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Circulating tumor cells: advances in detection methods, biological issues, and clinical relevance

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Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Circulating tumor cells (CTCs) have long been considered a reflection of tumor aggressiveness. Hematogenous spreading of CTCs from a primary tumor is a crucial step in the metastasis cascade, which leads ultimately to the formation of overt metastases. However, owing to the rarity of CTCs in peripheral blood, detecting these cells requires methods combined with high sensitivity and specificity, which sets tremendous challenges for the implementation of these assays into clinical routine.

Methods

Generally, CTCs detection methods are composed of the following two steps: enrichment (isolation) process (morphological and immunological techniques) and detection (identification) process (cytometric and nucleic acid techniques), which may or may not be separate from enrichment. Genetic and molecular characterization of CTCs carried out by fluorescent in situ hybridization (FISH), comparative genomic hybridization (CGH), PCR-based techniques, and biomarker immunofluorescent staining extract more information about malignant profile, metastatic potential of CTCs, and the extent to which CTCs are genetically identical to the primary tumor.

Results

Recent technical advances made it possible to detect CTCs. The efficacy of circulating tumor cell (CTC) detection among patients with solid malignancy has been investigated, which shows great potential to become a tool for real-time parameter of prognosis and serve as an early marker to assess the therapeutic response in overt cancers. Improvements in detection and characterization of CTCs will hopefully lead to refinement of clinical management of cancer patients.

Conclusion

This review addresses the majority of assays that have been published thus far, including the enrichment and detection steps and the markers used in these assays, accompanied by some biological issues of CTC and the results of clinical application harvested.

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References

  • Aktas B, Tewes M et al (2009) Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res 11(4):R46

    Article  PubMed  CAS  Google Scholar 

  • Alix-Panabieres C, Vendrell JP et al (2007) Detection and characterization of putative metastatic precursor cells in cancer patients. Clin Chem 53(3):537–539

    Article  PubMed  CAS  Google Scholar 

  • Alix-Panabieres C, Vendrell JP et al (2009) Full-length cytokeratin-19 is released by human tumor cells: a potential role in metastatic progression of breast cancer. Breast Cancer Res 11(3):R39

    Article  PubMed  CAS  Google Scholar 

  • Allard WJ, Matera J et al (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(20):6897–6904

    Article  PubMed  Google Scholar 

  • Andreopoulou E, Cristofanilli M (2010) Circulating tumor cells as prognostic marker in metastatic breast cancer. Expert Rev Anticancer Ther 10(2):171–177

    Article  PubMed  CAS  Google Scholar 

  • Ashida S, Okuda H et al (2000) Detection of circulating cancer cells with von hippel-lindau gene mutation in peripheral blood of patients with renal cell carcinoma. Clin Cancer Res 6(10):3817–3822

    PubMed  CAS  Google Scholar 

  • Attard G, Swennenhuis JF et al (2009) Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res 69(7):2912–2918

    Article  PubMed  CAS  Google Scholar 

  • Balic M, Dandachi N et al (2005) Comparison of two methods for enumerating circulating tumor cells in carcinoma patients. Cytometry B Clin Cytom 68(1):25–30

    PubMed  Google Scholar 

  • Barrallo-Gimeno A, Nieto MA (2005) The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 132(14):3151–3161

    Article  PubMed  CAS  Google Scholar 

  • Bartels CL, Tsongalis GJ (2009) MicroRNAs: novel biomarkers for human cancer. Clin Chem 55(4):623–631

    Article  PubMed  CAS  Google Scholar 

  • Bertazza L, Mocellin S et al (2009) Survivin gene levels in the peripheral blood of patients with gastric cancer independently predict survival. J Transl Med 7:111

    Article  PubMed  CAS  Google Scholar 

  • Bidard FC, Mathiot C et al (2010) Clinical value of circulating endothelial cells and circulating tumor cells in metastatic breast cancer patients treated first line with bevacizumab and chemotherapy. Ann Oncol 21(9):1765–1771

    Article  PubMed  Google Scholar 

  • Bluemke K, Bilkenroth U et al (2009) Detection of circulating tumor cells in peripheral blood of patients with renal cell carcinoma correlates with prognosis. Cancer Epidemiol Biomarkers Prev 18(8):2190–2194

    Article  PubMed  CAS  Google Scholar 

  • Blumke K, Bilkenroth U et al (2005) Detection of circulating tumor cells from renal carcinoma patients: experiences of a two-center study. Oncol Rep 14(4):895–899

