Genesis of Circulating Tumor Cells Through Epithelial–Mesenchymal Transition as a Mechanism for Distant Dissemination

Current Cancer Research

Volumn , Issue , 2016, Pages 139-182

  Khoo, Bee Luan ^a   Kumar, Prashant ^b   Lim, Chwee Teck ^a,c,d   Thiery, Jean Paul ^b,e,f  

^a NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^b INSTITUTE OF MOLECULAR AND CELL BIOLOGY   (Singapore)

^c SINGAPORE MIT ALLIANCE FOR RESEARCH AND TECHNOLOGY   (Singapore)

^d NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^e NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^f NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

Author keywords

Circulating tumor cells; Epithelial mesenchymal transition; Phenotype

Indexed keywords

BIOLOGICAL MARKER;

ANOIKIS; BLOOD CELL; CANCER GROWTH; CANCER MODEL; CANCER PROGNOSIS; CANCER STAGING; CANCER STEM CELL; CELL AGING; CELL ISOLATION; CELL NUCLEUS; CELL VIABILITY; CIRCULATING TUMOR CELL; EPITHELIAL MESENCHYMAL TRANSITION; EPITHELIUM CELL; HUMAN; IMMUNE RESPONSE; IMMUNOSURVEILLANCE; IN VITRO STUDY; IN VIVO STUDY; METASTASIS; PHENOTYPE; PRIMARY TUMOR; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; STEM CELL;

EID: 85061943868     PISSN: 21992584     EISSN: 21992592     Source Type: Book Series    
DOI: 10.1007/978-1-4939-3363-1_8     Document Type: Chapter

References (214)

1. Acloque H, Ocana OH, Matheu A, Rizzoti K, Wise C, Lovell-Badge R, Nieto MA (2011) Reciprocal repression between Sox3 and snail transcription factors defines embryonic territories at gastrulation. Dev Cell 21:546–558
2. Thiery JP, Lim CT (2013) Tumor dissemination an EMT affair. Cancer Cell 23:272–273
3. Barcellos-Hoff MH, Lyden D, Wang TC (2013) The evolution of the cancer niche during multistage carcinogenesis. Nat Rev Cancer 13:511–518
4. Robinson BD, Sica GL, Liu YF, Rohan TE, Gertler FB, Condeelis JS, Jones JG (2009) Tumor microenvironment of metastasis in human breast carcinoma a potential prognostic marker linked to hematogenous dissemination. Clin Cancer Res 15:2433–2441
5. Rohan TE, Xue X, Lin HM, D’Alfonso TM, Ginter PS, Oktay MH, Robinson BD, Ginsberg M, Gertler FB, Glass AG, Sparano JA, Condeelis JS, Jones JG (2014) Tumor microenvironment of metastasis and risk of distant metastasis of breast cancer. J Natl Cancer Inst 106(8), pii dju136
6. Labelle M, Begum S, Hynes RO (2011) Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 20:576–590
7. Butler TP, Gullino PM (1975) Quantitation of cell shedding into efferent blood of mammary adenocarcinoma. Cancer Res 35:512–516
8. Coumans FA, Siesling S, Terstappen LW (2013) Detection of cancer before distant metastasis. BMC Cancer 13:283
9. Riethdorf S, Pantel K (2009) Clinical relevance and current challenges of research on disseminating tumor cells in cancer patients. Breast Cancer Res 11(Suppl 3):S10
10. Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2:563–572
11. Paget S (1989) The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 8:98–101
12. Talmadge JE, Fidler IJ (2010) AACR centennial series the biology of cancer metastasis historical perspective. Cancer Res 70:5649–5669
13. Nguyen DX, Bos PD, Massague J (2009) Metastasis from dissemination to organ-specific colonization. Nat Rev Cancer 9:274–284
14. Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454
15. Davidson B, Holth A, Hellesylt E, Tan TZ, Huang RY, Tropé C, Nesland J, Thiery J (2015) The clinical role of epithelial-mesenchymal transition and stem cell markers in advanced-stage ovarian serous carcinoma effusions. Hum Pathol 46(1):1–8
16. Huang RY, Wong MK, Tan TZ, Kuay KT, Ng AH, Chung VY, Chu YS, Matsumura N, Lai HC, Lee YF, Sim WJ, Chai C, Pietschmann E, Mori S, Low JJ, Choolani M, Thiery JP (2013) An EMT spectrum defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to E-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530). Cell Death Dis 4:e915
17. Jordan NV, Johnson GL, Abell AN (2011) Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer. Cell Cycle 10:2865–2873
18. Stoker M, Gherardi E, Perryman M, Gray J (1987) Scatter factor is a fibroblast-derived modulator of epithelial cell mobility. Nature 327:239–242
19. Naldini L, Weidner KM, Vigna E, Gaudino G, Bardelli A, Ponzetto C, Narsimhan RP, Hartmann G, Zarnegar R, Michalopoulos GK et al (1991) Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor. EMBO J 10:2867–2878
20. Bellusci S, Moens G, Thiery JP, Jouanneau J (1994) A scatter factor-like factor is produced by a metastatic variant of a rat bladder carcinoma cell line. J Cell Sci 107(Pt 5):1277–1287
21. Gavrilovic J, Moens G, Thiery JP, Jouanneau J (1990) Expression of transfected transforming growth factor alpha induces a motile fibroblast-like phenotype with extracellular matrix-degrading potential in a rat bladder carcinoma cell line. Cell Regul 1:1003–1014
22. Valles AM, Boyer B, Badet J, Tucker GC, Barritault D, Thiery JP (1990) Acidic fibroblast growth factor is a modulator of epithelial plasticity in a rat bladder carcinoma cell line. Proc Natl Acad Sci U S A 87:1124–1128
23. Tucker GC, Delouvee A, Jouanneau J, Gavrilovic J, Moens G, Valles AM, Thiery JP (1991) Amplification of invasiveness in organotypic cultures after NBT-II rat bladder carcinoma stimulation with in vitro scattering factors. Invasion Metastasis 11:297–309
24. Lamouille S, Xu J, Derynck R (2014) Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 15:178–196
25. Massague J, Seoane J, Wotton D (2005) Smad transcription factors. Genes Dev 19:2783–2810
26. Moustakas A, Heldin CH (2009) The regulation of TGFbeta signal transduction. Development 136:3699–3714
