Circulating Tumor Cells: A Window to Understand Cancer Metastasis, Monitor and Fight Against Cancers


  • Lei Xu Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
  • Jonathan Shamash Centre for Experimental Medicine, Barts Cancer Institute, Queen Mary University of London, London, UK
  • Yong-Jie Lu Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK



Circulating tumor cells, metastases, genetic alterations, biomarkers, prognosis, treatment response.


 Metastases are the major culprits behind most cancer-related death and the central challenge to the eradication of a malignancy. Circulating tumor cells (CTCs) have the potential to help us understand how metastases form, to be utilized for cancer diagnosis and treatment selection and even to be targeted for cancer treatment. Many advances have been made regarding the isolation of these rare cells. However, several challenges and limitations in CTC analysis still exist. Multiple color immunofluorescence, genetic analysis (e.g. Fluorescence in situ Hybridization, microarray and next generation sequencing) and CTC culture will be effective tools to study CTCs and provide information on metastatic mechanism and clinical implication. In this review, we discuss the importance of CTC study in understanding cancer metastasis and their potential clinical application as biomarkers to predict cancer progression and treatment response, as well as the current situation for CTC isolation and analysis.


Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 2013; 49(6): 1374-403.

Society AC. Cancer facts & figures 2013. Atalanta: American Cancer Society 2013.

Plaks V, Koopman CD, Werb Z. Cancer. Circulating tumor cells. Science 2013; 341(6151): 1186-8.

Williams SC. Circulating tumor cells. Proc Natl Acad Sci U S A 2013; 110(13): 4861.

Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351(8): 781-91.

Kaiser J. Medicine. Cancer's circulation problem. Science 2010; 327(5969): 1072-4.

Pantel K, Brakenhoff RH. Dissecting the metastatic cascade. Nat Rev Cancer 2004; 4(6): 448-56.

Muller V, Stahmann N, Riethdorf S, Rau T, Zabel T, Goetz A, et al. Circulating tumor cells in breast cancer: correlation to bone marrow micrometastases, heterogeneous response to systemic therapy and low proliferative activity. Clin Cancer Res 2005; 11(10): 3678-85.

Suzuki H, Freije D, Nusskern DR, Okami K, Cairns P, Sidransky D, et al. Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues. Cancer Res 1998; 58(2): 204-9.

Racila E, Euhus D, Weiss AJ, Rao C, McConnell J, Terstappen LW, et al. Detection and characterization of carcinoma cells in the blood. Proc Natl Acad Sci U S A 1998; 95(8): 4589-94.

Butler TP, Gullino PM. Quantitation of cell shedding into efferent blood of mammary adenocarcinoma. Cancer Res 1975; 35(3): 512-6.

Chang YS, di Tomaso E, McDonald DM, Jones R, Jain RK, Munn LL. Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc Natl Acad Sci U S A 2000; 97(26): 14608-13.

Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002; 2(8): 563-72.

Kang Y, Pantel K. Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell 2013; 23(5): 573-81.

Uhr JW, Pantel K. Controversies in clinical cancer dormancy. Proc Natl Acad Sci U S A 2011; 108(30): 12396-400.

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.

Paez D, Labonte MJ, Bohanes P, Zhang W, Benhanim L, Ning Y, et al. Cancer dormancy: a model of early dissemination and late cancer recurrence. Clin Cancer Res 2012; 18(3): 645-53.

Paterlini-Brechot P, Benali NL. Circulating tumor cells (CTC) detection: clinical impact and future directions. Cancer Lett 2007; 253(2): 180-204.

Douma S, Van Laar T, Zevenhoven J, Meuwissen R, Van Garderen E, Peeper DS. Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature 2004; 430(7003): 1034-9.

Arya M, Bott SR, Shergill IS, Ahmed HU, Williamson M, Patel HR. The metastatic cascade in prostate cancer. Surg Oncol 2006; 15(3): 117-28.

Sanda MG, Restifo NP, Walsh JC, Kawakami Y, Nelson WG, Pardoll DM, et al. Molecular characterization of defective antigen processing in human prostate cancer. J Natl Cancer Inst 1995; 87(4): 280-5.

Chao MP, Weissman IL, Majeti R. The CD47-SIRPalpha pathway in cancer immune evasion and potential therapeutic implications. Curr Opin Immunol 2012; 24(2): 225-32.

Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A 2012; 109(17): 6662-7.