    PubMed  Google Scholar 

  • Botteri E, Sandri MT et al (2010) Modeling the relationship between circulating tumour cells number and prognosis of metastatic breast cancer. Breast Cancer Res Treat 122(1):211–217

    Article  PubMed  CAS  Google Scholar 

  • Busch R, Cesar D et al (2004) Isolation of peripheral blood CD4(+) T cells using RosetteSep and MACS for studies of DNA turnover by deuterium labeling. J Immunol Methods 286(1–2):97–109

    Article  PubMed  CAS  Google Scholar 

  • Cao W, Yang W et al (2011) Using detection of survivin-expressing circulating tumor cells in peripheral blood to predict tumor recurrence following curative resection of gastric cancer. J Surg Oncol 103(2):110–115

    Article  PubMed  Google Scholar 

  • Chen BT, Loberg RD et al (2005) Preliminary study of immunomagnetic quantification of circulating tumor cells in patients with advanced disease. Urology 65(3):616–621

    Article  PubMed  CAS  Google Scholar 

  • Chen TF, Jiang GL et al (2007) CK19 mRNA expression measured by reverse-transcription polymerase chain reaction (RT-PCR) in the peripheral blood of patients with non-small cell lung cancer treated by chemo-radiation: an independent prognostic factor. Lung Cancer 56(1):105–114

    Article  PubMed  Google Scholar 

  • Cheng GZ, Chan J et al (2007) Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res 67(5):1979–1987

    Article  PubMed  CAS  Google Scholar 

  • Christofori G (2006) New signals from the invasive front. Nature 441(7092):444–450

    Article  PubMed  CAS  Google Scholar 

  • Cohen SJ, Punt CJ et al (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(19):3213–3221

    Article  PubMed  Google Scholar 

  • Cohen SJ, Punt CJ et al (2009) Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol 20(7):1223–1229

    Article  PubMed  CAS  Google Scholar 

  • Coumans FA, Doggen CJ et al (2010) All circulating EpCAM+CK+CD45− objects predict overall survival in castration-resistant prostate cancer. Ann Oncol 21(9):1851–1857

    Article  PubMed  CAS  Google Scholar 

  • Cristofanilli M (2009) The biological information obtainable from circulating tumor cells. Breast 18(suppl 3):S38–S40

    Google Scholar 

  • Cristofanilli M, Budd GT et al (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351(8):781–791

    Article  PubMed  CAS  Google Scholar 

  • Cristofanilli M, Hayes DF et al (2005) Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol 23(7):1420–1430

    Article  PubMed  Google Scholar 

  • Danila DC, Heller G et al (2007) Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res 13(23):7053–7058

    Article  PubMed  CAS  Google Scholar 

  • Davis JW, Nakanishi H et al (2008) Circulating tumor cells in peripheral blood samples from patients with increased serum prostate specific antigen: initial results in early prostate cancer. J Urol 179(6):2187–2191; discussion 2191

    Google Scholar 

  • de Bono JS, Scher HI et al (2008) Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 14(19):6302–6309

    Article  PubMed  CAS  Google Scholar 

  • de Cremoux P, Extra JM et al (2000) Detection of MUC1-expressing mammary carcinoma cells in the peripheral blood of breast cancer patients by real-time polymerase chain reaction. Clin Cancer Res 6(8):3117–3122

    PubMed  Google Scholar 

  • Desmedt C, Ruiz-Garcia E et al (2008) Gene expression predictors in breast cancer: current status, limitations and perspectives. Eur J Cancer 44(18):2714–2720

    Article  PubMed  CAS  Google Scholar 

  • Drake JM, Strohbehn G et al (2009) ZEB1 enhances transendothelial migration and represses the epithelial phenotype of prostate cancer cells. Mol Biol Cell 20(8):2207–2217

    Article  PubMed  CAS  Google Scholar 

  • Dubois SG, Epling CL et al (2010) Flow cytometric detection of Ewing sarcoma cells in peripheral blood and bone marrow. Pediatr Blood Cancer 54(1):13–18

    Article  PubMed  Google Scholar 

  • Fabisiewicz A, Kulik J et al (2004) Detection of circulating breast cancer cells in peripheral blood by a two-marker reverse transcriptase-polymerase chain reaction assay. Acta Biochim Pol 51(3):747–755

    PubMed  CAS  Google Scholar 

  • Fehm T, Sagalowsky A et al (2002) Cytogenetic evidence that circulating epithelial cells in patients with carcinoma are malignant. Clin Cancer Res 8(7):2073–2084

