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Disseminated and circulating tumor cells in bone marrow and blood of breast cancer patients: properties, enrichment, and potential targets

  • Review – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Introduction

From the early days of pathology back in the nineteenth century until now, there has been an ongoing search for the missing link between solid tumors such as breast cancer and distant metastases, which sometimes occur many years after removal of the primary tumor. The “seed and soil” theory hypothesizes the early dissemination of occult tumor cells into blood or bone marrow, which can persist in a dormant state for a long time and then become precursors of metastases in distant organs which offer appropriate conditions.

Method

Advances in immunocytochemical methods have enabled the enrichment and visualization of those disseminated tumor cells in bone marrow (DTC-BM) or circulating tumor cells (CTC) in blood. Many studies could demonstrate prognostic significance of the detection of DTC-BM or CTC in different stages of breast cancer.

Conclusion

Further characterization of those cells by immunocytochemical stainings, fluorescence in situ hybridizations, or PCR-based molecular methods will help to understand the biology of tumor cell dissemination and metastasis formation, as well as to define potential drug targets.

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References

  • Adams DL, Stefansson S, Haudenschild C, Martin SS, Charpentier M, Chumsri S, Cristofanilli M, Tang CM, Alpaugh RK (2015) Cytometric characterization of circulating tumor cells captured by microfiltration and their correlation to the cellsearch((R)) CTC test. Cytom. Part A J Int Soc Anal Cytol 87:137–144

    Article  Google Scholar 

  • Aft R, Naughton M, Trinkaus K, Watson M, Ylagan L, Chavez-MacGregor M, Zhai J, Kuo S, Shannon W, Diemer K, Herrmann V, Dietz J, Ali A, Ellis M, Weiss P, Eberlein T, Ma C, Fracasso PM, Zoberi I, Taylor M, Gillanders W, Pluard T, Mortimer J, Weilbaecher K (2010) Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer: an open label, randomised, phase 2 trial. Lancet Oncol 11:421–428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ahr A, Scharl A, Muller M, von Minckwitz G, Gatje R, Pantel K, Kaufmann M (1999) Cross-reactive staining of normal bone-marrow cells by monoclonal antibody 2E11. Int J Cancer 84:502–505

    Article  CAS  PubMed  Google Scholar 

  • Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer S (2009) Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res 11:R46

    Article  PubMed  PubMed Central  Google Scholar 

  • Aktas B, Muller V, Tewes M, Zeitz J, Kasimir-Bauer S, Loehberg CR, Rack B, Schneeweiss A, Fehm T (2011) Comparison of estrogen and progesterone receptor status of circulating tumor cells and the primary tumor in metastatic breast cancer patients. Gynecol Oncol 122:356–360

    Article  CAS  PubMed  Google Scholar 

  • Alix-Panabieres C (2012) EPISPOT assay: detection of viable DTCs/CTCs in solid tumor patients. Recent Results Cancer Res 195:69–76

    Article  PubMed  Google Scholar 

  • Ashworth T (1869) A case of cancer in which cells similar to those in the tumours were seen in the blood after death. Aust Med J 14:146–147

    Google Scholar 

  • Balic M, Lin H, Young L, Hawes D, Giuliano A, McNamara G, Datar RH, Cote RJ (2006) Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res Off J Am Assoc Cancer Res 12:5615–5621

    Article  CAS  Google Scholar 

  • Banys M, Solomayer EF, Gebauer G, Janni W, Krawczyk N, Lueck HJ, Becker S, Huober J, Kraemer B, Wackwitz B, Hirnle P, Wallwiener D, Fehm T (2013) Influence of zoledronic acid on disseminated tumor cells in bone marrow and survival: results of a prospective clinical trial. BMC Cancer 13:480

    Article  PubMed  PubMed Central  Google Scholar 

  • Bock C, Rack B, Kuhn C, Hofmann S, Finkenzeller C, Jager B, Jeschke U, Doisneau-Sixou SF (2012) Heterogeneity of ERalpha and ErbB2 status in cell lines and circulating tumor cells of metastatic breast cancer patients. Transl Oncol 5:475–485

