Tumor Biology

, Volume 37, Issue 5, pp 5663–5674 | Cite as

Phenotype of circulating tumor cell: face-off between epithelial and mesenchymal masks

  • Yupeng Hong
  • Qi Zhang


Most patients with cancers died of distant metastasis. It is always difficult to find cancer metastasis in early time, let alone to prevent or cure it. Currently, oncologists place high hopes on circulating tumor cell (CTC), which, compared to current imaging methods, is found more sensitive for early metastasis. Recently, techniques for CTC enrichment and identification are developing quickly. However, there are great challenges in the clinical interpretation of CTC assessments. Increasing studies have shown the heterogeneity of CTCs, which may play different roles in cancer metastasis. Epithelial-mesenchymal transition is not only the main mechanism of the cancer cells invading the circulation system but also a distinguished characteristic of CTCs. Investigators are trying to differentiate specific subgroups of CTCs that are truly responsible for cancer metastasis. Here, we reviewed the current evidences on epithelial-mesenchymal transition of CTCs from perspectives of enrichment methods, biology, and its subgroups.


Epithelial-mesenchymal transition ISET EpCAM CTC cluster Phenotype switch Metastasis 



This work was financially supported by the National Natural Science Foundation of China (No. 81401954) and the Medical Science & Technology Program of Zhejiang Province, China (2015KYA114). We appreciate Dr. Ziduo Li from ANZAC Research Institute, University of Sydney, Australia for help of search and full-text paper acquisition.

Author contributions

Hong Y and Zhang Q wrote the manuscript. Both authors approved the manuscript.

Compliance with ethical standards

Conflicts of interest



  1. 1.
    Krebs MG, Metcalf RL, Carter L, Brady G, Blackhall FH, Dive C. Molecular analysis of circulating tumour cells—biology and biomarkers. Nat Rev Clin Oncol. 2014;11(3):129–44.PubMedGoogle Scholar
  2. 2.
    Miyamoto DT, Zheng Y, Wittner BS, Lee RJ, Zhu H, Broderick KT, et al. RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science. 2015;349(6254):1351–6.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344(6190):1396–401.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Bai X, Zhang Q, Wu S, Zhang X, Wang M, He F, et al. Characteristics of tumor infiltrating lymphocyte and circulating lymphocyte repertoires in pancreatic cancer by the sequencing of T cell receptors. Sci Rep. 2015;5:13664.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Robins HS, Ericson NG, Guenthoer J, O’Briant KC, Tewari M, Drescher CW, et al. Digital genomic quantification of tumor-infiltrating lymphocytes. Sci Transl Med. 2013;5(214), 214ra169.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014;158(5):1110–22.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Wit S, Dalum G, Lenferink AT, Tibbe AG, Hiltermann TJ, Groen HJ, et al. The detection of EpCAM(+) and EpCAM(−) circulating tumor cells. Sci Rep. 2015;5:12270.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Chen JF, Ho H, Lichterman J, Lu YT, Zhang Y, Garcia MA, et al. Posadas EM. Subclassification of prostate cancer circulating tumor cells by nuclear size reveals very small nuclear circulating tumor cells in patients with visceral metastases. Cancer. 2015;121(18):3240–51.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013;339(6119):580–4.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Paoletti C, Li Y, Muniz MC, Kidwell KM, Aung K, Thomas DG, et al. Translational breast cancer research C. Significance of circulating tumor cells in metastatic triple-negative breast cancer patients within a randomized, phase II trial: TBCRC 019. Clin Cancer Res. 2015;21(12):2771–9.PubMedGoogle Scholar
  11. 11.
    Wallwiener M, Hartkopf AD, Riethdorf S, Nees J, Sprick MR, Schonfisch B, et al. The impact of HER2 phenotype of circulating tumor cells in metastatic breast cancer: a retrospective study in 107 patients. BMC Cancer. 2015;15:403.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Tsuji T, Ibaragi S, Hu GF. Epithelial-mesenchymal transition and cell cooperativity in metastasis. Cancer Res. 2009;69(18):7135–9.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Meng S, Tripathy D, Frenkel EP, Shete S, Naftalis EZ, Huth JF, et al. Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res. 2004;10(24):8152–62.PubMedGoogle Scholar
  14. 14.