    PubMed  CAS  Google Scholar 

  • Fehm T, Hoffmann O et al (2009) Detection and characterization of circulating tumor cells in blood of primary breast cancer patients by RT-PCR and comparison to status of bone marrow disseminated cells. Breast Cancer Res 11(4):R59

    Article  PubMed  CAS  Google Scholar 

  • Findeisen P, Rockel M et al (2008) Systematic identification and validation of candidate genes for detection of circulating tumor cells in peripheral blood specimens of colorectal cancer patients. Int J Oncol 33(5):1001–1010

    PubMed  CAS  Google Scholar 

  • Fong SM, Lee MK et al (2009) Fluorescence-expressing viruses allow rapid identification and separation of rare tumor cells in spiked samples of human whole blood. Surgery 146(3):498–505

    Article  PubMed  Google Scholar 

  • Gallagher DJ, Milowsky MI et al (2009) Detection of circulating tumor cells in patients with urothelial cancer. Ann Oncol 20(2):305–308

    Article  PubMed  CAS  Google Scholar 

  • Garcia JA, Rosenberg JE et al (2007) Evaluation and significance of circulating epithelial cells in patients with hormone-refractory prostate cancer. BJU Int 99(3):519–524

    Article  PubMed  Google Scholar 

  • Geiger TR, Peeper DS (2009) Metastasis mechanisms. Biochim Biophys Acta 1796(2):293–308

    PubMed  CAS  Google Scholar 

  • Gertler R, Rosenberg R et al (2003) Detection of circulating tumor cells in blood using an optimized density gradient centrifugation. Recent Results Cancer Res 162:149–155

    PubMed  Google Scholar 

  • Goeminne JC, Guillaume T et al (2000) Pitfalls in the detection of disseminated non-hematological tumor cells. Ann Oncol 11(7):785–792

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez-Roca E, Garcia-Albeniz X et al (2010) Accurate expression profiling of very small cell populations. PLoS One 5(12):e14418

    Article  PubMed  CAS  Google Scholar 

  • Goodman OB Jr, Fink LM et al (2009) Circulating tumor cells in patients with castration-resistant prostate cancer baseline values and correlation with prognostic factors. Cancer Epidemiol Biomarkers Prev 18(6):1904–1913

    Article  PubMed  CAS  Google Scholar 

  • Gradilone A, Raimondi C et al (2011) Circulating tumor cells lacking cytokeratin in breast cancer: the importance of being mesenchymal. J Cell Mol Med 15(5):1066–1070

    Google Scholar 

  • Guzzo TJ, McNeil BK et al (2009) The presence of circulating tumor cells does not predict extravesical disease in bladder cancer patients prior to radical cystectomy. Urol Oncol [Epub ahead of print]

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  PubMed  CAS  Google Scholar 

  • Hartkopf AD, Wagner P et al (2011) Changing levels of circulating tumor cells in monitoring chemotherapy response in patients with metastatic breast cancer. Anticancer Res 31(3):979–984

    PubMed  Google Scholar 

  • Hayes DF, Cristofanilli M et al (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(14 Pt 1):4218–4224

    Google Scholar 

  • Hayes GM, Busch R et al (2010) Isolation of malignant B cells from patients with chronic lymphocytic leukemia (CLL) for analysis of cell proliferation: validation of a simplified method suitable for multi-center clinical studies. Leuk Res 34(6):809–815

    Article  PubMed  CAS  Google Scholar 

  • Hofman V, Ilie MI et al (2010) 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 [Epub ahead of print]

  • Hofman V, Bonnetaud C et al (2011) Preoperative circulating tumor cell detection using the isolation by size of epithelial tumor cell method for patients with lung cancer is a new prognostic biomarker. Clin Cancer Res 17(4):827–835

    Article  PubMed  CAS  Google Scholar 

  • Hou JM, Greystoke A et al (2009) Evaluation of circulating tumor cells and serological cell death biomarkers in small cell lung cancer patients undergoing chemotherapy. Am J Pathol 175(2):808–816

    Article  PubMed  CAS  Google Scholar 

  • Hou JM, Krebs M et al (2011) Circulating tumor cells as a window on metastasis biology in lung cancer. Am J Pathol 178(3):989–996

    Article  PubMed  Google Scholar 

  • Howard EW, Leung SC et al (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(5):497–508