    Article  PubMed  PubMed Central  Google Scholar 

  • Braun S, Hepp F, Kentenich CR, Janni W, Pantel K, Riethmuller G, Willgeroth F, Sommer HL (1999) Monoclonal antibody therapy with edrecolomab in breast cancer patients: monitoring of elimination of disseminated cytokeratin-positive tumor cells in bone marrow. Clin Cancer Res 5:3999–4004

    CAS  PubMed  Google Scholar 

  • Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich CR, Gastroph S, Wischnik A, Dimpfl T, Kindermann G, Riethmuller G, Schlimok G (2000a) Cytokeratin-positive cells in the bone marrow and survival of patients with stage I II, or III breast cancer. N Engl J Med 342:525–533

    Article  CAS  PubMed  Google Scholar 

  • Braun S, Kentenich C, Janni W, Hepp F, de Waal J, Willgeroth F, Sommer H, Pantel K (2000b) Lack of effect of adjuvant chemotherapy on the elimination of single dormant tumor cells in bone marrow of high-risk breast cancer patients. J Clin Oncol Off J Am Soc Clin Oncol 18:80–86

    CAS  Google Scholar 

  • Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, Schlimok G, Diel IJ, Gerber B, Gebauer G, Pierga JY, Marth C, Oruzio D, Wiedswang G, Solomayer EF, Kundt G, Strobl B, Fehm T, Wong GY, Bliss J, Vincent-Salomon A, Pantel K (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353:793–802

    Article  CAS  PubMed  Google Scholar 

  • Budd GT, Cristofanilli M, Ellis MJ, Stopeck A, Borden E, Miller MC, Matera J, Repollet M, Doyle GV, Terstappen LW, Hayes DF (2006) Circulating tumor cells versus imaging–predicting overall survival in metastatic breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res 12:6403–6409

    Article  CAS  Google Scholar 

  • Cheng B, Wang S, Chen Y, Fang Y, Chen F, Wang Z, Xiong B (2014) A combined negative and positive enrichment assay for cancer cells isolation and purification. Tech Cancer Res Treat. doi:10.7785/tcrt.2012.500447

  • Chou T, Sano M, Ogura M, Morishima Y, Itagaki H, Tokuda Y (2005) Isolation and transplantation of highly purified autologous peripheral CD34+ progenitor cells: purging efficacy, hematopoietic reconstitution following high dose chemotherapy in patients with breast cancer: results of a feasibility study in Japan. Breast Cancer 12:178–188

    Article  PubMed  Google Scholar 

  • Chung YK, Reboud J, Lee KC, Lim HM, Lim PY, Wang KY, Tang KC, Ji H, Chen Y (2011) An electrical biosensor for the detection of circulating tumor cells. Biosens Bioelectron 26:2520–2526

    Article  CAS  PubMed  Google Scholar 

  • Coumans FA, van Dalum G, Beck M, Terstappen LW (2013) Filter characteristics influencing circulating tumor cell enrichment from whole blood. PLoS One 8:e61770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781–791

    Article  CAS  PubMed  Google Scholar 

  • Dearnaley DP, Sloane JP, Ormerod MG, Steele K, Coombes RC, Clink HM, Powles TJ, Ford HT, Gazet JC, Neville AM (1981) Increased detection of mammary carcinoma cells in marrow smears using antisera to epithelial membrane antigen. Br J Cancer 44:85–90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deng G, Herrler M, Burgess D, Manna E, Krag D, Burke JF (2008) Enrichment with anti-cytokeratin alone or combined with anti-EpCAM antibodies significantly increases the sensitivity for circulating tumor cell detection in metastatic breast cancer patients. Breast Cancer Res 10:R69

    Article  PubMed  PubMed Central  Google Scholar 

  • Domschke C, Diel IJ, Englert S, Kalteisen S, Mayer L, Rom J, Heil J, Sohn C, Schuetz F (2013) Prognostic value of disseminated tumor cells in the bone marrow of patients with operable primary breast cancer: a long-term follow-up study. Ann Surg Oncol 20:1865–1871