27. Padua D, Massague J (2009) Roles of TGFbeta in metastasis. Cell Res 19:89–102
28. Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7:131–142
29. Ahringer J (2000) NuRD and SIN3 histone deacetylase complexes in development. Trends Genet 16:351–356
30. Peinado H, Ballestar E, Esteller M, Cano A (2004) Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol Cell Biol 24:306–319
31. De Craene B, Berx G (2013) Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 13:97–110
32. Tam WL, Weinberg RA (2013) The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med 19:1438–1449
33. Tian XJ, Zhang H, Xing J (2013) Coupled reversible and irreversible bistable switches underlying TGFbeta-induced epithelial to mesenchymal transition. Biophys J 105:1079–1089
34. 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
35. Gumbiner BM, Kim NG (2014) The Hippo-YAP signaling pathway and contact inhibition of growth. J Cell Sci 127:709–717
36. Huang JM, Nagatomo I, Suzuki E, Mizuno T, Kumagai T, Berezov A, Zhang H, Karlan B, Greene MI, Wang Q (2013) YAP modifies cancer cell sensitivity to EGFR and survivin inhibitors and is negatively regulated by the non-receptor type protein tyrosine phosphatase 14. Oncogene 32:2220–2229
37. Wang S, Liu K, Liu J, Yu ZT, Xu X, Zhao L, Lee T, Lee EK, Reiss J, Lee YK, Chung LW, Huang J, Rettig M, Seligson D, Duraiswamy KN, Shen CK, Tseng HR (2011) Highly efficient capture of circulating tumor cells by using nanostructured silicon substrates with integrated chaotic micromixers. Angew Chem Int Ed Engl 50:3084–3088
38. Wheelock MJ, Shintani Y, Maeda M, Fukumoto Y, Johnson KR (2008) Cadherin switching. J Cell Sci 121:727–735
39. Huang J, Huang Y, Yu H, Subramanian D, Padmanabhan A, Thadani R, Tao Y, Tang X, Wedlich-Soldner R, Balasubramanian MK (2012) Nonmedially assembled F-actin cables incorporate into the actomyosin ring in fission yeast. J Cell Biol 199:831–847
40. Paoli P, Cirri P, Caselli A, Ranaldi F, Bruschi G, Santi A, Camici G (2013) The insulin-mimetic effect of Morin a promising molecule in diabetes treatment. Biochim Biophys Acta 1830:3102–3111
41. Janes SM, Watt FM (2004) Switch from alphavbeta5 to alphavbeta6 integrin expression protects squamous cell carcinomas from anoikis. J Cell Biol 166:419–431
42. Smit MA, Peeper DS (2011) Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis. Oncogene 30:3735–3744
43. 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
44. 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
45. Zhao B, Li L, Wang L, Wang CY, Yu J, Guan KL (2012) Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev 26:54–68
46. Schlegelmilch K, Mohseni M, Kirak O, Pruszak J, Rodriguez JR, Zhou D, Kreger BT, Vasioukhin V, Avruch J, Brummelkamp TR, Camargo FD (2011) Yap1 acts downstream of alpha-catenin to control epidermal proliferation. Cell 144:782–795
47. Varelas X, Wrana JL (2012) Coordinating developmental signaling novel roles for the Hippo pathway. Trends Cell Biol 22:88–96
48. Azzolin L, Panciera T, Soligo S, Enzo E, Bicciato S, Dupont S, Bresolin S, Frasson C, Basso G, Guzzardo V, Fassina A, Cordenonsi M, Piccolo S (2014) YAP/TAZ incorporation in the beta-catenin destruction complex orchestrates the Wnt response. Cell 158:157–170
49. Chiarugi P, Pani G, Giannoni E, Taddei L, Colavitti R, Raugei G, Symons M, Borrello S, Galeotti T, Ramponi G (2003) Reactive oxygen species as essential mediators of cell adhesion the oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion. J Cell Biol 161:933–944
50. Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J, Shannon MF, Goodall GJ (2008) A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res 68:7846–7854
51. Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, Brabletz T (2008) A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep 9:582–589
52. Chang CJ, Chao CH, Xia W, Yang JY, Xiong Y, Li CW, Yu WH, Rehman SK, Hsu JL, Lee HH, Liu M, Chen CT, Yu D, Hung MC (2011) p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nat Cell Biol 13:317–323
53. Kim T, Veronese A, Pichiorri F, Lee TJ, Jeon YJ, Volinia S, Pineau P, Marchio A, Palatini J, Suh SS, Alder H, Liu CG, Dejean A, Croce CM (2011) p53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEB1 and ZEB2. J Exp Med 208:875–883
54. Howe EN, Cochrane DR, Richer JK (2011) Targets of miR-200c mediate suppression of cell motility and anoikis resistance. Breast Cancer Res 13:R45
55. Taylor MA, Sossey-Alaoui K, Thompson CL, Danielpour D, Schiemann WP (2013) TGFbeta upregulates miR-181a expression to promote breast cancer metastasis. J Clin Invest 123:150–163
56. Ansieau S, Courtois-Cox S, Morel AP, Puisieux A (2011) Failsafe program escape and EMT a deleterious partnership. Semin Cancer Biol 21:392–396
57. Yang MH, Hsu DS, Wang HW, Wang HJ, Lan HY, Yang WH, Huang CH, Kao SY, Tzeng CH, Tai SK, Chang SY, Lee OK, Wu KJ (2010) Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat Cell Biol 12:982–992
58. 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
59. Morel AP, Lievre M, Thomas C, Hinkal G, Ansieau S, Puisieux A (2008) Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One 3:e2888
60. Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO, Brooks M, Reinhardt F, Su Y, Polyak K, Arendt LM, Kuperwasser C, Bierie B, Weinberg RA (2011) Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci U S A 108:7950–7955
61. Guo W, Keckesova Z, Donaher JL, Shibue T, Tischler V, Reinhardt F, Itzkovitz S, Noske A, Zurrer-Hardi U, Bell G, Tam WL, Mani SA, van Oudenaarden A, Weinberg RA (2012) Slug and Sox9 cooperatively determine the mammary stem cell state. Cell 148:1015–1028