    Article  PubMed  CAS  Google Scholar 

  • Hsieh HB, Marrinucci D et al (2006) High speed detection of circulating tumor cells. Biosens Bioelectron 21(10):1893–1899

    Article  PubMed  CAS  Google Scholar 

  • Hu Y, Fan L et al (2010) Detection of circulating tumor cells in breast cancer patients utilizing multiparameter flow cytometry and assessment of the prognosis of patients in different CTCs levels. Cytometry A 77(3):213–219

    PubMed  Google Scholar 

  • Iinuma H, Watanabe T et al (2011) Clinical significance of circulating tumor cells, including cancer stem-like cells, in peripheral blood for recurrence and prognosis in patients with dukes’ stage B and C colorectal cancer. J Clin Oncol 29(12):1547–1555

    Article  PubMed  Google Scholar 

  • Ikeguchi M, Kaibara N (2005) Detection of circulating cancer cells after a gastrectomy for gastric cancer. Surg Today 35(6):436–441

    Article  PubMed  CAS  Google Scholar 

  • Ingber DE (2003) Tensegrity I. Cell structure and hierarchical systems biology. J Cell Sci 116(Pt 7):1157–1173

    Article  PubMed  CAS  Google Scholar 

  • Kajita M, McClinic KN et al (2004) Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress. Mol Cell Biol 24(17):7559–7566

    Article  PubMed  CAS  Google Scholar 

  • Kajiyama H, Shibata K et al (2007) Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells. Int J Oncol 31(2):277–283

    PubMed  CAS  Google Scholar 

  • Kallergi G, Mavroudis D et al (2007) Phosphorylation of FAK, PI-3K, and impaired actin organization in CK-positive micrometastatic breast cancer cells. Mol Med 13(1–2):79–88

    PubMed  CAS  Google Scholar 

  • Kallergi G, Agelaki S et al (2008) Phosphorylated EGFR and PI3K/Akt signaling kinases are expressed in circulating tumor cells of breast cancer patients. Breast Cancer Res 10(5):R80

    Article  PubMed  CAS  Google Scholar 

  • Kallergi G, Markomanolaki H et al (2009) Hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression in circulating tumor cells of breast cancer patients. Breast Cancer Res 11(6):R84

    Article  PubMed  CAS  Google Scholar 

  • Kim MY, Oskarsson T et al (2009) Tumor self-seeding by circulating cancer cells. Cell 139(7):1315–1326

    Article  PubMed  Google Scholar 

  • Klein CA, Blankenstein TJ et al (2002) Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet 360(9334):683–689

    Article  PubMed  CAS  Google Scholar 

  • Koyanagi K, Bilchik AJ et al (2008) Prognostic relevance of occult nodal micrometastases and circulating tumor cells in colorectal cancer in a prospective multicenter trial. Clin Cancer Res 14(22):7391–7396

    Article  PubMed  CAS  Google Scholar 

  • Krebs MG, Sloane R et al (2011) Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J Clin Oncol 29(12):1556–1563

    Article  PubMed  Google Scholar 

  • Krivacic RT, Ladanyi A et al (2004) A rare-cell detector for cancer. Proc Natl Acad Sci USA 101(29):10501–10504

    Article  PubMed  CAS  Google Scholar 

  • Lambrechts AC, Bosma AJ et al (1999) Comparison of immunocytochemistry, reverse transcriptase polymerase chain reaction, and nucleic acid sequence-based amplification for the detection of circulating breast cancer cells. Breast Cancer Res Treat 56(3):219–231

    Article  PubMed  CAS  Google Scholar 

  • Lankiewicz S, Zimmermann S et al (2008) Circulating tumour cells as a predictive factor for response to systemic chemotherapy in patients with advanced colorectal cancer. Mol Oncol 2(4):349–355

    Article  PubMed  Google Scholar 

  • Leversha MA, Han J et al (2009) Fluorescence in situ hybridization analysis of circulating tumor cells in metastatic prostate cancer. Clin Cancer Res 15(6):2091–2097

    Article  PubMed  CAS  Google Scholar 

  • Li G, Passebosc-Faure K et al (2005) Cadherin-6 gene expression in conventional renal cell carcinoma: a useful marker to detect circulating tumor cells. Anticancer Res 25(1A):377–381

    Google Scholar 

  • Liu MC, Shields PG et al (2009) Circulating tumor cells: a useful predictor of treatment efficacy in metastatic breast cancer. J Clin Oncol 27(31):5153–5159