    Article  PubMed  Google Scholar 

  • Fehm T, Muller V, Aktas B, Janni W, Schneeweiss A, Stickeler E, Lattrich C, Lohberg CR, Solomayer E, Rack B, Riethdorf S, Klein C, Schindlbeck C, Brocker K, Kasimir-Bauer S, Wallwiener D, Pantel K (2010) HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial. Breast Cancer Res Treat 124:403–412

    Article  CAS  PubMed  Google Scholar 

  • Fidler IJ (2003) The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 3:453–458

    Article  CAS  PubMed  Google Scholar 

  • Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, Jeong JH, Wolmark N (2002) Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233–1241

    Article  PubMed  Google Scholar 

  • Franken B, de Groot MR, Mastboom WJ, Vermes I, van der Palen J, Tibbe AG, Terstappen LW (2012) Circulating tumor cells, disease recurrence and survival in newly diagnosed breast cancer. Breast Cancer Res 14:R133

    Article  PubMed  PubMed Central  Google Scholar 

  • Gebauer G, Fehm T, Merkle E, Beck EP, Lang N, Jager W (2001) Epithelial cells in bone marrow of breast cancer patients at time of primary surgery: clinical outcome during long-term follow-up. J Clin Oncol 19:3669–3674

    CAS  PubMed  Google Scholar 

  • Georgoulias V, Bozionelou V, Agelaki S, Perraki M, Apostolaki S, Kallergi G, Kalbakis K, Xyrafas A, Mavroudis D (2012) Trastuzumab decreases the incidence of clinical relapses in patients with early breast cancer presenting chemotherapy-resistant CK-19mRNA-positive circulating tumor cells: results of a randomized phase II study. Ann Oncol 23:1744–1750

    Article  CAS  PubMed  Google Scholar 

  • Gerber B, Krause A, Muller H, Richter D, Reimer T, Makovitzky J, Herrnring C, Jeschke U, Kundt G, Friese K (2001) Simultaneous immunohistochemical detection of tumor cells in lymph nodes and bone marrow aspirates in breast cancer and its correlation with other prognostic factors. J Clin Oncol 19:960–971

    CAS  PubMed  Google Scholar 

  • Giuliano M, Giordano A, Jackson S, De Giorgi U, Mego M, Cohen EN, Gao H, Anfossi S, Handy BC, Ueno NT, Alvarez RH, De Placido S, Valero V, Hortobagyi GN, Reuben JM, Cristofanilli M (2014) Circulating tumor cells as early predictors of metastatic spread in breast cancer patients with limited metastatic dissemination. Breast Cancer Res 16:440

    Article  PubMed  PubMed Central  Google Scholar 

  • Hartkopf AD, Wagner P, Wallwiener D, Fehm T, Rothmund R (2011) Changing levels of circulating tumor cells in monitoring chemotherapy response in patients with metastatic breast cancer. Anticancer Res 31:979–984

    PubMed  Google Scholar 

  • Hartkopf AD, Banys M, Meier-Stiegen F, Hahn M, Rohm C, Hoffmann J, Helms G, Taran FA, Wallwiener M, Walter C, Neubauer H, Wallwiener D, Fehm T (2013) The HER2 status of disseminated tumor cells in the bone marrow of early breast cancer patients is independent from primary tumor and predicts higher risk of relapse. Breast Cancer Res Treat 138:509–517

    Article  CAS  PubMed  Google Scholar 

  • Hartkopf AD, Taran FA, Wallwiener M, Hahn M, Becker S, Solomayer EF, Brucker SY, Fehm TN, Wallwiener D (2014) Prognostic relevance of disseminated tumour cells from the bone marrow of early stage breast cancer patients—results from a large single-centre analysis. Eur J Cancer 50:2550–2559

    Article  PubMed  Google Scholar 

  • Hartkopf AD, Wallwiener M, Fehm TN, Hahn M, Walter CB, Gruber I, Brucker SY, Taran FA (2015) Disseminated tumor cells from the bone marrow of patients with nonmetastatic primary breast cancer are predictive of locoregional relapse. Ann Oncol 26:1155–1160