62. Liu S, Cong Y, Wang D, Sun Y, Deng L, Liu Y, Martin-Trevino R, Shang L, McDermott SP, Landis MD, Hong S, Adams A, D’Angelo R, Ginestier C, Charafe-Jauffret E, Clouthier SG, Birnbaum D, Wong ST, Zhan M, Chang JC, Wicha MS (2014) Breast cancer stem cells tran-sition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Reports 2:78–91
63. Kudo-Saito C, Shirako H, Takeuchi T, Kawakami Y (2009) Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell 15:195–206
64. Akalay I, Janji B, Hasmim M, Noman MZ, Andre F, De Cremoux P, Bertheau P, Badoual C, Vielh P, Larsen AK, Sabbah M, Tan TZ, Keira JH, Hung NT, Thiery JP, Mami-Chouaib F, Chouaib S (2013) Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote escape from T-cell-mediated lysis. Cancer Res 73:2418–2427
65. Akalay I, Tan TZ, Kumar P, Janji B, Mami-Chouaib F, Charpy C, Vielh P, Larsen AK, Thiery JP, Sabbah M, Chouaib S (2015) Targeting WNT1-inducible signaling pathway protein 2 alters human breast cancer cell susceptibility to specific lysis through regulation of KLF-4 and miR-7 expression. Oncogene 34(17):2261–2271
66. Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, Schlimok G, Diel IJ, Gerber B, Gebauer G, Pierga JY, Marth C, Oruzio D, Wiedswang G, Solomayer EF, Kundt G, Strobl B, Fehm T, Wong GY, Bliss J, Vincent-Salomon A, Pantel K (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353:793–802
67. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781–791
68. Bidard FC, Peeters DJ, Fehm T, Nole F, Gisbert-Criado R, Mavroudis D, Grisanti S, Generali D, Garcia-Saenz JA, Stebbing J, Caldas C, Gazzaniga P, Manso L, Zamarchi R, de Lascoiti AF, De Mattos-Arruda L, Ignatiadis M, Lebofsky R, van Laere SJ, Meier-Stiegen F, Sandri MT, Vidal-Martinez J, Politaki E, Consoli F, Bottini A, Diaz-Rubio E, Krell J, Dawson SJ, Raimondi C, Rutten A, Janni W, Munzone E, Caranana V, Agelaki S, Almici C, Dirix L, Solomayer EF, Zorzino L, Johannes H, Reis-Filho JS, Pantel K, Pierga JY, Michiels S (2014) Clinical validity of circulating tumour cells in patients with metastatic breast cancer a pooled analysis of individual patient data. Lancet Oncol 15:406–414
69. Alix-Panabieres C, Pantel K (2014) Challenges in circulating tumour cell research. Nat Rev Cancer 14:623–631
70. Pantel K, Alix-Panabieres C, Riethdorf S (2009) Cancer micrometastases. Nat Rev Clin Oncol 6:339–351
71. Krebs MG, Metcalf RL, Carter L, Brady G, Blackhall FH, Dive C (2014) Molecular analysis of circulating tumour cells-biology and biomarkers. Nat Rev Clin Oncol 11:129–144
72. Farace F, Massard C, Vimond N, Drusch F, Jacques N, Billiot F, Laplanche A, Chauchereau A, Lacroix L, Planchard D, Le Moulec S, Andre F, Fizazi K, Soria JC, Vielh P (2011) A direct comparison of CellSearch and ISET for circulating tumour-cell detection in patients with metastatic carcinomas. Br J Cancer 105:847–853
73. Hou HW, Warkiani ME, Khoo BL, Li ZR, Soo RA, Tan DS, Lim WT, Han J, Bhagat AA, Lim CT (2013) Isolation and retrieval of circulating tumor cells using centrifugal forces. Sci Rep 3:1259
74. Stott SL, Hsu CH, Tsukrov DI, Yu M, Miyamoto DT, Waltman BA, Rothenberg SM, Shah AM, Smas ME, Korir GK, Floyd FP Jr, Gilman AJ, Lord JB, Winokur D, Springer S, Irimia D, Nagrath S, Sequist LV, Lee RJ, Isselbacher KJ, Maheswaran S, Haber DA, Toner M (2010) Isolation of circulating tumor cells using a microvortex-generating herringbone-chip. Proc Natl Acad Sci U S A 107:18392–18397
75. Wu CJ, Mannan P, Lu M, Udey MC (2013) Epithelial cell adhesion molecule (EpCAM) regulates claudin dynamics and tight junctions. J Biol Chem 288:12253–12268
76. Meng S, Tripathy D, Frenkel EP, Shete S, Naftalis EZ, Huth JF, Beitsch PD, Leitch M, Hoover S, Euhus D, Haley B, Morrison L, Fleming TP, Herlyn D, Terstappen LW, Fehm T, Tucker TF, Lane N, Wang J, Uhr JW (2004) Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 10:8152–8162
77. Camerer E, Qazi AA, Duong DN, Cornelissen I, Advincula R, Coughlin SR (2004) Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis. Blood 104:397–401
78. Nieswandt B, Hafner M, Echtenacher B, Mannel DN (1999) Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 59:1295–1300
79. Khoo BL, Lee SC, Kumar P, Tan TZ, Warkiani ME, Ow SGW, Nandi S, Lim CT, Thiery JP (2015) Expansion of breast circulating cancer cells predicts response to anti-cancer therapy. Oncotarget 6(17):15578–15593
80. 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
81. Sosa MS, Bragado P, Aguirre-Ghiso JA (2014) Mechanisms of disseminated cancer cell dormancy an awakening field. Nat Rev Cancer 14:611–622
82. Gleghorn JP, Pratt ED, Denning D, Liu H, Bander NH, Tagawa ST, Nanus DM, Giannakakou PA, Kirby BJ (2010) Capture of circulating tumor cells from whole blood of prostate cancer patients using geometrically enhanced differential immunocapture (GEDI) and a prostate-specific antibody. Lab Chip 10:27–29
83. Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, Smith MR, Kwak EL, Digumarthy S, Muzikansky A, Ryan P, Balis UJ, Tompkins RG, Haber DA, Toner M (2007) Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450:1235–1239
84. Du Z, Cheng KH, Vaughn MW, Collie NL, Gollahon LS (2007) Recognition and capture of breast cancer cells using an antibody-based platform in a microelectromechanical systems device. Biomed Microdevices 9:35–42
85. Shao N, Wickstrom E, Panchapakesan B (2008) Nanotube-antibody biosensor arrays for the detection of circulating breast cancer cells. Nanotechnology 19:465101