    Luzzi KJ, MacDonald IC, Schmidt EE, Kerkvliet N, Morris VL, Chambers AF, et al. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol. 1998;153(3):865–73.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Giuliano M, Giordano A, Jackson S, Hess KR, De Giorgi U, Mego M, et al. Circulating tumor cells as prognostic and predictive markers in metastatic breast cancer patients receiving first-line systemic treatment. Breast Cancer Res. 2011;13(3):R67.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Scher HI, Heller G, Molina A, Attard G, Danila DC, Jia X, et al. Circulating tumor cell biomarker panel as an individual-level surrogate for survival in metastatic castration-resistant prostate cancer. J Clin Oncol. 2015;33(12):1348–55.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, et al. Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol. 2009;20(7):1223–9.PubMedGoogle Scholar
  18. 18.
    Krebs MG, Sloane R, Priest L, Lancashire L, Hou JM, Greystoke A, et al. Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J Clin Oncol. 2011;29(12):1556–63.PubMedGoogle Scholar
  19. 19.
    Yang JD, Campion MB, Liu MC, Chaiteerakij R, Giama NH, Ahmed Mohammed H, et al. Circulating tumor cells are associated with poor overall survival in patients with cholangiocarcinoma. Hepatology. 2015.Google Scholar
  20. 20.
    Bonnomet A, Brysse A, Tachsidis A, Waltham M, Thompson EW, Polette M, et al. Epithelial-to-mesenchymal transitions and circulating tumor cells. J Mammary Gland Biol Neoplasia. 2010;15(2):261–73.PubMedGoogle Scholar
  21. 21.
    Javaid S, Zhang J, Smolen GA, Yu M, Wittner BS, Singh A, et al. MAPK7 regulates EMT features and modulates the generation of CTCs. Mol Cancer Res. 2015;13(5):934–43.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Liotta LA, Kohn E. Anoikis: cancer and the homeless cell. Nature. 2004;430(7003):973–4.PubMedGoogle Scholar
  23. 23.
    Hou JM, Krebs M, Ward T, Sloane R, Priest L, Hughes A, et al. Circulating tumor cells as a window on metastasis biology in lung cancer. Am J Pathol. 2011;178(3):989–96.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Mehes G, Witt A, Kubista E, Ambros PF. Circulating breast cancer cells are frequently apoptotic. Am J Pathol. 2001;159(1):17–20.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Wu S, Liu S, Liu Z, Huang J, Pu X, Li J, et al. Classification of circulating tumor cells by epithelial-mesenchymal transition markers. PLoS One. 2015;10(4), e0123976.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Raimondi C, Gradilone A, Naso G, Vincenzi B, Petracca A, Nicolazzo C, et al. Epithelial-mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. Breast Cancer Res Treat. 2011;130(2):449–55.PubMedGoogle Scholar
  27. 27.
    Agelaki S, Kalykaki A, Markomanolaki H, Papadaki MA, Kallergi G, Hatzidaki D, et al. Efficacy of Lapatinib in therapy-resistant HER2-positive circulating tumor cells in metastatic breast cancer. PLoS One. 2015;10(6), e0123683.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Mazel M, Jacot W, Pantel K, Bartkowiak K, Topart D, Cayrefourcq L, et al. Frequent expression of PD-L1 on circulating breast cancer cells. Mol Oncol. 2015;9(9):1773–82.PubMedGoogle Scholar
  29. 29.
    Harouaka RA, Zhou MD, Yeh YT, Khan WJ, Das A, Liu X, et al. Flexible micro spring array device for high-throughput enrichment of viable circulating tumor cells. Clin Chem. 2014;60(2):323–33.PubMedGoogle Scholar
  30. 30.
    Bednarz-Knoll N, Alix-Panabieres C, Pantel K. Plasticity of disseminating cancer cells in patients with epithelial malignancies. Cancer Metastasis Rev. 2012;31(3–4):673–87.PubMedGoogle Scholar
  31. 31.
    Frisch SM, Schaller M, Cieply B. Mechanisms that link the oncogenic epithelial-mesenchymal transition to suppression of anoikis. J Cell Sci. 2013;126(Pt 1):21–9.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Samatov TR, Tonevitsky AG, Schumacher U. Epithelial-mesenchymal transition: focus on metastatic cascade, alternative splicing, non-coding RNAs and modulating compounds. Mol Cancer. 2013;12(1):107.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Lv Q, Gong L, Zhang T, Ye J, Chai L, Ni C, et al. Prognostic value of circulating tumor cells in metastatic breast cancer: a systemic review and meta-analysis. Clin Transl Oncol. 2015.Google Scholar
  34. 34.