    Article  PubMed  Google Scholar 

  • Lu J, Fan T et al (2010) Isolation of circulating epithelial and tumor progenitor cells with an invasive phenotype from breast cancer patients. Int J Cancer 126(3):669–683

    Article  PubMed  CAS  Google Scholar 

  • Maheswaran S, Sequist LV et al (2008) Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 359(4):366–377

    Article  PubMed  CAS  Google Scholar 

  • Mao X, Shaw G et al (2008) Detection of TMPRSS2:ERG fusion gene in circulating prostate cancer cells. Asian J Androl 10(3):467–473

    Article  PubMed  CAS  Google Scholar 

  • Marrinucci D, Bethel K et al (2010) Cytomorphology of circulating colorectal tumor cells: a small case series. J Oncol 2010:861341

    PubMed  Google Scholar 

  • Matrone MA, Whipple RA et al (2010) Microtentacles tip the balance of cytoskeletal forces in circulating tumor cells. Cancer Res 70(20):7737–7741

    Article  PubMed  CAS  Google Scholar 

  • Matsusaka S, Suenaga M et al (2011) Circulating tumor cells as a surrogate marker for determining response to chemotherapy in Japanese patients with metastatic colorectal cancer. Cancer Sci 102(6):1188–1192

    Google Scholar 

  • Matsusaka S, Chin K et al (2010) Circulating tumor cells as a surrogate marker for determining response to chemotherapy in patients with advanced gastric cancer. Cancer Sci 101(4):1067–1071

    Article  PubMed  CAS  Google Scholar 

  • McShane LM, Altman DG et al (2005) REporting recommendations for tumour MARKer prognostic studies (REMARK). Eur J Cancer 41(12):1690–1696

    Article  PubMed  Google Scholar 

  • Monteiro J, Fodde R (2010) Cancer stemness and metastasis: therapeutic consequences and perspectives. Eur J Cancer 46(7):1198–1203

    Article  PubMed  CAS  Google Scholar 

  • Moreno JG, Miller MC et al (2005) Circulating tumor cells predict survival in patients with metastatic prostate cancer. Urology 65(4):713–718

    Article  PubMed  Google Scholar 

  • Nagrath S, Sequist LV et al (2007) Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450(7173):1235–1239

    Article  PubMed  CAS  Google Scholar 

  • Nakagawa T, Martinez SR et al (2007) Detection of circulating tumor cells in early-stage breast cancer metastasis to axillary lymph nodes. Clin Cancer Res 13(14):4105–4110

    Article  PubMed  CAS  Google Scholar 

  • Nakamura S, Yagata H et al (2010) Multi-center study evaluating circulating tumor cells as a surrogate for response to treatment and overall survival in metastatic breast cancer. Breast Cancer 17(3):199–204

    Article  PubMed  Google Scholar 

  • Naoe M, Ogawa Y et al (2007) Detection of circulating urothelial cancer cells in the blood using the CellSearch System. Cancer 109(7):1439–1445

    Article  PubMed  Google Scholar 

  • Navin N, Kendall J et al (2011) Tumour evolution inferred by single-cell sequencing. Nature 472(7341):90–94

    Article  PubMed  CAS  Google Scholar 

  • Negin BP, Cohen SJ (2010) Circulating tumor cells in colorectal cancer: past, present, and future challenges. Curr Treat Options Oncol 11(1–2):1–13

    Article  PubMed  Google Scholar 

  • Nezos A, Pissimisis N et al (2009) Detection of circulating tumor cells in bladder cancer patients. Cancer Treat Rev 35(3):272–279

    Article  PubMed  Google Scholar 

  • Nolan T, Hands RE et al (2006) Quantification of mRNA using real-time RT-PCR. Nat Protoc 1(3):1559–1582

    Article  PubMed  CAS  Google Scholar 

  • O’Brien CA, Pollett A et al (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445(7123):106–110

    Article  PubMed  CAS  Google Scholar 

  • Okegawa T, Nutahara K et al (2009) Prognostic significance of circulating tumor cells in patients with hormone refractory prostate cancer. J Urol 181(3):1091–1097

    Article  PubMed  Google Scholar 

  • Olmos D, Arkenau HT et al (2009) Circulating tumour cell (CTC) counts as intermediate end points in castration-resistant prostate cancer (CRPC): a single-centre experience. Ann Oncol 20(1):27–33

    Article  PubMed  CAS  Google Scholar 

  • Ota I, Li XY et al (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(48):20318–20323