86. Mittal S, Wong IY, Deen WM, Toner M (2012) Antibody-functionalized fluid-permeable surfaces for rolling cell capture at high flow rates. Biophys J 102:721–730
87. He W, Wang H, Hartmann LC, Cheng JX, Low PS (2007) In vivo quantitation of rare circulating tumor cells by multiphoton intravital flow cytometry. Proc Natl Acad Sci U S A 104:11760–11765
88. Allan AL, Vantyghem SA, Tuck AB, Chambers AF, Chin-Yee IH, Keeney M (2005) Detection and quantification of circulating tumor cells in mouse models of human breast cancer using immunomagnetic enrichment and multiparameter flow cytometry. Cytometry A 65:4–14
89. Cruz I, Ciudad J, Cruz JJ, Ramos M, Gomez-Alonso A, Adansa JC, Rodriguez C, Orfao A (2005) Evaluation of multiparameter flow cytometry for the detection of breast cancer tumor cells in blood samples. Am J Clin Pathol 123:66–74
90. Riethdorf S, Fritsche H, Muller V, Rau T, Schindlbeck C, Rack B, Janni W, Coith C, Beck K, Janicke 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 CellSearch system. Clin Cancer Res 13:920–928
91. Krivacic RT, Ladanyi A, Curry DN, Hsieh HB, Kuhn P, Bergsrud DE, Kepros JF, Barbera T, Ho MY, Chen LB, Lerner RA, Bruce RH (2004) A rare-cell detector for cancer. Proc Natl Acad Sci U S A 101:10501–10504
92. Smirnov DA, Zweitzig DR, Foulk BW, Miller MC, Doyle GV, Pienta KJ, Meropol NJ, Weiner LM, Cohen SJ, Moreno JG, Connelly MC, Terstappen LW, O’Hara SM (2005) Global gene expression profiling of circulating tumor cells. Cancer Res 65:4993–4997
93. Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, Tibbe AG, Uhr JW, Terstappen LW (2004) Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 10:6897–6904
94. Deng G, Herrler M, Burgess D, Manna E, Krag D, Burke JF (2008) Enrichment with anti-cytokeratin alone or combined with anti-EpCAM antibodies significantly increases the sensitivity for circulating tumor cell detection in metastatic breast cancer patients. Breast Cancer Res 10:R69
95. 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
96. Tan SJ, Lakshmi RL, Chen P, Lim WT, Yobas L, Lim CT (2010) Versatile label free biochip for the detection of circulating tumor cells from peripheral blood in cancer patients. Biosens Bioelectron 26:1701–1705
97. Vona G, Sabile A, Louha M, Sitruk V, Romana S, Schutze K, Capron F, Franco D, Pazzagli M, Vekemans M, Lacour B, Brechot C, Paterlini-Brechot P (2000) Isolation by size of epithelial tumor cells a new method for the immunomorphological and molecular characterization of circulating tumor cells. Am J Pathol 156:57–63
98. Gertler R, Rosenberg R, Fuehrer K, Dahm M, Nekarda H, Siewert JR (2003) Detection of circulating tumor cells in blood using an optimized density gradient centrifugation. Recent Results Cancer Res 162:149–155
99. Moon HS, Kwon K, Kim SI, Han H, Sohn J, Lee S, Jung HI (2011) Continuous separation of breast cancer cells from blood samples using multi-orifice flow fractionation (MOFF) and dielectrophoresis (DEP). Lab Chip 11:1118–1125
100. Ozkumur E, Shah AM, Ciciliano JC, Emmink BL, Miyamoto DT, Brachtel E, Yu M, Chen PI, Morgan B, Trautwein J, Kimura A, Sengupta S, Stott SL, Karabacak NM, Barber TA, Walsh JR, Smith K, Spuhler PS, Sullivan JP, Lee RJ, Ting DT, Luo X, Shaw AT, Bardia A, Sequist LV, Louis DN, Maheswaran S, Kapur R, Haber DA, Toner M (2013) Inertial focusing for tumor antigen-dependent and independent sorting of rare circulating tumor cells. Sci Transl Med 5:179ra147
101. Bhagat AA, Bow H, Hou HW, Tan SJ, Han J, Lim CT (2010) Microfluidics for cell separation. Med Biol Eng Comput 48:999–1014
102. Khoo BL, Warkiani ME, Tan DS, Bhagat AA, Irwin D, Lau DP, Lim AS, Lim KH, Krisna SS, Lim WT, Yap YS, Lee SC, Soo RA, Han J, Lim CT (2014) Clinical validation of an ultra high-throughput spiral microfluidics for the detection and enrichment of viable circulating tumor cells. PLoS One 9:e99409
103. Bhagat AA, Kuntaegowdanahalli SS, Papautsky I (2008) Continuous particle separation in spiral microchannels using Dean flows and differential migration. Lab Chip 8:1906–1914
104. Di Carlo D, Irimia D, Tompkins RG, Toner M (2007) Continuous inertial focusing, ordering, and separation of particles in microchannels. Proc Natl Acad Sci U S A 104:18892–18897
105. Galanzha EI, Shashkov EV, Spring PM, Suen JY, Zharov VP (2009) In vivo, noninvasive, label-free detection and eradication of circulating metastatic melanoma cells using two-color photoacoustic flow cytometry with a diode laser. Cancer Res 69:7926–7934
106. Gascoyne PR, Noshari J, Anderson TJ, Becker FF (2009) Isolation of rare cells from cell mixtures by dielectrophoresis. Electrophoresis 30:1388–1398
107. Zhang L, Ridgway LD, Wetzel MD, Ngo J, Yin W, Kumar D, Goodman JC, Groves MD, Marchetti D (2013) The identification and characterization of breast cancer CTCs competent for brain metastasis. Sci Transl Med 5:180ra148
108. Gao D, Vela I, Sboner A, Iaquinta PJ, Karthaus WR, Gopalan A, Dowling C, Wanjala JN, Undvall EA, Arora VK, Wongvipat J, Kossai M, Ramazanoglu S, Barboza LP, Di W, Cao Z, Zhang QF, Sirota I, Ran L, MacDonald TY, Beltran H, Mosquera JM, Touijer KA, Scardino PT, Laudone VP, Curtis KR, Rathkopf DE, Morris MJ, Danila DC, Slovin SF, Solomon SB, Eastham JA, Chi P, Carver B, Rubin MA, Scher HI, Clevers H, Sawyers CL, Chen Y (2014) Organoid cultures derived from patients with advanced prostate cancer. Cell 159:176–187