    Peeters DJ, Van den Eynden GG, van Dam PJ, Prove A, Benoy IH, van Dam PA, et al. Circulating tumour cells in the central and the peripheral venous compartment in patients with metastatic breast cancer. Br J Cancer. 2011;104(9):1472–7.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Ogunwobi OO, Puszyk W, Dong HJ, Liu C. Epigenetic upregulation of HGF and c-Met drives metastasis in hepatocellular carcinoma. PLoS One. 2013;8(5), e63765.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Serrano MJ, Ortega FG, Alvarez-Cubero MJ, Nadal R, Sanchez-Rovira P, Salido M, et al. EMT and EGFR in CTCs cytokeratin negative non-metastatic breast cancer. Oncotarget. 2014;5(17):7486–97.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Stamenkovic I. Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol. 2000;10(6):415–33.PubMedGoogle Scholar
  38. 38.
    Mego M, Gao H, Lee BN, Cohen EN, Tin S, Giordano A, et al. Prognostic value of EMT-circulating tumor cells in metastatic breast cancer patients undergoing high-dose chemotherapy with autologous hematopoietic stem cell transplantation. J Cancer. 2012;3:369–80.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Kim YJ, Koo GB, Lee JY, Moon HS, Kim DG, Lee DG, et al. A microchip filter device incorporating slit arrays and 3-D flow for detection of circulating tumor cells using CAV1-EpCAM conjugated microbeads. Biomaterials. 2014;35(26):7501–10.PubMedGoogle Scholar
  40. 40.
    Denes V, Lakk M, Makarovskiy A, Jakso P, Szappanos S, Graf L, et al. Metastasis blood test by flow cytometry: in vivo cancer spheroids and the role of hypoxia. Int J Cancer. 2015;136(7):1528–36.PubMedGoogle Scholar
  41. 41.
    Yokobori T, Iinuma H, Shimamura T, Imoto S, Sugimachi K, Ishii H, et al. Plastin3 is a novel marker for circulating tumor cells undergoing the epithelial-mesenchymal transition and is associated with colorectal cancer prognosis. Cancer Res. 2013;73(7):2059–69.PubMedGoogle Scholar
  42. 42.
    Sieuwerts AM, Kraan J, Bolt J, van der Spoel P, Elstrodt F, Schutte M, et al. Anti-epithelial cell adhesion molecule antibodies and the detection of circulating normal-like breast tumor cells. J Natl Cancer Inst. 2009;101(1):61–6.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Mohamadi RM, Besant JD, Mepham A, Green B, Mahmoudian L, Gibbs T, et al. Nanoparticle-mediated binning and profiling of heterogeneous circulating tumor cell subpopulations. Angew Chem. 2015;54(1):139–43.Google Scholar
  44. 44.
    Schneck H, Blassl C, Meier-Stiegen F, Neves RP, Janni W, Fehm T, et al. Analysing the mutational status of PIK3CA in circulating tumor cells from metastatic breast cancer patients. Mol Oncol. 2013;7(5):976–86.PubMedGoogle Scholar
  45. 45.
    Wicha MS, Hayes DF. Circulating tumor cells: not all detected cells are bad and not all bad cells are detected. J Clin Oncol. 2011;29(12):1508–11.PubMedGoogle Scholar
  46. 46.
    Friedlander TW, Ngo VT, Dong H, Premasekharan G, Weinberg V, Doty S, et al. Detection and characterization of invasive circulating tumor cells derived from men with metastatic castration-resistant prostate cancer. Int J Cancer. 2014;134(10):2284–93.PubMedGoogle Scholar
  47. 47.
    Matsusaka S, Kozuka M, Takagi H, Ito H, Minowa S, Hirai M, et al. A novel detection strategy for living circulating tumor cells using 5-aminolevulinic acid. Cancer Lett. 2014;355(1):113–20.PubMedGoogle Scholar
  48. 48.