    Article  PubMed  CAS  Google Scholar 

  • Pantel K, Brakenhoff RH et al (2008) Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer 8(5):329–340

    Article  PubMed  CAS  Google Scholar 

  • Paris PL, Kobayashi Y et al (2009) Functional phenotyping and genotyping of circulating tumor cells from patients with castration resistant prostate cancer. Cancer Lett 277(2):164–173

    Article  PubMed  CAS  Google Scholar 

  • Peinado H, Marin F et al (2004) Snail and E47 repressors of E-cadherin induce distinct invasive and angiogenic properties in vivo. J Cell Sci 117(Pt 13):2827–2839

    Article  PubMed  CAS  Google Scholar 

  • Pestrin M, Bessi S et al (2009) Correlation of HER2 status between primary tumors and corresponding circulating tumor cells in advanced breast cancer patients. Breast Cancer Res Treat 118(3):523–530

    Article  PubMed  CAS  Google Scholar 

  • Pierga JY, Bidard FC et al (2008) Circulating tumor cell detection predicts early metastatic relapse after neoadjuvant chemotherapy in large operable and locally advanced breast cancer in a phase II randomized trial. Clin Cancer Res 14(21):7004–7010

    Article  PubMed  CAS  Google Scholar 

  • Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9(4):265–273

    Article  PubMed  CAS  Google Scholar 

  • Puisieux A, Valsesia-Wittmann S (2006) Cancer cells escape from failsafe programs in a simple Twist. Bull Cancer 93(3):251–256

    PubMed  CAS  Google Scholar 

  • Rahbari NN, Aigner M et al (2010) Meta-analysis shows that detection of circulating tumor cells indicates poor prognosis in patients with colorectal cancer. Gastroenterology 138(5):1714–1726

    Article  PubMed  Google Scholar 

  • Raimondi C, Gradilone A et al (2011) Epithelial-mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. Breast Cancer Res Treat [Epub ahead of print]

  • Ring A, Smith IE et al (2004) Circulating tumour cells in breast cancer. Lancet Oncol 5(2):79–88

    Article  PubMed  Google Scholar 

  • Ring AE, Zabaglo L et al (2005) Detection of circulating epithelial cells in the blood of patients with breast cancer: comparison of three techniques. Br J Cancer 92(5):906–912

    Article  PubMed  CAS  Google Scholar 

  • Royston P, Altman DG et al (2006) Dichotomizing continuous predictors in multiple regression: a bad idea. Stat Med 25(1):127–141

    Article  PubMed  Google Scholar 

  • Sabbah M, Emami S et al (2008) Molecular signature and therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial cancers. Drug Resist Updat 11(4–5):123–151

    Article  PubMed  CAS  Google Scholar 

  • Sayan AE, Griffiths TR et al (2009) SIP1 protein protects cells from DNA damage-induced apoptosis and has independent prognostic value in bladder cancer. Proc Natl Acad Sci USA 106(35):14884–14889

    Article  PubMed  CAS  Google Scholar 

  • Sboner A, Demichelis F et al (2010) Molecular sampling of prostate cancer: a dilemma for predicting disease progression. BMC Med Genomics 3:8

    Article  PubMed  CAS  Google Scholar 

  • Scatton O, Chiappini F et al (2006) Fate and characterization of circulating tumor cells in a NOD/SCID mouse model of human hepatocellular carcinoma. Oncogene 25(29):4067–4075

    Article  PubMed  CAS  Google Scholar 

  • Scher HI, Jia X et al (2009) Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data. Lancet Oncol 10(3):233–239

    Article  PubMed  CAS  Google Scholar 

  • Seo JH, Choi CW et al (2005) Follow-up study of peripheral blood carcinoembryonic antigen mRNA using reverse transcription-polymerase chain reaction as an early marker of clinical recurrence in patients with curatively resected gastric cancer. Am J Clin Oncol 28(1):24–29

    Article  PubMed  CAS  Google Scholar 

  • Serrano MJ, Sanchez-Rovira P et al (2009) Detection of circulating tumor cells in the context of treatment: prognostic value in breast cancer. Cancer Biol Ther 8(8):671–675

    Article  PubMed  Google Scholar 

  • Shen C, Hu L et al (2009) The detection of circulating tumor cells of breast cancer patients by using multimarker (Survivin, hTERT and hMAM) quantitative real-time PCR. Clin Biochem 42(3):194–200