Chay CH, Cooper CR, Gendernalik JD, Dhanasekaran SM, Chinnaiyan AM, Rubin MA, et al. A functional thrombin receptor (PAR1) is expressed on bone-derived prostate cancer cell lines. Urology 2002; 60(5): 760-5.

Trikha M, Nakada MT. Platelets and cancer: implications for antiangiogenic therapy. Semin Thromb Hemost 2002; 28(1): 39-44.

Borsig L, Wong R, Feramisco J, Nadeau DR, Varki NM, Varki A. Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis. Proc Natl Acad Sci U S A 2001; 98(6): 3352-7.

Trikha M, Raso E, Cai Y, Fazakas Z, Paku S, Porter AT, et al. Role of alphaII(b)beta3 integrin in prostate cancer metastasis. Prostate 1998; 35(3): 185-92.<185::AID-PROS4>3.0.CO;2-G

Jones ML, Siddiqui J, Pienta KJ, Getzenberg RH. Circulating fibroblast-like cells in men with metastatic prostate cancer. Prostate 2013; 73(2): 176-81.

Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 2007; 450(7173): 1235-9.

Rhim AD, Mirek ET, Aiello NM, Maitra A, Bailey JM, McAllister F, et al. EMT and dissemination precede pancreatic tumor formation. Cell 2012; 148(1-2): 349-61.

Husemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E, et al. Systemic spread is an early step in breast cancer. Cancer Cell 2008; 13(1): 58-68.

Eyles J, Puaux AL, Wang X, Toh B, Prakash C, Hong M, et al. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J Clin Invest 2010; 120(6): 2030-9.

Rack B, Schindlbeck C, Juckstock J, Andergassen U, Hepp P, Zwingers T, et al. Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst 2014; 106(5).

Lucci A, Hall CS, Lodhi AK, Bhattacharyya A, Anderson AE, Xiao L, et al. Circulating tumour cells in non-metastatic breast cancer: a prospective study. Lancet Oncol 2012; 13(7): 688-95.

Wan L, Pantel K, Kang Y. Tumor metastasis: moving new biological insights into the clinic. Nat Med 2013; 19(11): 1450-64.

Baccelli I, Schneeweiss A, Riethdorf S, Stenzinger A, Schillert A, Vogel V, et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol 2013; 31(6): 539-44.

Aft R, Naughton M, Trinkaus K, Watson M, Ylagan L, Chavez-MacGregor M, et al. Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol 2010; 11(5): 421-8.

Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Postlberger S, Menzel C, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009; 360(7): 679-91.

Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fossa SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369(3): 213-23.

Liu W, Laitinen S, Khan S, Vihinen M, Kowalski J, Yu G, et al. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat Med 2009; 15(5): 559-65.

Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer 2009; 9(4): 302-12.

Stoecklein NH, Klein CA. Genetic disparity between primary tumours, disseminated tumour cells, and manifest metastasis. Int J Cancer 2010; 126(3): 589-98.

Schardt JA, Meyer M, Hartmann CH, Schubert F, Schmidt-Kittler O, Fuhrmann C, et al. Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer. Cancer Cell 2005; 8(3): 227-39.

Schmidt-Kittler O, Ragg T, Daskalakis A, Granzow M, Ahr A, Blankenstein TJ, et al. From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci U S A 2003; 100(13): 7737-42.

Stoecklein NH, Hosch SB, Bezler M, Stern F, Hartmann CH, Vay C, et al. Direct genetic analysis of single disseminated cancer cells for prediction of outcome and therapy selection in esophageal cancer. Cancer Cell 2008; 13(5): 441-53.

Weckermann D, Polzer B, Ragg T, Blana A, Schlimok G, Arnholdt H, et al. Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer. J Clin Oncol 2009; 27(10): 1549-56.

Mego M, Mani SA, Lee BN, Li C, Evans KW, Cohen EN, et al. Expression of epithelial-mesenchymal transition-inducing transcription factors in primary breast cancer: The effect of neoadjuvant therapy. Int J Cancer 2012; 130(4): 808-16.

Zhu ML, Kyprianou N. Role of androgens and the androgen receptor in epithelial-mesenchymal transition and invasion of prostate cancer cells. FASEB J 2010; 24(3): 769-77.