    Kojic N, Milosevic M, Petrovic D, Isailovic V, Sarioglu AF, Haber DA, et al. A computational study of circulating large tumor cells traversing microvessels. Comput Biol Med. 2015;63:187–95.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Polioudaki H, Agelaki S, Chiotaki R, Politaki E, Mavroudis D, Matikas A, et al. Variable expression levels of keratin and vimentin reveal differential EMT status of circulating tumor cells and correlation with clinical characteristics and outcome of patients with metastatic breast cancer. BMC Cancer. 2015;15:399.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Nel I, Baba HA, Ertle J, Weber F, Sitek B, Eisenacher M, et al. Individual profiling of circulating tumor cell composition and therapeutic outcome in patients with hepatocellular carcinoma. Transl Oncol. 2013;6(4):420–8.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Adams DL, Stefansson S, Haudenschild C, Martin SS, Charpentier M, Chumsri S, et al. Cytometric characterization of circulating tumor cells captured by microfiltration and their correlation to the cellsearch CTC test. Cytometry A. 2015;87(2):137–44.PubMedGoogle Scholar
  52. 52.
    Welinder C, Jansson B, Lindell G, Wenner J. Cytokeratin 20 improves the detection of circulating tumor cells in patients with colorectal cancer. Cancer Lett. 2015;358(1):43–6.PubMedGoogle Scholar
  53. 53.
    Qin X, Park S, Duffy SP, Matthews K, Ang RR, Todenhofer T, et al. Size and deformability based separation of circulating tumor cells from castrate resistant prostate cancer patients using resettable cell traps. Lab Chip. 2015;15(10):2278–86.PubMedGoogle Scholar
  54. 54.
    Kaifi JT, Kunkel M, Das A, Harouaka RA, Dicker DT, Li G, et al. Circulating tumor cell isolation during resection of colorectal cancer lung and liver metastases: a prospective trial with different detection techniques. Cancer Biol Ther. 2015;16(5):699–708.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Lecharpentier A, Vielh P, Perez-Moreno P, Planchard D, Soria JC, Farace F. Detection of circulating tumour cells with a hybrid (epithelial/mesenchymal) phenotype in patients with metastatic non-small cell lung cancer. Br J Cancer. 2011;105(9):1338–41.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Ge F, Zhang H, Wang DD, Li L, Lin PP. Enhanced detection and comprehensive in situ phenotypic characterization of circulating and disseminated heteroploid epithelial and glioma tumor cells. Oncotarget. 2015;6(29):27049–64.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Wang HY, Ahn S, Kim S, Park S, Jung D, Park S, et al. Detection of circulating tumor cell-specific markers in breast cancer patients using the quantitative RT-PCR assay. Int J Clin Oncol. 2015;20(5):878–90.PubMedGoogle Scholar
  58. 58.
    Lang JE, Scott JH, Wolf DM, Novak P, Punj V, Magbanua MJ, et al. Expression profiling of circulating tumor cells in metastatic breast cancer. Breast Cancer Res Treat. 2015;149(1):121–31.PubMedGoogle Scholar
  59. 59.
    Wang Z, Cui K, Xue Y, Tong F, Li S. Prognostic value of circulating tumor cells in patients with squamous cell carcinoma of the head and neck: a systematic review and meta-analysis. Med Oncol. 2015;32(5):164.PubMedGoogle Scholar
  60. 60.
    Fan JL, Yang YF, Yuan CH, Chen H, Wang FB. Circulating tumor cells for predicting the prognostic of patients with hepatocellular carcinoma: a meta analysis. Cell Physiol Biochem. 2015;37(2):629–40.PubMedGoogle Scholar
  61. 61.
    Han L, Chen W, Zhao Q. Prognostic value of circulating tumor cells in patients with pancreatic cancer: a meta-analysis. Tumour Biol. 2014;35(3):2473–80.PubMedGoogle Scholar
  62. 62.
    Ma XL, Xiao ZL, Liu L, Liu XX, Nie W, Li P, et al. Meta-analysis of circulating tumor cells as a prognostic marker in lung cancer. Asian Pac J Cancer Prev. 2012;13(4):1137–44.PubMedGoogle Scholar
  63. 63.
    Zhang L, Riethdorf S, Wu G, Wang T, Yang K, Peng G, et al. Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin Cancer Res. 2012;18(20):5701–10.PubMedGoogle Scholar
  64. 64.
    Wang FB, Yang XQ, Yang S, Wang BC, Feng MH, Tu JC. A higher number of circulating tumor cells (CTC) in peripheral blood indicates poor prognosis in prostate cancer patients--a meta-analysis. Asian Pac J Cancer Prev. 2011;12(10):2629–35.PubMedGoogle Scholar
  65. 65.
    Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res. 2004;10(20):6897–904.PubMedGoogle Scholar
  66. 66.