109. Yu M, Bardia A, Aceto N, Bersani F, Madden MW, Donaldson MC, Desai R, Zhu H, Comaills V, Zheng Z, Wittner BS, Stojanov P, Brachtel E, Sgroi D, Kapur R, Shioda T, Ting DT, Ramaswamy S, Getz G, Iafrate AJ, Benes C, Toner M, Maheswaran S, Haber DA (2014) Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science 345:216–220
110. Lacroix M, Leclercq G (2004) Relevance of breast cancer cell lines as models for breast tumours an update. Breast Cancer Res Treat 83:249–289
111. van Staveren WC, Solis DY, Hebrant A, Detours V, Dumont JE, Maenhaut C (2009) Human cancer cell lines: experimental models for cancer cells in situ? For cancer stem cells? Biochim Biophys Acta 1795:92–103
112. Racila E, Euhus D, Weiss AJ, Rao C, McConnell J, Terstappen LW, Uhr JW (1998) Detection and characterization of carcinoma cells in the blood. Proc Natl Acad Sci U S A 95:4589–4594
113. Zheng S, Lin HK, Lu B, Williams A, Datar R, Cote RJ, Tai YC (2011) 3D microfilter device for viable circulating tumor cell (CTC) enrichment from blood. Biomed Microdevices 13:203–213
114. Warkiani ME, Khoo BL, Tan DS, Bhagat AA, Lim WT, Yap YS, Lee SC, Soo RA, Han J, Lim CT (2014) An ultra-high-throughput spiral microfluidic biochip for the enrichment of circulating tumor cells. Analyst 139:3245–3255
115. Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, Picus J, Morse M, Mitchell E, Miller MC, Doyle GV, Tissing H, Terstappen LW, Meropol NJ (2008) Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 26:3213–3221
116. Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Miller MC, Matera J, Allard WJ, Doyle GV, Terstappen LW (2006) Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res 12:4218–4224
117. Riethdorf S, Muller V, Zhang L, Rau T, Loibl S, Komor M, Roller M, Huober J, Fehm T, Schrader I, Hilfrich J, Holms F, Tesch H, Eidtmann H, Untch M, von Minckwitz G, Pantel K (2010) Detection and HER2 expression of circulating tumor cells prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial. Clin Cancer Res 16:2634–2645
118. Herlyn M, Steplewski Z, Herlyn D, Koprowski H (1979) Colorectal carcinoma-specific antigen detection by means of monoclonal antibodies. Proc Natl Acad Sci U S A 76:1438–1442
119. Nagao K, Zhu J, Heneghan MB, Hanson JC, Morasso MI, Tessarollo L, Mackem S, Udey MC (2009) Abnormal placental development and early embryonic lethality in EpCAM-null mice. PLoS One 4:e8543
120. Litvinov SV, Velders MP, Bakker HA, Fleuren GJ, Warnaar SO (1994) Ep-CAM a human epithelial antigen is a homophilic cell-cell adhesion molecule. J Cell Biol 125:437–446
121. Pantel K, Woelfle U (2005) Detection and molecular characterisation of disseminated tumour cells implications for anti-cancer therapy. Biochim Biophys Acta 1756:53–64
122. Goeminne JC, Guillaume T, Symann M (2000) Pitfalls in the detection of disseminated non-hematological tumor cells. Ann Oncol 11:785–792
123. Ring A, Smith IE, Dowsett M (2004) Circulating tumour cells in breast cancer. Lancet Oncol 5:79–88
124. Jung R, Kruger W, Hosch S, Holweg M, Kroger N, Gutensohn K, Wagener C, Neumaier M, Zander AR (1998) Specificity of reverse transcriptase polymerase chain reaction assays designed for the detection of circulating cancer cells is influenced by cytokines in vivo and in vitro. Br J Cancer 78:1194–1198
125. Kowalewska M, Chechlinska M, Markowicz S, Kober P, Nowak R (2006) The relevance of RT-PCR detection of disseminated tumour cells is hampered by the expression of markers regarded as tumour-specific in activated lymphocytes. Eur J Cancer 42:2671–2674
126. Fehm T, Solomayer EF, Meng S, Tucker T, Lane N, Wang J, Gebauer G (2005) Methods for isolating circulating epithelial cells and criteria for their classification as carcinoma cells. Cytotherapy 7:171–185
127. Spizzo G, Went P, Dirnhofer S, Obrist P, Simon R, Spichtin H, Maurer R, Metzger U, von Castelberg B, Bart R, Stopatschinskaya S, Kochli OR, Haas P, Mross F, Zuber M, Dietrich H, Bischoff S, Mirlacher M, Sauter G, Gastl G (2004) High Ep-CAM expression is associated with poor prognosis in node-positive breast cancer. Breast Cancer Res Treat 86:207–213
128. Sun YF, Yang XR, Zhou J, Qiu SJ, Fan J, Xu Y (2011) Circulating tumor cells advances in detection methods, biological issues, and clinical relevance. J Cancer Res Clin Oncol 137:1151–1173
129. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406:747–752
130. Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, He X, Perou CM (2010) Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 12:R68
131. Sieuwerts AM, Kraan J, Bolt J, van der Spoel P, Elstrodt F, Schutte M, Martens JW, Gratama JW, Sleijfer S, Foekens JA (2009) Anti-epithelial cell adhesion molecule antibodies and the detection of circulating normal-like breast tumor cells. J Natl Cancer Inst 101:61–66
132. Borgen E, Naume B, Nesland JM, Kvalheim G, Beiske K, Fodstad O, Diel I, Solomayer EF, Theocharous P, Coombes RC, Smith BM, Wunder E, Marolleau JP, Garcia J, Pantel K (1999) Standardization of the immunocytochemical detection of cancer cells in BM and blood: I. Establishment of objective criteria for the evaluation of immunostained cells. Cytotherapy 1:377–388
133. Marrinucci D, Bethel K, Lazar D, Fisher J, Huynh E, Clark P, Bruce R, Nieva J, Kuhn P (2010) Cytomorphology of circulating colorectal tumor cells: a small case series. J Oncol 2010:861341
134. Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H, Brannigan BW, Kapur R, Stott SL, Shioda T, Ramaswamy S, Ting DT, Lin CP, Toner M, Haber DA, Maheswaran S (2014) Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158:1110–1122
135. Christiansen JJ, Rajasekaran AK (2006) Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 66:8319–8326
136. Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9:239–252
137. Friedl P, Wolf K (2003) Tumour-cell invasion and migration diversity and escape mechanisms. Nat Rev Cancer 3:362–374
138. Wittekind C, Neid M (2005) Cancer invasion and metastasis. Oncology 69(Suppl 1):14–16
139. Al-Mehdi AB, Tozawa K, Fisher AB, Shientag L, Lee A, Muschel RJ (2000) Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat Med 6:100–102
140. Friedl P, Gilmour D (2009) Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol 10:445–457
141. Glinsky VV, Glinsky GV, Glinskii OV, Huxley VH, Turk JR, Mossine VV, Deutscher SL, Pienta KJ, Quinn TP (2003) Intravascular metastatic cancer cell homotypic aggregation at the sites of primary attachment to the endothelium. Cancer Res 63:3805–3811
142. 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
143. Luzzi KJ, MacDonald IC, Schmidt EE, Kerkvliet N, Morris VL, Chambers AF, Groom AC (1998) Multistep nature of metastatic inefficiency dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 153:865–873
144. Pachmann K (2005) Longtime recirculating tumor cells in breast cancer patients. Clin Cancer Res 11:5657, author reply 5657–5658
145. Barrier A, Olaya N, Chiappini F, Roser F, Scatton O, Artus C, Franc B, Dudoit S, Flahault A, Debuire B, Azoulay D, Lemoine A (2005) Ischemic preconditioning modulates the expression of several genes, leading to the overproduction of IL-1Ra, iNOS, and Bcl-2 in a human model of liver ischemia-reperfusion. FASEB J 19:1617–1626
146. Yang J, Mani SA, Weinberg RA (2006) Exploring a new twist on tumor metastasis. Cancer Res 66:4549–4552
147. Kim MY, Oskarsson T, Acharyya S, Nguyen DX, Zhang XH, Norton L, Massague J (2009) Tumor self-seeding by circulating cancer cells. Cell 139:1315–1326
148. Ito S, Nakanishi H, Ikehara Y, Kato T, Kasai Y, Ito K, Akiyama S, Nakao A, Tatematsu M (2001) Real-time observation of micrometastasis formation in the living mouse liver using a green fluorescent protein gene-tagged rat tongue carcinoma cell line. Int J Cancer 93:212–217
149. Sahai E (2007) Illuminating the metastatic process. Nat Rev Cancer 7:737–749
150. Chambers AF, MacDonald IC, Schmidt EE, Koop S, Morris VL, Khokha R, Groom AC (1995) Steps in tumor metastasis new concepts from intravital videomicroscopy. Cancer Metastasis Rev 14:279–301
151. Holmgren L, O’Reilly MS, Folkman J (1995) Dormancy of micrometastases balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1:149–153
152. Schirrmacher V (2001) T-cell immunity in the induction and maintenance of a tumour dormant state. Semin Cancer Biol 11:285–295
153. Went PT, Lugli A, Meier S, Bundi M, Mirlacher M, Sauter G, Dirnhofer S (2004) Frequent EpCam protein expression in human carcinomas. Hum Pathol 35:122–128
154. Fehm T, Sagalowsky A, Clifford E, Beitsch P, Saboorian H, Euhus D, Meng S, Morrison L, Tucker T, Lane N, Ghadimi BM, Heselmeyer-Haddad K, Ried T, Rao C, Uhr J (2002) Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant. Clin Cancer Res 8:2073–2084
155. Willipinski-Stapelfeldt B, Riethdorf S, Assmann V, Woelfle U, Rau T, Sauter G, Heukeshoven J, Pantel K (2005) Changes in cytoskeletal protein composition indicative of an epithelial-mesenchymal transition in human micrometastatic and primary breast carcinoma cells. Clin Cancer Res 11:8006–8014
156. Clevers H (2011) The cancer stem cell premises, promises and challenges. Nat Med 17:313–319
157. Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance an emerging axis of evil in the war on cancer. Oncogene 29:4741–4751
158. Gal A, Sjoblom T, Fedorova L, Imreh S, Beug H, Moustakas A (2008) Sustained TGF beta exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis. Oncogene 27:1218–1230
159. Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, Asselin-Labat ML, Gyorki DE, Ward T, Partanen A, Feleppa F, Huschtscha LI, Thorne HJ, Fox SB, Yan M, French JD, Brown MA, Smyth GK, Visvader JE, Lindeman GJ (2009) Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 15:907–913
160. Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT, Chi JT, Jeffrey SS, Giaccia AJ (2006) Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440:1222–1226
161. Sahlgren C, Gustafsson MV, Jin S, Poellinger L, Lendahl U (2008) Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci U S A 105:6392–6397
162. Ring AE, Zabaglo L, Ormerod MG, Smith IE, Dowsett M (2005) Detection of circulating epithelial cells in the blood of patients with breast cancer comparison of three techniques. Br J Cancer 92:906–912
163. Vona G, Estepa L, Beroud C, Damotte D, Capron F, Nalpas B, Mineur A, Franco D, Lacour B, Pol S, Brechot C, Paterlini-Brechot P (2004) Impact of cytomorphological detection of circulating tumor cells in patients with liver cancer. Hepatology 39:792–797
164. Gala JL, Heusterspreute M, Loric S, Hanon F, Tombal B, Van Cangh P, De Nayer P, Philippe M (1998) Expression of prostate-specific antigen and prostate-specific membrane antigen transcripts in blood cells implications for the detection of hematogenous prostate cells and standardization. Clin Chem 44:472–481
165. Fischer JC, Niederacher D, Topp SA, Honisch E, Schumacher S, Schmitz N, Zacarias Fohrding L, Vay C, Hoffmann I, Kasprowicz NS, Hepp PG, Mohrmann S, Nitz U, Stresemann A, Krahn T, Henze T, Griebsch E, Raba K, Rox JM, Wenzel F, Sproll C, Janni W, Fehm T, Klein CA, Knoefel WT, Stoecklein NH (2013) Diagnostic leukapheresis enables reliable detection of circulating tumor cells of nonmetastatic cancer patients. Proc Natl Acad Sci U S A 110:16580–16585
