-Bueno G, Acloque H, Vega S, Barrallo-Gimeno A, Cano A, Nieto MA (2012) Metastatic colonization requires the repression of the epithelial–mesenchymal transition inducer Prrx1. Cancer Cell 22:709–724
65. Ogunwobi OO, Puszyk W, Dong HJ, Liu C (2013) Epigenetic upregulation of HGF and c-Met drives metastasis in hepatocellular carcinoma. PLoS ONE 8:e63765
66. Oltean S, Sorg BS, Albrecht T, Bonano VI, Brazas RM, Dewhirst MW, Garcia-Blanco MA (2006) Alternative inclusion of fibroblast growth factor receptor 2 exon IIIc in Dunning prostate tumors reveals unexpected epithelial mesenchymal plasticity. Proc Natl Acad Sci USA 103:14116–14121
67. Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA (2008) Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res 68:3645–3654
68. Ota I, Li XY, Hu Y, Weiss SJ (2009) Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. Proc Natl Acad Sci USA 106:20318–20323
69. Pecot CV, Bischoff FZ, Mayer JA, Wong KL, Pham T, Bottsford-Miller J, Stone RL, Lin YG, Jaladurgam P, Roh JW, Goodman BW, Merritt WM, Pircher TJ, Mikolajczyk SD, Nick AM, Celestino J, Eng C, Ellis LM, Deavers MT, Sood AK (2011) A novel platform for detection of CK + and CK − CTCs. Cancer Discov 1:580–586
70. Peinado H, Marin F, Cubillo E, Stark HJ, Fusenig N, Nieto MA, Cano A (2004) Snail and E47 repressors of E-cadherin induce distinct invasive and angiogenic properties in vivo. J Cell Sci 117:2827–2839
71. Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7:415–428
72. Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9:265–273
73. Powell AA, Talasaz AH, Zhang H, Coram MA, Reddy A, Deng G, Telli ML, Advani RH, Carlson RW, Mollick JA, Sheth S, Kurian AW, Ford JM, Stockdale FE, Quake SR, Pease RF, Mindrinos MN, Bhanot G, Dairkee SH, Davis RW, Jeffrey SS (2012) Single cell profiling of circulating tumor cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PLoS ONE 7:e33788
74. Qi J, Chen N, Wang J, Siu CH (2005) Transendothelial migration of melanoma cells involves N-cadherin-mediated adhesion and activation of the beta-catenin signaling pathway. Mol Biol Cell 16:4386–4397
75. Raimondi C, Gradilone A, Naso G, Vincenzi B, Petracca A, Nicolazzo C, Palazzo A, Saltarelli R, Spremberg F, Cortesi E, Gazzaniga P (2011) Epithelial–mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. Breast Cancer Res Treat 130:449–455
76. Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, Reichert M, Beatty GL, Rustgi AK, Vonderheide RH, Leach SD, Stanger BZ (2012) EMT and dissemination precede pancreatic tumor formation. Cell 148:349–361
77. Riethdorf S, Fritsche H, Müller V, Rau T, Schindlbeck C, Rack B, Janni W, Coith C, Beck K, Jänicke F, Jackson S, Gornet T, Cristofanilli M, Pantel K (2007) Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the cell search system. Clin Cancer Res 13:920–928
78. Rossi E, Basso U, Celadin R, Zilio F, Pucciarelli S, Aieta M, Barile C, Sava T, Bonciarelli G, Tumolo S, Ghiotto C, Magro C, Jirillo A, Indraccolo S, Amadori A, Zamarchi R (2010) M30 neoepitope expression in epithelial cancer: quantification of apoptosis in circulating tumor cells by cell search analysis. Clin Cancer Res 16:5233–5243
79. Saha B, Chaiwun B, Imam SS, Tsao-Wei DD, Groshen S, Naritoku WY, Imam SA (2007) Overexpression of E-cadherin protein in metastatic breast cancer cells in bone. Anticancer Res 27:3903–3908
80. Sandig M, Voura EB, Kalnins VI, Siu CH (1997) Role of cadherins in the transendothelial migration of melanoma cells in culture. Cell Motil Cytoskelet 38:351–364
81. Savagner P, Yamada KM, Thiery JP (1997) 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
82. Schmidt H, De Angelis G, Bettendorf O, Eltze E, Semjonow A, Knichwitz G, Brandt B (2004) Frequent detection and immunophenotyping of prostate-derived cell clusters in the peripheral blood of prostate cancer patients. Int J Biol Markers 19:93–99
83. Setoyama T, Natsugoe S, Okumura H, Matsumoto M, Uchikado Y, Aikou T (2007) Isolated tumour cells in blood and E-cadherin expression in oesophageal squamous cell cancer. Br J Surg 94:984–991
84. Shah AN, Summy JM, Zhang J, Park SI, Parikh NU, Gallick GE (2007) Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann Surg Oncol 14:3629–3637
85. Shih JY, Tsai MF, Chang TH, Chang YL, Yuan A, Yu CJ, Lin SB, Liou GY, Lee ML, Chen JJ, Hong TM, Yang SC, Su JL, Lee YC, Yang PC (2005) Transcription repressor slug promotes carcinoma invasion and predicts outcome of patients with lung adenocarcinoma. Clin Cancer Res 11:8070–8078