    Sotelo MJ, Sastre J, Maestro ML, Veganzones S, Vieitez JM, Alonso V, et al. Role of circulating tumor cells as prognostic marker in resected stage III colorectal cancer. Ann Oncol. 2015;26(3):535–41.PubMedGoogle Scholar
  67. 67.
    Murray NP, Albarran V, Perez G, Villalon R, Ruiz A. Secondary circulating tumor cells (CTCs) but not primary CTCs are associated with the clinico-pathological parameters in Chilean patients with Colo-rectal cancer. Asian Pac J Cancer Prev. 2015;16(11):4745–9.PubMedGoogle Scholar
  68. 68.
    Pecot CV, Bischoff FZ, Mayer JA, Wong KL, Pham T, Bottsford-Miller J, et al. A novel platform for detection of CK+ and CK- CTCs. Cancer Discov. 2011;1(7):580–6.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Barriere G, Riouallon A, Renaudie J, Tartary M, Rigaud M. Mesenchymal characterization: alternative to simple CTC detection in two clinical trials. Anticancer Res. 2012;32(8):3363–9.PubMedGoogle Scholar
  70. 70.
    Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer S. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res. 2009;11(4):R46.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Crespo M, van Dalum G, Ferraldeschi R, Zafeiriou Z, Sideris S, Lorente D, et al. Androgen receptor expression in circulating tumour cells from castration-resistant prostate cancer patients treated with novel endocrine agents. Br J Cancer. 2015;112(7):1166–74.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Juan O, Vidal J, Gisbert R, Munoz J, Macia S, Gomez-Codina J. Prognostic significance of circulating tumor cells in advanced non-small cell lung cancer patients treated with docetaxel and gemcitabine. Clin Transl Oncol. 2014;16(7):637–43.PubMedGoogle Scholar
  73. 73.
    Satelli A, Mitra A, Brownlee Z, Xia X, Bellister S, Overman MJ, et al. Epithelial-mesenchymal transitioned circulating tumor cells capture for detecting tumor progression. Clin Cancer Res. 2015;21(4):899–906.PubMedGoogle Scholar
  74. 74.
    Nicolazzo C, Gradilone A. Significance of circulating tumor cells in soft tissue sarcoma. Anal Cell Pathol. 2015;2015:697395.Google Scholar
  75. 75.
    Raphael J, Massard C, Gong IY, Farace F, Margery J, Billiot F, et al. Detection of circulating tumour cells in peripheral blood of patients with malignant pleural mesothelioma. Cancer Biomark. 2015;15(2):151–6.PubMedGoogle Scholar
  76. 76.
    Satelli A, Brownlee Z, Mitra A, Meng QH, Li S. Circulating tumor cell enumeration with a combination of epithelial cell adhesion molecule- and cell-surface vimentin-based methods for monitoring breast cancer therapeutic response. Clin Chem. 2015;61(1):259–66.PubMedGoogle Scholar
  77. 77.
    Ortega FG, Lorente JA, Garcia Puche JL, Ruiz MP, Sanchez-Martin RM, de Miguel-Perez D, et al. miRNA in situ hybridization in circulating tumor cells—MishCTC. Sci Rep. 2015;5:9207.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Ni J, Cozzi P, Hao J, Beretov J, Chang L, Duan W, et al. Epithelial cell adhesion molecule (EpCAM) is associated with prostate cancer metastasis and chemo/radioresistance via the PI3K/Akt/mTOR signaling pathway. Int J Biochem Cell Biol. 2013;45(12):2736–48.PubMedGoogle Scholar
  79. 79.
    Pal SK, He M, Wilson T, Liu X, Zhang K, Carmichael C, et al. Detection and phenotyping of circulating tumor cells in high-risk localized prostate cancer. Clin Genitourin Cancer. 2015;13(2):130–6.PubMedGoogle Scholar
  80. 80.
    Liu Z, Fusi A, Klopocki E, Schmittel A, Tinhofer I, Nonnenmacher A, et al. Negative enrichment by immunomagnetic nanobeads for unbiased characterization of circulating tumor cells from peripheral blood of cancer patients. J Transl Med. 2011;9:70.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Sun YF, Xu Y, Yang XR, Guo W, Zhang X, Qiu SJ, et al. Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection. Hepatology. 2013;57(4):1458–68.PubMedGoogle Scholar
  82. 82.
    Bitting RL, Healy P, Halabi S, George DJ, Goodin M, Armstrong AJ. Clinical phenotypes associated with circulating tumor cell enumeration in metastatic castration-resistant prostate cancer. Urol Oncol. 2015;33(3), 110.e1-9.PubMedGoogle Scholar
  83. 83.