166. Pinzani P, Salvadori B, Simi L, Bianchi S, Distante V, Cataliotti L, Pazzagli M, Orlando C (2006) Isolation by size of epithelial tumor cells in peripheral blood of patients with breast cancer correlation with real-time reverse transcriptase-polymerase chain reaction results and feasibility of molecular analysis by laser microdissection. Hum Pathol 37:711–718
167. Polzer B, Medoro G, Pasch S, Fontana F, Zorzino L, Pestka A, Andergassen U, Meier-Stiegen F, Czyz ZT, Alberter B, Treitschke S, Schamberger T, Sergio M, Bregola G, Doffini A, Gianni S, Calanca A, Signorini G, Bolognesi C, Hartmann A, Fasching PA, Sandri MT, Rack B, Fehm T, Giorgini G, Manaresi N, Klein CA (2014) Molecular profiling of single circulating tumor cells with diagnostic intention. EMBO Mol Med 6:1371–1386
168. Mocellin S, Keilholz U, Rossi CR, Nitti D (2006) Circulating tumor cells the ‘leukemic phase’ of solid cancers. Trends Mol Med 12:130–139
169. Theil G, Haubold K, Fornara P, Stresemann A, Schmitz A, Krahn T, Lücke K (2014) Comparison of CTC capture efficiency of the CellCollector™ technology versus CellSearch® in prostate cancer patients at multiple time points (Abstract). Proceedings of the 105th annual meeting of the American Association for Cancer Research 7419
170. Stevens LC, Bunker MC (1964) Karyotype and sex of primary testicular teratomas in mice. J Natl Cancer Inst 33:65–78
171. Kahan BW, Ephrussi B (1970) Developmental potentialities of clonal in vitro cultures of mouse testicular teratoma. J Natl Cancer Inst 44:1015–1036
172. Kleinsmith LJ, Pierce GB Jr (1964) Multipotentiality of single embryonal carcinoma cells. Cancer Res 24:1544–1551
173. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367:645–648
174. Bui M, Reiter RE (1998) Stem cell genes in androgen-independent prostate cancer. Cancer Metastasis Rev 17:391–399
175. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828
176. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100:3983–3988
177. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, Schott A, Hayes D, Birnbaum D, Wicha MS, Dontu G (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1:555–567
178. Charpentier M, Martin S (2013) Interplay of stem cell characteristics, EMT, and microtenta-cles in circulating breast tumor cells. Cancers (Basel) 5:1545–1565
179. Nishi M, Akutsu H, Kudoh A, Kimura H, Yamamoto N, Umezawa A, Lee SW, Ryo A (2014) Induced cancer stem-like cells as a model for biological screening and discovery of agents targeting phenotypic traits of cancer stem cell. Oncotarget 5:8665–8680
180. Tan TZ, Miow QH, Huang RY, Wong MK, Ye J, Lau JA, Wu MC, Bin Abdul Hadi LH, Soong R, Choolani M, Davidson B, Nesland JM, Wang LZ, Matsumura N, Mandai M, Konishi I, Goh BC, Chang JT, Thiery JP, Mori S (2013) Functional genomics identifies five distinct molecular subtypes with clinical relevance and pathways for growth control in epithelial ovarian cancer. EMBO Mol Med 5:983–998
181. Chua KN, Sim WJ, Racine V, Lee SY, Goh BC, Thiery JP (2012) A cell-based small molecule screening method for identifying inhibitors of epithelial-mesenchymal transition in carcinoma. PLoS One 7:e33183
182. Zhuo WL, Wang Y, Zhuo XL, Zhang YS, Chen ZT (2008) Short interfering RNA directed against TWIST, a novel zinc finger transcription factor, increases A549 cell sensitivity to cis-platin via MAPK/mitochondrial pathway. Biochem Biophys Res Commun 369:1098–1102
183. Gan R, Yang Y, Yang X, Zhao L, Lu J, Meng QH (2014) Downregulation of miR-221/222 enhances sensitivity of breast cancer cells to tamoxifen through upregulation of TIMP3. Cancer Gene Ther 21:290–296
184. Bao B, Ahmad A, Li Y, Azmi AS, Ali S, Banerjee S, Kong D, Sarkar FH (2012) Targeting CSCs within the tumor microenvironment for cancer therapy a potential role of mesenchymal stem cells. Expert Opin Ther Targets 16:1041–1054
185. Nagai T, Arao T, Furuta K, Sakai K, Kudo K, Kaneda H, Tamura D, Aomatsu K, Kimura H, Fujita Y, Matsumoto K, Saijo N, Kudo M, Nishio K (2011) Sorafenib inhibits the hepatocyte growth factor-mediated epithelial mesenchymal transition in hepatocellular carcinoma. Mol Cancer Ther 10:169–177
186. Bocca C, Bozzo F, Cannito S, Parola M, Miglietta A (2012) Celecoxib inactivates epithelial-mesenchymal transition stimulated by hypoxia and/or epidermal growth factor in colon cancer cells. Mol Carcinog 51:783–795
187. Qu C, Zhang W, Zheng G, Zhang Z, Yin J, He Z (2014) Metformin reverses multidrug resistance and epithelial-mesenchymal transition (EMT) via activating AMP-activated protein kinase (AMPK) in human breast cancer cells. Mol Cell Biochem 386:63–71
188. Karim SA, Creedon H, Patel H, Carragher NO, Morton JP, Muller WJ, Evans TR, Gusterson B, Sansom OJ, Brunton VG (2013) Dasatinib inhibits mammary tumour development in a genetically engineered mouse model. J Pathol 230:430–440
189. Foroni C, Broggini M, Generali D, Damia G (2012) Epithelial-mesenchymal transition and breast cancer role, molecular mechanisms and clinical impact. Cancer Treat Rev 38:689–697
190. Yew KH, Crow J, Hirst J, Pessetto Z, Godwin AK (2013) Epimorphin-induced MET sensitizes ovarian cancer cells to platinum. PLoS One 8:e72637
191. Zhu XL, Wang YL, Chen JP, Duan LL, Cong PF, Qu YC, Li-Ling J, Zhang MX (2013) Alternol inhibits migration and invasion of human hepatocellular carcinoma cells by targeting epithelial-to-mesenchymal transition. Tumour Biol 35(2):1627–1635
192. Wu Y, Fu Y, Zheng L, Lin G, Ma J, Lou J, Zhu H, He Q, Yang B (2014) Nutlin-3 inhibits epithelial-mesenchymal transition by interfering with canonical transforming growth factor-beta1-Smad-Snail/Slug axis. Cancer Lett 342:82–91