    Article  CAS  PubMed  Google Scholar 

  • Hoffmann O, Aktas B, Goldnau C, Heubner M, Oberhoff C, Kimmig R, Kasimir-Bauer S (2011) Effect of ibandronate on disseminated tumor cells in the bone marrow of patients with primary breast cancer: a pilot study. Anticancer Res 31:3623–3628

    CAS  PubMed  Google Scholar 

  • Janni W, Gastroph S, Hepp F, Kentenich C, Rjosk D, Schindlbeck C, Dimpfl T, Sommer H, Braun S (2000) Prognostic significance of an increased number of micrometastatic tumor cells in the bone marrow of patients with first recurrence of breast carcinoma. Cancer 88:2252–2259

    Article  CAS  PubMed  Google Scholar 

  • Janni W, Vogl FD, Wiedswang G, Synnestvedt M, Fehm T, Juckstock J, Borgen E, Rack B, Braun S, Sommer H, Solomayer E, Pantel K, Nesland J, Friese K, Naume B (2011) Persistence of disseminated tumor cells in the bone marrow of breast cancer patients predicts increased risk for relapse—a European pooled analysis. Clin Cancer Res Off J Am Assoc Cancer Res 17:2967–2976

    Article  Google Scholar 

  • Kahn HJ, Presta A, Yang LY, Blondal J, Trudeau M, Lickley L, Holloway C, McCready DR, Maclean D, Marks A (2004) Enumeration of circulating tumor cells in the blood of breast cancer patients after filtration enrichment: correlation with disease stage. Breast Cancer Res Treat 86:237–247

    Article  PubMed  Google Scholar 

  • Kallergi G, Papadaki MA, Politaki E, Mavroudis D, Georgoulias V, Agelaki S (2011) Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients. Breast Cancer Res 13:R59

    Article  PubMed  PubMed Central  Google Scholar 

  • Kang JH, Krause S, Tobin H, Mammoto A, Kanapathipillai M, Ingber DE (2012) A combined micromagnetic-microfluidic device for rapid capture and culture of rare circulating tumor cells. Lab Chip 12:2175–2181

    Article  CAS  PubMed  Google Scholar 

  • Karabacak NM, Spuhler PS, Fachin F, Lim EJ, Pai V, Ozkumur E, Martel JM, Kojic N, Smith K, Chen PI, Yang J, Hwang H, Morgan B, Trautwein J, Barber TA, Stott SL, Maheswaran S, Kapur R, Haber DA, Toner M (2014) Microfluidic, marker-free isolation of circulating tumor cells from blood samples. Nat Protoco 9:694–710

    Article  CAS  Google Scholar 

  • Kasimir-Bauer S, Hoffmann O, Wallwiener D, Kimmig R, Fehm T (2012) Expression of stem cell and epithelial-mesenchymal transition markers in primary breast cancer patients with circulating tumor cells. Breast Cancer Res 14:R15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Konigsberg R, Obermayr E, Bises G, Pfeiler G, Gneist M, Wrba F, de Santis M, Zeillinger R, Hudec M, Dittrich C (2011) Detection of EpCAM positive and negative circulating tumor cells in metastatic breast cancer patients. Acta Oncol 50:700–710

    Article  PubMed  Google Scholar 

  • Kruger WH, Stockschlader M, Hennings S, Aschenbrenner M, Gruber M, Gutensohn K, Loliger C, Gieseking F, Jonat W, Zander AR (1996) Detection of cancer cells in peripheral blood stem cells of women with breast cancer by RT-PCR and cell culture. Bone Marrow Transplant 18(Suppl 1):S18–S20

    PubMed  Google Scholar 

  • Kruger W, Datta C, Badbaran A, Togel F, Gutensohn K, Carrero I, Kroger N, Janicke F, Zander AR (2000) Immunomagnetic tumor cell selection—implications for the detection of disseminated cancer cells. Transfusion 40:1489–1493

    Article  CAS  PubMed  Google Scholar 

  • Lee SW, Hyun KA, Kim SI, Kang JY, Jung HI (2014) Enrichment of circulating tumor cells using a centrifugal affinity plate system. J Chromatogr A 1373:25–30