    Eigl BJ, North S, Winquist E, Finch D, Wood L, Sridhar SS, et al. A phase II study of the HDAC inhibitor SB939 in patients with castration resistant prostate cancer: NCIC clinical trials group study IND195. Investig New Drugs. 2015;33(4):969–76.Google Scholar
  84. 84.
    Gonzalez-Angulo AM, Lei X, Alvarez RH, Green MC, Murray JL, Valero V, et al. Phase II randomized study of ixabepilone versus observation in patients with significant residual disease after neoadjuvant systemic therapy for HER2-negative breast cancer. Clin Breast Cancer. 2015;15(5):325–31.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Pierga JY, Petit T, Levy C, Ferrero JM, Campone M, Gligorov J, et al. Pathological response and circulating tumor cell count identifies treated HER2+ inflammatory breast cancer patients with excellent prognosis: BEVERLY-2 survival data. Clin Cancer Res. 2015;21(6):1298–304.PubMedGoogle Scholar
  86. 86.
    Yap TA, Olmos D, Brunetto AT, Tunariu N, Barriuso J, Riisnaes R, et al. Phase I trial of a selective c-MET inhibitor ARQ 197 incorporating proof of mechanism pharmacodynamic studies. J Clin Oncol. 2011;29(10):1271–9.PubMedGoogle Scholar
  87. 87.
    Shigeyasu K, Tazawa H, Hashimoto Y, Mori Y, Nishizaki M, Kishimoto H, et al. Fluorescence virus-guided capturing system of human colorectal circulating tumour cells for non-invasive companion diagnostics. Gut. 2015;64(4):627–35.PubMedGoogle Scholar
  88. 88.
    Xu MJ, Cooke M, Steinmetz D, Karakousis G, Saxena D, Bartlett E, et al. A novel approach for the detection and genetic analysis of live melanoma circulating tumor cells. PLoS One. 2015;10(3), e0123376.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Azarin SM, Yi J, Gower RM, Aguado BA, Sullivan ME, Goodman AG, et al. In vivo capture and label-free detection of early metastatic cells. Nat Commun. 2015;6:8094.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Peeters DJ, Brouwer A, Van den Eynden GG, Rutten A, Onstenk W, Sieuwerts AM, et al. Circulating tumour cells and lung microvascular tumour cell retention in patients with metastatic breast and cervical cancer. Cancer Lett. 2015;356(2 Pt B):872–9.PubMedGoogle Scholar
  91. 91.
    Khoo BL, Lee SC, Kumar P, Tan TZ, Warkiani ME, Ow SG, et al. Short-term expansion of breast circulating cancer cells predicts response to anti-cancer therapy. Oncotarget. 2015;6(17):15578–93.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Cho EH, Wendel M, Luttgen M, Yoshioka C, Marrinucci D, Lazar D, et al. Characterization of circulating tumor cell aggregates identified in patients with epithelial tumors. Phys Biol. 2012;9(1):016001.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Mascalchi M, Falchini M, Maddau C, Salvianti F, Nistri M, Bertelli E, et al. Prevalence and number of circulating tumour cells and microemboli at diagnosis of advanced NSCLC. J Cancer Res Clin Oncol. 2015.Google Scholar
  94. 94.
    Molnar B, Ladanyi A, Tanko L, Sreter L, Tulassay Z. Circulating tumor cell clusters in the peripheral blood of colorectal cancer patients. Clin Cancer Res. 2001;7(12):4080–5.PubMedGoogle Scholar
  95. 95.
    Geng Y, Chandrasekaran S, Hsu JW, Gidwani M, Hughes AD, King MR. Phenotypic switch in blood: effects of pro-inflammatory cytokines on breast cancer cell aggregation and adhesion. PLoS One. 2013;8(1), e54959.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Zhang Q, Bai X, Chen W, Ma T, Hu Q, Liang C, et al. Wnt/beta-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1alpha signaling. Carcinogenesis. 2013;34(5):962–73.PubMedGoogle Scholar
  97. 97.
    De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13(2):97–110.PubMedGoogle Scholar
  98. 98.
    Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell. 2011;20(5):576–90.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Sarioglu AF, Aceto N, Kojic N, Donaldson MC, Zeinali M, Hamza B, et al. A microfluidic device for label-free, physical capture of circulating tumor cell clusters. Nat Methods. 2015;12(7):685–91.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Stott SL, Hsu CH, Tsukrov DI, Yu M, Miyamoto DT, Waltman BA, et al. Isolation of circulating tumor cells using a microvortex-generating herringbone-chip. Proc Natl Acad Sci U S A. 2010;107(43):18392–7.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Yoon HJ, Kozminsky M, Nagrath S. Emerging role of nanomaterials in circulating tumor cell isolation and analysis. ACS Nano. 2014;8(3):1995–2017.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Kim S, Han SI, Park MJ, Jeon CW, Joo YD, Choi IH, et al. Circulating tumor cell microseparator based on lateral magnetophoresis and immunomagnetic nanobeads. Anal Chem. 2013;85(5):2779–86.PubMedGoogle Scholar
  103. 103.
    Onstenk W, Kraan J, Mostert B, Timmermans MM, Charehbili A, Smit VT, et al. Improved circulating tumor cell detection by a combined EpCAM and MCAM cell search enrichment approach in patients with breast cancer undergoing neoadjuvant chemotherapy. Mol Cancer Ther. 2015;14(3):821–7.PubMedGoogle Scholar
  104. 104.
    Barriere G, Tartary M, Rigaud M. Epithelial mesenchymal transition: a new insight into the detection of circulating tumor cells. ISRN Oncol. 2012;2012:382010.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Pearl ML, Dong H, Tulley S, Zhao Q, Golightly M, Zucker S, et al. Treatment monitoring of patients with epithelial ovarian cancer using invasive circulating tumor cells (iCTCs). Gynecol Oncol. 2015;137(2):229–38.PubMedGoogle Scholar
  106. 106.
    Wang H, Hara Y, Liu X, Reuben JM, Xie Y, Xu H, et al. Detection and enumeration of circulating tumor cells based on their invasive property. Oncotarget. 2015;6(29):27304–11.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Mitchell MJ, Castellanos CA, King MR. Immobilized surfactant-nanotube complexes support selectin-mediated capture of viable circulating tumor cells in the absence of capture antibodies. J Biomed Mater Res A. 2015;103(10):3407–18.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Alix-Panabieres C, Pantel K. Challenges in circulating tumour cell research. Nat Rev Cancer. 2014;14(9):623–31.PubMedGoogle Scholar
  109. 109.
    Low WS, Wan Abas WA. Benchtop technologies for circulating tumor cells separation based on biophysical properties. BioMed Res Int. 2015;2015:239362.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Harouaka RA, Nisic M, Zheng SY. Circulating tumor cell enrichment based on physical properties. J Lab Autom. 2013;18(6):455–68.PubMedGoogle Scholar
  111. 111.
    Rye PD, Hoifodt HK, Overli GE, Fodstad O. Immunobead filtration: a novel approach for the isolation and propagation of tumor cells. Am J Pathol. 1997;150(1):99–106.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Fan X, Jia C, Yang J, Li G, Mao H, Jin Q, et al. A microfluidic chip integrated with a high-density PDMS-based microfiltration membrane for rapid isolation and detection of circulating tumor cells. Biosens Bioelectron. 2015;71:380–6.PubMedGoogle Scholar
  113. 113.
    Vona G, Sabile A, Louha M, Sitruk V, Romana S, Schutze K, et al. Isolation by size of epithelial tumor cells: a new method for the immunomorphological and molecular characterization of circulatingtumor cells. Am J Pathol. 2000;156(1):57–63.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Zheng S, Lin H, Liu JQ, Balic M, Datar R, Cote RJ, et al. Membrane microfilter device for selective capture, electrolysis and genomic analysis of human circulating tumor cells. J Chromatogr A. 2007;1162(2):154–61.PubMedGoogle Scholar
  115. 115.
    Kang YT, Doh I, Cho YH. Tapered-slit membrane filters for high-throughput viable circulating tumor cell isolation. Biomed Microdevices. 2015;17(2):45.PubMedGoogle Scholar
  116. 116.
    Zheng S, Lin HK, Lu B, Williams A, Datar R, Cote RJ, et al. 3D microfilter device for viable circulating tumor cell (CTC) enrichment from blood. Biomed Microdevices. 2011;13(1):203–13.PubMedGoogle Scholar
  117. 117.
    Lee SW, Hyun KA, Kim SI, Kang JY, Jung HI. Continuous enrichment of circulating tumor cells using a microfluidic lateral flow filtration chip. J Chromatogr A. 2015;1377:100–5.PubMedGoogle Scholar
  118. 118.