    Article  PubMed  CAS  Google Scholar 

  • Shih JY, Tsai MF et al (2005) Transcription repressor slug promotes carcinoma invasion and predicts outcome of patients with lung adenocarcinoma. Clin Cancer Res 11(22):8070–8078

    Article  PubMed  CAS  Google Scholar 

  • Shimazui T, Yoshikawa K et al (2003) Detection of cadherin-6 mRNA by nested RT-PCR as a potential marker for circulating cancer cells in renal cell carcinoma. Int J Oncol 23(4):1049–1054

    PubMed  CAS  Google Scholar 

  • Sieuwerts AM, Mostert B et al (2011) mRNA and microRNA expression profiles in circulating tumor cells and primary tumors of metastatic breast cancer patients. Clin Cancer Res 17(11):3600–3618

    Google Scholar 

  • Sieuwerts AM, Kraan J et al (2009) Molecular characterization of circulating tumor cells in large quantities of contaminating leukocytes by a multiplex real-time PCR. Breast Cancer Res Treat 118(3):455–468

    Article  PubMed  CAS  Google Scholar 

  • Silva AL, Tome MJ et al (2002) Human mammaglobin RT-PCR assay for detection of occult breast cancer cells in hematopoietic products. Ann Oncol 13(3):422–429

    Article  PubMed  CAS  Google Scholar 

  • Sleijfer S, Gratama JW et al (2007) Circulating tumour cell detection on its way to routine diagnostic implementation? Eur J Cancer 43(18):2645–2650

    Article  PubMed  CAS  Google Scholar 

  • Smit MA, Peeper DS (2011) Zeb1 is required for TrkB-induced epithelial-mesenchymal transition, anoikis resistance and metastasis. Oncogene [Epub ahead of print]

  • Smit MA, Geiger TR et al (2009) A Twist-Snail axis critical for TrkB-induced epithelial-mesenchymal transition-like transformation, anoikis resistance, and metastasis. Mol Cell Biol 29(13):3722–3737

    Article  PubMed  CAS  Google Scholar 

  • Stein JP, Lieskovsky G et al (2001) Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 19(3):666–675

    PubMed  CAS  Google Scholar 

  • Stott SL, Lee RJ et al (2010b) Isolation and characterization of circulating tumor cells from patients with localized and metastatic prostate cancer. Sci Transl Med 2(25):25ra23

    Google Scholar 

  • Stott SL, Hsu CH et al (2010) Isolation of circulating tumor cells using a microvortex-generating herringbone-chip. Proc Natl Acad Sci USA 107(43):18392–18397

    Article  PubMed  CAS  Google Scholar 

  • Sun T, Zhao N et al (2010) Expression and functional significance of Twist1 in hepatocellular carcinoma: its role in vasculogenic mimicry. Hepatology 51(2):545–556

    PubMed  CAS  Google Scholar 

  • Swennenhuis JF, Tibbe AG et al (2009) Characterization of circulating tumor cells by fluorescence in situ hybridization. Cytometry A 75(6):520–527

    PubMed  Google Scholar 

  • Tan SJ, Yobas L et al (2009) Microdevice for the isolation and enumeration of cancer cells from blood. Biomed Microdevices 11(4):883–892

    Article  PubMed  Google Scholar 

  • Tanaka F, Yoneda K et al (2009) Circulating tumor cell as a diagnostic marker in primary lung cancer. Clin Cancer Res 15(22):6980–6986

    Article  PubMed  CAS  Google Scholar 

  • Tewes M, Aktas B et al (2009) Molecular profiling and predictive value of circulating tumor cells in patients with metastatic breast cancer: an option for monitoring response to breast cancer related therapies. Breast Cancer Res Treat 115(3):581–590

    Article  PubMed  Google Scholar 

  • Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7(2):131–142

    Article  PubMed  CAS  Google Scholar 

  • Thiery JP, Acloque H et al (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890

    Article  PubMed  CAS  Google Scholar 

  • Uen YH, Lu CY et al (2008) Persistent presence of postoperative circulating tumor cells is a poor prognostic factor for patients with stage I-III colorectal cancer after curative resection. Ann Surg Oncol 15(8):2120–2128

    Article  PubMed  Google Scholar 

  • Van der Auwera I, Peeters D et al (2010) Circulating tumour cell detection: a direct comparison between the CellSearch System, the AdnaTest and CK-19/mammaglobin RT-PCR in patients with metastatic breast cancer. Br J Cancer 102(2):276–284

    Article  PubMed  CAS  Google Scholar 

  • Vona G, Sabile A et al (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(1):57–63