    Article  CAS  PubMed  Google Scholar 

  • Lin HK, Zheng S, Williams AJ, Balic M, Groshen S, Scher HI, Fleisher M, Stadler W, Datar RH, Tai YC, Cote RJ (2010) Portable filter-based microdevice for detection and characterization of circulating tumor cells. Clin Cancer Res 16:5011–5018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu MC, Shields PG, Warren RD, Cohen P, Wilkinson M, Ottaviano YL, Rao SB, Eng-Wong J, Seillier-Moiseiwitsch F, Noone AM, Isaacs C (2009) Circulating tumor cells: a useful predictor of treatment efficacy in metastatic breast cancer. J Clin Oncol 27:5153–5159

    Article  PubMed  PubMed Central  Google Scholar 

  • Lucci A, Hall CS, Lodhi AK, Bhattacharyya A, Anderson AE, Xiao L, Bedrosian I, Kuerer HM, Krishnamurthy S (2012) Circulating tumour cells in non-metastatic breast cancer: a prospective study. Lancet Oncol 13:688–695

    Article  PubMed  Google Scholar 

  • Mansi JL, Berger U, Easton D, McDonnell T, Redding WH, Gazet JC, McKinna A, Powles TJ, Coombes RC (1987) Micrometastases in bone marrow in patients with primary breast cancer: evaluation as an early predictor of bone metastases. Br Med J 295:1093–1096

    Article  CAS  Google Scholar 

  • Martin VM, Siewert C, Scharl A, Harms T, Heinze R, Ohl S, Radbruch A, Miltenyi S, Schmitz J (1998) Immunomagnetic enrichment of disseminated epithelial tumor cells from peripheral blood by MACS. Exp Hematol 26:252–264

    CAS  PubMed  Google Scholar 

  • Moon HS, Kwon K, Kim SI, Han H, Sohn J, Lee S, Jung HI (2011) Continuous separation of breast cancer cells from blood samples using multi-orifice flow fractionation (MOFF) and dielectrophoresis (DEP). Lab Chip 11:1118–1125

    Article  CAS  PubMed  Google Scholar 

  • Mostert B, Kraan J, Sieuwerts AM, van der Spoel P, Bolt-de Vries J, Prager-van der Smissen WJ, Smid M, Timmermans AM, Martens JW, Gratama JW, Foekens JA, Sleijfer S (2012) CD49f-based selection of circulating tumor cells (CTCs) improves detection across breast cancer subtypes. Cancer Lett 319:49–55

    Article  CAS  PubMed  Google Scholar 

  • Muller V, Stahmann N, Riethdorf S, Rau T, Zabel T, Goetz A, Janicke F, Pantel K (2005) Circulating tumor cells in breast cancer: correlation to bone marrow micrometastases, heterogeneous response to systemic therapy and low proliferative activity. Clin Cancer Res 11:3678–3685

    Article  PubMed  Google Scholar 

  • Munzone E, Nole F, Goldhirsch A, Botteri E, Esposito A, Zorzino L, Curigliano G, Minchella I, Adamoli L, Cassatella MC, Casadio C, Sandri MT (2010) Changes of HER2 status in circulating tumor cells compared with the primary tumor during treatment for advanced breast cancer. Clin Breast Cancer 10:392–397

    Article  CAS  PubMed  Google Scholar 

  • Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, Smith MR, Kwak EL, Digumarthy S, Muzikansky A, Ryan P, Balis UJ, Tompkins RG, Haber DA, Toner M (2007) Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450:1235–1239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Naume B, Borgen E, Nesland JM, Beiske K, Gilen E, Renolen A, Ravnas G, Qvist H, Karesen R, Kvalheim G (1998) Increased sensitivity for detection of micrometastases in bone-marrow/peripheral-blood stem-cell products from breast-cancer patients by negative immunomagnetic separation. Int J Cancer 78:556–560

    Article  CAS  PubMed  Google Scholar 

  • Naume B, Synnestvedt M, Falk RS, Wiedswang G, Weyde K, Risberg T, Kersten C, Mjaaland I, Vindi L, Sommer HH, Saetersdal AB, Rypdal MC, Bendigtsen Schirmer C, Wist EA, Borgen E (2014) Clinical outcome with correlation to disseminated tumor cell (DTC) status after DTC-guided secondary adjuvant treatment with docetaxel in early breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 32:3848–3857