86. Smit MA, Geiger TR, Song JY, Gitelman I, Peeper DS (2009) A Twist-Snail axis critical for TrkB-induced epithelial–mesenchymal transition-like transformation, anoikis resistance, and metastasis. Mol Cell Biol 29:3722–3737
87. Stoletov K, Kato H, Zardouzian E, Kelber J, Yang J, Shattil S, Klemke R (2010) Visualizing extravasation dynamics of metastatic tumor cells. J Cell Sci 123:2332–2341
88. Strati A, Markou A, Parisi C, Politaki E, Mavroudis D, Georgoulias V, Lianidou E (2011) Gene expression profile of circulating tumor cells in breast cancer by RT-qPCR. BMC Cancer 11:422
89. Sun B, Zhang X, Cheng X, Zhang Y, Chen L, Shi L, Liu Z, Qian H, Wu M, Yin Z (2013) Intratumoral hepatic stellate cells as a poor prognostic marker and a new treatment target for hepatocellular carcinoma. PLoS ONE 8:e80212
90. Swennenhuis JF, Tibbe AG, Levink R, Sipkema RC, Terstappen LW (2009) Characterization of circulating tumour cells by fluorescence in situ hybridization. Cytom A 75:520–527
91. Taddei ML, Giannoni E, Fiaschi T, Chiarugi P (2012) Anoikis: an emerging hallmark in health and diseases. J Pathol 226:380–393
92. Thiery JP (2002) Epithelial–mesenchymal transitions in tumor progression. Nat Rev Cancer 2:442–454
93. Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial–mesenchymal transitions. Nat Rev Mol Cell Biol 7:131–142
94. Thomson S, Buck E, Petti F, Griffin G, Brown E, Ramnarine N, Iwata KK, Gibson N, Haley JD (2005) Epithelial to mesenchymal transition is a determinant of sensitivity of nonsmall-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res 65:9455–9462
95. Tsai JH, Yang J (2013) Epithelial–mesenchymal plasticity in carcinoma metastasis. Genes Dev 27:2192–2206
96. Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J (2012) Spatiotemporal regulation of epithelial–mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22:725–736
97. Tsuji T, Ibaragi S, Shima K, Hu MG, Katsurano M, Sasaki A, Hu GF (2008) Epithelial–mesenchymal transition induced by growth suppressor p12CDK2-AP1 promotes tumor cell local invasion but suppresses distant colony growth. Cancer Res 68:10377–10386
98. Turner NC, Reis-Filho JS (2012) Genetic heterogeneity and cancer drug resistance. Lancet Oncol 13:e178–e185
99. Xie M, Zhang L, He CS, Xu F, Liu JL, Hu ZH, Zhao LP, Tian Y (2012) Activation of Notch-1 enhances epithelial–mesenchymal transition in gefitinib-acquired resistant lung cancer cells. J Cell Biochem 113:1501–1513
100. Yang J, Weinberg RA (2008) Epithelial–mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14:818–829
101. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117:927–939
102. Yang AD, Fan F, Camp ER, van Buren G, Liu W, Somcio R, Gray MJ, Cheng H, Hoff PM, Ellis LM (2006) Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res 12:4147–4153
103. Yauch RL, Januario T, Eberhard DA, Cavet G, Zhu W, Fu L, Pham TQ, Soriano R, Stinson J, Seshagiri S, Modrusan Z, Lin CY, O’Neill V, Amler LC (2005) Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin Cancer Res 11:8686–8698
104. Yokobori T, Iinuma H, Shimamura T, Imoto S, Sugimachi K, Ishii H, Iwatsuki M, Ota D, Ohkuma M, Iwaya T, Nishida N, Kogo R, Sudo T, Tanaka F, Shibata K, Toh H, Sato T, Barnard GF, Fukagawa T, Yamamoto S, Nakanishi H, Sasaki S, Miyano S, Watanabe T, Kuwano H, Mimori K, Pantel K, Mori M (2013) Plastin3 is a novel marker for circulating tumor cells undergoing the epithelial–mesenchymal transition and is associated with colorectal cancer prognosis. Cancer Res 73:2059–2069
105. Yu SR, Wei J, Qian XP, Liu BR (2009) Circulating tumor cells and individualized chemotherapy. Ai Zheng 28:1225–1232
106. Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, Isakoff SJ, Ciciliano JC, Wells MN, Shah AM, Concannon KF, Donaldson MC, Sequist LV, Brachtel E, Sgroi D, Baselga J, Ramaswamy S, Toner M, Haber DA, Maheswaran S (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339:580–584
107. Zhang Y, Li J, Cao L, Xu W, Yin Z (2012) Circulating tumor cells in hepatocellular carcinoma: detection techniques, clinical implications, and future perspectives. Semin Oncol 39:449–460
108. Zhuo W, Wang Y, Zhuo X, Zhang Y, Ao X, Chen Z (2008a) Knockdown of Snail, a novel zinc finger transcription factor, via RNA interference increases A549 cell sensitivity to cisplatin via JNK/mitochondrial pathway. Lung Cancer 62:8–14
109. Zhuo WL, Wang Y, Zhuo XL, Zhang YS, Chen ZT (2008b) Short interfering RNA directed against TWIST, a novel zinc finger transcription factor, increases A549 cell sensitivity to cisplatin via MAPK/mitochondrial pathway. Biochem Biophys Res Commun 369:1098–1102