    Article  PubMed  CAS  Google Scholar 

  • Vona G, Estepa L et al (2004) Impact of cytomorphological detection of circulating tumor cells in patients with liver cancer. Hepatology 39(3):792–797

    Article  PubMed  Google Scholar 

  • Wang L, Wang Y et al (2009) Flow cytometric analysis of CK19 expression in the peripheral blood of breast carcinoma patients: relevance for circulating tumor cell detection. J Exp Clin Cancer Res 28:57

    Article  PubMed  CAS  Google Scholar 

  • Willipinski-Stapelfeldt B, Riethdorf S et al (2005) Changes in cytoskeletal protein composition indicative of an epithelial-mesenchymal transition in human micrometastatic and primary breast carcinoma cells. Clin Cancer Res 11(22):8006–8014

    Article  PubMed  CAS  Google Scholar 

  • Wu CH, Lin SR et al (2006) Molecular detection of disseminated tumor cells in the peripheral blood of patients with gastric cancer: evaluation of their prognostic significance. Dis Markers 22(3):103–109

    PubMed  CAS  Google Scholar 

  • Wu C, Hao H et al (2009) Preliminary investigation of the clinical significance of detecting circulating tumor cells enriched from lung cancer patients. J Thorac Oncol 4(1):30–36

    Article  PubMed  Google Scholar 

  • Xi L, Nicastri DG et al (2007) Optimal markers for real-time quantitative reverse transcription PCR detection of circulating tumor cells from melanoma, breast, colon, esophageal, head and neck, and lung cancers. Clin Chem 53(7):1206–1215

    Article  PubMed  CAS  Google Scholar 

  • Xu W, Cao L et al (2011) Isolation of circulating tumor cells in patients with hepatocellular carcinoma using an asialoglycoprotein receptor-based magnetic cell separation strategy. Clin Cancer Res 17(11):3783–3793

    Google Scholar 

  • Yagata H, Nakamura S et al (2008) Evaluation of circulating tumor cells in patients with breast cancer: multi-institutional clinical trial in Japan. Int J Clin Oncol 13(3):252–256

    Article  PubMed  Google Scholar 

  • Yang AD, Fan F et al (2006) Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res 12(14 Pt 1):4147–4153

    Google Scholar 

  • Yang J, Weinberg RA (2008) Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14(6):818–829

    Article  PubMed  CAS  Google Scholar 

  • Yang ZF, Ngai P et al (2008) Identification of local and circulating cancer stem cells in human liver cancer. Hepatology 47(3):919–928

    Article  PubMed  CAS  Google Scholar 

  • Yie SM, Lou B et al (2008) Detection of survivin-expressing circulating cancer cells (CCCs) in peripheral blood of patients with gastric and colorectal cancer reveals high risks of relapse. Ann Surg Oncol 15(11):3073–3082

    Article  PubMed  Google Scholar 

  • You F, Roberts LA et al (2008) Low-level expression of HER2 and CK19 in normal peripheral blood mononuclear cells: relevance for detection of circulating tumor cells. J Hematol Oncol 1:2

    Article  PubMed  CAS  Google Scholar 

  • Zach O, Kasparu H et al (1999) Detection of circulating mammary carcinoma cells in the peripheral blood of breast cancer patients via a nested reverse transcriptase polymerase chain reaction assay for mammaglobin mRNA. J Clin Oncol 17(7):2015–2019

    PubMed  CAS  Google Scholar 

  • Zhou H, Guo JM et al (2010) Detection of circulating tumor cells in peripheral blood from patients with gastric cancer using microRNA as a marker. J Mol Med 88(7):709–717

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was jointly supported by grants from the National Natural Science Foundation of China (No. 30973492, 81030038, 81000927, and 81071661), the National Key Sci-Tech Special Project of Infectious Diseases (No. 2008ZX10002-019 and 2008ZX10002-022), the Shanghai Rising-Star Follow-up Program Funds (No. 10QH1400500), and Research Fund for the Doctoral Program of Higher Education of China (20100071120064).

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No potential conflicts of interest were disclosed.

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Sun, YF., Yang, XR., Zhou, J. et al. Circulating tumor cells: advances in detection methods, biological issues, and clinical relevance. J Cancer Res Clin Oncol 137, 1151–1173 (2011). https://doi.org/10.1007/s00432-011-0988-y

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  • DOI: https://doi.org/10.1007/s00432-011-0988-y

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