Sun Y, Wang BE, Leong KG, Yue P, Li L, Jhunjhunwala S, et al. Androgen deprivation causes epithelial-mesenchymal transition in the prostate: implications for androgen-deprivation therapy. Cancer Res 2012; 72(2): 527-36.

Danila DC, Fleisher M, Scher HI. Circulating tumor cells as biomarkers in prostate cancer. Clin Cancer Res 2011; 17(12): 3903-12.

Fehm T, Becker S, Duerr-Stoerzer S, Sotlar K, Mueller V, Wallwiener D, et al. Determination of HER2 status using both serum HER2 levels and circulating tumor cells in patients with recurrent breast cancer whose primary tumor was HER2 negative or of unknown HER2 status. Breast Cancer Res 2007; 9(5): R74.

Tewes M, Aktas B, Welt A, Mueller S, Hauch S, Kimmig R, et al. 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 2009; 115(3): 581-90.

Giordano A, Egleston BL, Hajage D, Bland J, Hortobagyi GN, Reuben JM, et al. Establishment and validation of circulating tumor cell-based prognostic nomograms in first-line metastatic breast cancer patients. Clin Cancer Res 2013; 19(6): 1596-602.

Kawasaki M, Iwasa Y. Electronics: 'Cut and stick' ion gels. Nature 2012; 489(7417): 510-1.

Marchesi V. Breast cancer: Circulating tumour cells help to guide treatment. Nat Rev Clin Oncol 2013; 10(3): 124.

Stebbing J, Payne R, Reise J, Frampton AE, Avery M, Woodley L, et al. The efficacy of lapatinib in metastatic breast cancer with HER2 non-amplified primary tumors and EGFR positive circulating tumor cells: a proof-of-concept study. PLoS One 2013; 8(5): e62543.

Pantel K, Alix-Panabieres C. The potential of circulating tumor cells as a liquid biopsy to guide therapy in prostate cancer. Cancer Discov 2012; 2(11): 974-5.

Balasubramanian P, Yang L, Lang JC, Jatana KR, Schuller D, Agrawal A, et al. Confocal images of circulating tumor cells obtained using a methodology and technology that removes normal cells. Mol Pharm 2009; 6(5): 1402-8.

Bjartell A. Circulating tumour cells as surrogate biomarkers in castration-resistant prostate cancer trials. Eur Urol 2011; 60(5): 905-7.

Scher HI, Jia X, de Bono JS, Fleisher M, Pienta KJ, Raghavan D, et al. Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data. Lancet Oncol 2009; 10(3): 233-9.

Amato RJ, Melnikova V, Zhang Y, Liu W, Saxena S, Shah PK, et al. Epithelial cell adhesion molecule-positive circulating tumor cells as predictive biomarker in patients with prostate cancer. Urology 2013; 81(6): 1303-7.

Costa DB. Identification of somatic genomic alterations in circulating tumors cells: another step forward in non-small-cell lung cancer? J Clin Oncol 2013; 31(18): 2236-9.

Pirozzi G, Tirino V, Camerlingo R, La Rocca A, Martucci N, Scognamiglio G, et al. Prognostic value of cancer stem cells, epithelial-mesenchymal transition and circulating tumor cells in lung cancer. Oncol Rep 2013; 29(5): 1763-8.

Zhu WF, Li J, Yu LC, Wu Y, Tang XP, Hu YM, et al. Prognostic value of EpCAM/MUC1 mRNA-positive cells in non-small cell lung cancer patients. Tumour Biol 2013.

Pesta M, Fichtl J, Kulda V, Topolcan O, Treska V. Monitoring of circulating tumor cells in patients undergoing surgery for hepatic metastases from colorectal cancer. Anticancer Res 2013; 33(5): 2239-43.

Lu CY, Tsai HL, Uen YH, Hu HM, Chen CW, Cheng TL, et al. Circulating tumor cells as a surrogate marker for determining clinical outcome to mFOLFOX chemotherapy in patients with stage III colon cancer. Br J Cancer 2013; 108(4): 791-7.

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.

Tjensvoll K, Nordgard O, Smaaland R. Circulating tumor cells in pancreatic cancer patients: Methods of detection and clinical implications. Int J Cancer 2013.

Uenosono Y, Arigami T, Kozono T, Yanagita S, Hagihara T, Haraguchi N, et al. Clinical significance of circulating tumor cells in peripheral blood from patients with gastric cancer. Cancer 2013.

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.