193. Smerage JB, Barlow WE, Hortobagyi GN, Winer EP, Leyland-Jones B, Srkalovic G, Tejwani S, Schott AF, O’Rourke MA, Lew DL, Doyle GV, Gralow JR, Livingston RB, Hayes DF (2014) Circulating tumor cells and response to chemotherapy in metastatic breast cancer SWOG S0500. J Clin Oncol 32:3483–3489
194. Tan TZ, Miow QH, Miki Y, Noda T, Mori S, Huang RY, Thiery JP (2014) Epithelial-mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients. EMBO Mol Med 6:1279–1293
195. De Giorgi V, Pinzani P, Salvianti F, Panelos J, Paglierani M, Janowska A, Grazzini M, Wechsler J, Orlando C, Santucci M, Lotti T, Pazzagli M, Massi D (2010) Application of a filtration-and isolation-by-size technique for the detection of circulating tumor cells in cutaneous melanoma. J Invest Dermatol 130:2440–2447
196. Hofman V, Ilie MI, Long E, Selva E, Bonnetaud C, Molina T, Venissac N, Mouroux J, Vielh P, Hofman P (2011) Detection of circulating tumor cells as a prognostic factor in patients undergoing radical surgery for non-small-cell lung carcinoma comparison of the efficacy of the CellSearch Assay and the isolation by size of epithelial tumor cell method. Int J Cancer 129:1651–1660
197. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS (2009) Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15:232–239
198. MacDonald IC, Groom AC, Chambers AF (2002) Cancer spread and micrometastasis development quantitative approaches for in vivo models. Bioessays 24:885–893
199. Talasaz AH, Powell AA, Huber DE, Berbee JG, Roh KH, Yu W, Xiao W, Davis MM, Pease RF, Mindrinos MN, Jeffrey SS, Davis RW (2009) Isolating highly enriched populations of circulating epithelial cells and other rare cells from blood using a magnetic sweeper device. Proc Natl Acad Sci U S A 106:3970–3975
200. Saliba AE, Saias L, Psychari E, Minc N, Simon D, Bidard FC, Mathiot C, Pierga JY, Fraisier V, Salamero J, Saada V, Farace F, Vielh P, Malaquin L, Viovy JL (2010) Microfluidic sorting and multimodal typing of cancer cells in self-assembled magnetic arrays. Proc Natl Acad Sci U S A 107:14524–14529
201. Andreopoulou E, Yang LY, Rangel KM, Reuben JM, Hsu L, Krishnamurthy S, Valero V, Fritsche HA, Cristofanilli M (2012) Comparison of assay methods for detection of circulating tumor cells in metastatic breast cancer AdnaGen AdnaTest BreastCancer Select/Detect versus Veridex CellSearch system. Int J Cancer 130:1590–1597
202. Hosokawa M, Kenmotsu H, Koh Y, Yoshino T, Yoshikawa T, Naito T, Takahashi T, Murakami H, Nakamura Y, Tsuya A, Shukuya T, Ono A, Akamatsu H, Watanabe R, Ono S, Mori K, Kanbara H, Yamaguchi K, Tanaka T, Matsunaga T, Yamamoto N (2013) Size-based isolation of circulating tumor cells in lung cancer patients using a microcavity array system. PLoS One 8:e67466
203. Sollier E, Go DE, Che J, Gossett DR, O’Byrne S, Weaver WM, Kummer N, Rettig M, Goldman J, Nickols N, McCloskey S, Kulkarni RP, Di Carlo D (2014) Size-selective collection of circulating tumor cells using Vortex technology. Lab Chip 14:63–77
204. Gupta V, Jafferji I, Garza M, Melnikova VO, Hasegawa DK, Pethig R, Davis DW (2012) ApoStream(™), a new dielectrophoretic device for antibody independent isolation and recovery of viable cancer cells from blood. Biomicrofluidics 6:24133
205. Lu J, Fan T, Zhao Q, Zeng W, Zaslavsky E, Chen JJ, Frohman MA, Golightly MG, Madajewicz S, Chen WT (2010) Isolation of circulating epithelial and tumor progenitor cells with an invasive phenotype from breast cancer patients. Int J Cancer 126:669–683
206. Molloy TJ, Bosma AJ, van’t Veer LJ (2008) Towards an optimized platform for the detection, enrichment, and semi-quantitation circulating tumor cells. Breast Cancer Res Treat 112:297–307
207. Xu T, Lu B, Tai YC, Goldkorn A (2010) A cancer detection platform which measures telomerase activity from live circulating tumor cells captured on a microfilter. Cancer Res 70:6420–6426
208. Wu YL, Dudognon C, Nguyen E, Hillion J, Pendino F, Tarkanyi I, Aradi J, Lanotte M, Tong JH, Chen GQ, Segal-Bendirdjian E (2006) Immunodetection of human telomerase reverse-transcriptase (hTERT) re-appraised nucleolin and telomerase cross paths. J Cell Sci 119:2797–2806
209. Hautkappe AL, Lu M, Mueller H, Bex A, Harstrick A, Roggendorf M, Ruebben H (2000) Detection of germ-cell tumor cells in the peripheral blood by nested reverse transcription-polymerase chain reaction for alpha-fetoprotein-messenger RNA and beta human chorionic gonadotropin-messenger RNA. Cancer Res 60:3170–3174
210. Wu CH, Lin SR, Yu FJ, Wu DC, Pan YS, Hsieh JS, Huang SY, Wang JY (2006) Development of a high-throughput membrane-array method for molecular diagnosis of circulating tumor cells in patients with gastric cancers. Int J Cancer 119:373–379
211. Kaganoi J, Shimada Y, Kano M, Okumura T, Watanabe G, Imamura M (2004) Detection of circulating oesophageal squamous cancer cells in peripheral blood and its impact on prognosis. Br J Surg 91:1055–1060
212. Kruger WH, Jung R, Detlefsen B, Mumme S, Badbaran A, Brandner J, Renges H, Kroger N, Zander AR (2001) Interference of cytokeratin-20 and mammaglobin-reverse-transcriptase polymerase chain assays designed for the detection of disseminated cancer cells. Med Oncol 18:33–38
213. Mehes G, Witt A, Kubista E, Ambros PF (2001) Circulating breast cancer cells are frequently apoptotic. Am J Pathol 159:17–20
214. de Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, Doyle GV, Terstappen LW, Pienta KJ, Raghavan D (2008) Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 14:6302–6309