    Jung SY, Ahn S, Seo E, Lee SJ. Detection of circulating tumor cells via an X-ray imaging technique. J Synchrotron Radiat. 2013;20(Pt 2):324–31.PubMedGoogle Scholar
  119. 119.
    Chiu TK, Lei KF, Hsieh CH, Hsiao HB, Wang HM, Wu MH. Development of a microfluidic-based optical sensing device for label-free detection of circulating tumor cells (CTCs) through their lactic acid metabolism. Sensors. 2015;15(3):6789–806.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Viraka Nellore BP, Kanchanapally R, Pramanik A, Sinha SS, Chavva SR, Hamme 2nd A, et al. Aptamer-conjugated graphene oxide membranes for highly efficient capture and accurate identification of multiple types of circulating tumor cells. Bioconjug Chem. 2015;26(2):235–42.PubMedPubMedCentralGoogle Scholar
  121. 121.
    Huang SB, Wu MH, Lin YH, Hsieh CH, Yang CL, Lin HC, et al. High-purity and label-free isolation of circulating tumor cells (CTCs) in a microfluidic platform by using optically-induced-dielectrophoretic (ODEP) force. Lab Chip. 2013;13(7):1371–83.PubMedGoogle Scholar
  122. 122.
    Shay JW, Zou Y, Hiyama E, Wright WE. Telomerase and cancer. Hum Mol Genet. 2001;10(7):677–85.PubMedGoogle Scholar
  123. 123.
    Dorsey JF, Kao GD, MacArthur KM, Ju M, Steinmetz D, Wileyto EP, et al. Tracking viable circulating tumor cells (CTCs) in the peripheral blood of non-small cell lung cancer (NSCLC) patients undergoing definitive radiation therapy: pilot study results. Cancer. 2015;121(1):139–49.PubMedGoogle Scholar
  124. 124.
    Dieguez L, Winter MA, Pocock KJ, Bremmell KE, Thierry B. Efficient microfluidic negative enrichment of circulating tumor cells in blood using roughened PDMS. Analyst. 2015;140(10):3565–72.PubMedGoogle Scholar
  125. 125.
    Hyun KA, Lee TY, Jung HI. Negative enrichment of circulating tumor cells using a geometrically activated surface interaction chip. Anal Chem. 2013;85(9):4439–45.PubMedGoogle Scholar
  126. 126.
    Lu Y, Liang H, Yu T, Xie J, Chen S, Dong H, et al. Isolation and characterization of living circulating tumor cells in patients by immunomagnetic negative enrichment coupled with flow cytometry. Cancer. 2015;121(17):3036–45.PubMedGoogle Scholar
  127. 127.
    Ma Y, Hao S, Wang S, Zhao Y, Lim B, Lei M, et al. A combinatory strategy for detection of live CTCs using microfiltration and a new telomerase-selective adenovirus. Mol Cancer Ther. 2015;14(3):835–43.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Zhang J, Li S, Liu F, Zhou L, Shao N, Zhao X. SELEX aptamer used as a probe to detect circulating tumor cells in peripheral blood of pancreatic cancer patients. PLoS One. 2015;10(3), e0121920.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Ozkumur E, Shah AM, Ciciliano JC, Emmink BL, Miyamoto DT, Brachtel E, et al. Inertial focusing for tumor antigen-dependent and -independent sorting of rare circulating tumor cells. Sci Transl Med. 2013;5(179), 179ra147.Google Scholar
  130. 130.
    Liu Z, Zhang W, Huang F, Feng H, Shu W, Xu X, et al. High throughput capture of circulating tumor cells using an integrated microfluidic system. Biosens Bioelectron. 2013;47:113–9.PubMedGoogle Scholar
  131. 131.
    Hyun KA, Lee TY, Lee SH, Jung HI. Two-stage microfluidic chip for selective isolation of circulating tumor cells (CTCs). Biosens Bioelectron. 2015;67:86–92.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  1. 1.Department of OncologyZhejiang Provincial People’s HospitalHangzhouChina
  2. 2.Department of Hepatobiliary and Pancreatic SurgeryThe Second Affiliated Hospital, Zhejiang University School of MedicineHangzhouChina
  3. 3.Key Laboratory of Cancer Prevention and InterventionNational Ministry of EducationHangzhouChina

Personalised recommendations