Parkinson DR, Dracopoli N, Petty BG, Compton C, Cristofanilli M, Deisseroth A, et al. Considerations in the development of circulating tumor cell technology for clinical use. J Transl Med 2012; 10: 138.

Budd GT, Cristofanilli M, Ellis MJ, Stopeck A, Borden E, Miller MC, et al. Circulating tumor cells versus imaging--predicting overall survival in metastatic breast cancer. Clin Cancer Res 2006; 12(21): 6403-9.

Stott SL, Lee RJ, Nagrath S, Yu M, Miyamoto DT, Ulkus L, et al. Isolation and characterization of circulating tumor cells from patients with localized and metastatic prostate cancer. Sci Transl Med 2010; 2(25): 25ra3.

Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 2007; 25(33): 5287-312.

de Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 2008; 14(19): 6302-9.

Danila DC, Heller G, Gignac GA, Gonzalez-Espinoza R, Anand A, Tanaka E, et al. Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res 2007; 13(23): 7053-8.

Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26(19): 3213-21.

Resel Folkersma L, San Jose Manso L, Galante Romo I, Moreno Sierra J, Olivier Gomez C. Prognostic significance of circulating tumor cell count in patients with metastatic hormone-sensitive prostate cancer. Urology 2012; 80(6): 1328-32.

Lowes LE, Lock M, Rodrigues G, D'Souza D, Bauman G, Ahmad B, et al. Circulating tumour cells in prostate cancer patients receiving salvage radiotherapy. Clin Transl Oncol 2012; 14(2): 150-6.

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.

Cristofanilli M, Hayes DF, Budd GT, Ellis MJ, Stopeck A, Reuben JM, et al. Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol 2005; 23(7): 1420-30.

Shah RB, Mehra R, Chinnaiyan AM, Shen R, Ghosh D, Zhou M, et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res 2004; 64(24): 9209-16.

Qin J, Liu X, Laffin B, Chen X, Choy G, Jeter CR, et al. The PSA(-/lo) prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration. Cell Stem Cell 2012; 10(5): 556-69.

Luo J, Solimini NL, Elledge SJ. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 2009; 136(5): 823-37.

Lackner MR. Prospects for personalized medicine with inhibitors targeting the RAS and PI3K pathways. Expert Rev Mol Diagn 2010; 10(1): 75-87.

Carden CP, Sarker D, Postel-Vinay S, Yap TA, Attard G, Banerji U, et al. Can molecular biomarker-based patient selection in Phase I trials accelerate anticancer drug development? Drug Discov Today 2010; 15(3-4): 88-97.

Danila DC, Anand A, Sung CC, Heller G, Leversha MA, Cao L, et al. TMPRSS2-ERG status in circulating tumor cells as a predictive biomarker of sensitivity in castration-resistant prostate cancer patients treated with abiraterone acetate. Eur Urol 2011; 60(5): 897-904.

Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371(11): 1028-38.

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353(16): 1659-72.

Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Jr., Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353(16): 1673-84.

Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002; 20(3): 719-26.

Meng S, Tripathy D, Shete S, Ashfaq R, Haley B, Perkins S, et al. HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci U S A 2004; 101(25): 9393-8.

Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med 2008; 358(11): 1160-74.

Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res 2009; 69(5): 1851-7.

Gasch C, Bauernhofer T, Pichler M, Langer-Freitag S, Reeh M, Seifert AM, et al. Heterogeneity of epidermal growth factor receptor status and mutations of KRAS/PIK3CA in circulating tumor cells of patients with colorectal cancer. Clin Chem 2013; 59(1): 252-60.

Shamash J, Jacob J, Agrawal S, Powles T, Mutsvangwa K, Wilson P, et al. Whole blood stem cell reinfusion and escalated dose melphalan in castration-resistant prostate cancer: a phase 1 study. Clin Cancer Res 2012; 18(8): 2352-9.

Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Miller MC, et al. 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 2006; 12(14 Pt 1): 4218-24.

Mandel P, Metais P. [Not Available]. C R Seances Soc Biol Fil 1948; 142(3-4): 241-3.

Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 2013; 497(7447): 108-12.

Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med 2008; 14(9): 985-90.




How to Cite

Lei Xu, Jonathan Shamash, & Yong-Jie Lu. (2015). Circulating Tumor Cells: A Window to Understand Cancer Metastasis, Monitor and Fight Against Cancers. Journal of Cancer Research Updates, 4(1),  13–29.