    Article  Google Scholar 

  • Pachmann K, Heiss P, Demel U, Tilz G (2001) Detection and quantification of small numbers of circulating tumour cells in peripheral blood using laser scanning cytometer (LSC). Clin Chem Lab Med 39:811–817

    Article  CAS  PubMed  Google Scholar 

  • Pachmann K, Clement JH, Schneider CP, Willen B, Camara O, Pachmann U, Hoffken K (2005) Standardized quantification of circulating peripheral tumor cells from lung and breast cancer. Clin Chem Lab Med CCLM/FESCC 43:617–627

    CAS  Google Scholar 

  • Paget S (1889) The distribution of secondary growths in cancer of the breast. Lancet 133:571–573

    Article  Google Scholar 

  • Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T, Hiller W, Fisher ER, Wickerham DL, Bryant J, Wolmark N (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817–2826

    Article  CAS  PubMed  Google Scholar 

  • Pantel K, Schlimok G, Angstwurm M, Weckermann D, Schmaus W, Gath H, Passlick B, Izbicki JR, Riethmuller G (1994) Methodological analysis of immunocytochemical screening for disseminated epithelial tumor cells in bone marrow. J Hematother 3:165–173

    Article  CAS  PubMed  Google Scholar 

  • Papadaki MA, Kallergi G, Zafeiriou Z, Manouras L, Theodoropoulos PA, Mavroudis D, Georgoulias V, Agelaki S (2014) Co-expression of putative stemness and epithelial-to-mesenchymal transition markers on single circulating tumour cells from patients with early and metastatic breast cancer. BMC Cancer 14:651

    Article  PubMed  PubMed Central  Google Scholar 

  • Polzer B, Medoro G, Pasch S, Fontana F, Zorzino L, Pestka A, Andergassen U, Meier-Stiegen F, Czyz ZT, Alberter B, Treitschke S, Schamberger T, Sergio M, Bregola G, Doffini A, Gianni S, Calanca A, Signorini G, Bolognesi C, Hartmann A, Fasching PA, Sandri MT, Rack B, Fehm T, Giorgini G, Manaresi N, Klein CA (2014) Molecular profiling of single circulating tumor cells with diagnostic intention. EMBO Mol Med 6:1371–1386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rack B, Schindlbeck C, Juckstock J, Genss EM, Hepp P, Lorenz R, Tesch H, Schneeweiss A, Beckmann MW, Lichtenegger W, Sommer H, Friese K, Janni B, Group SS (2010a) Prevalence of CA 27.29 in primary breast cancer patients before the start of systemic treatment. Anticancer Res 30:1837–1841

    CAS  PubMed  Google Scholar 

  • Rack B, Juckstock J, Genss EM, Schoberth A, Schindlbeck C, Strobl B, Heinrigs M, Rammel G, Zwingers T, Sommer H, Friese K, Janni W (2010b) Effect of zoledronate on persisting isolated tumour cells in patients with early breast cancer. Anticancer Res 30:1807–1813

    CAS  PubMed  Google Scholar 

  • Rack B, Juckstock J, Gunthner-Biller M, Andergassen U, Neugebauer J, Hepp P, Schoberth A, Mayr D, Zwingers T, Schindlbeck C, Friese K, Janni W (2012) Trastuzumab clears HER2/neu-positive isolated tumor cells from bone marrow in primary breast cancer patients. Arch Gynecol Obstet 285:485–492

    Article  CAS  PubMed  Google Scholar 

  • Rack B, Schindlbeck C, Juckstock J, Andergassen U, Hepp P, Zwingers T, Friedl TW, Lorenz R, Tesch H, Fasching PA, Fehm T, Schneeweiss A, Lichtenegger W, Beckmann MW, Friese K, Pantel, K, Janni W, Group SS (2014) Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst 106(5):1–11. doi:10.1093/jnci/dju066

  • Raimondi C, Gradilone A, Naso G, Vincenzi B, Petracca A, Nicolazzo C, Palazzo A, Saltarelli R, Spremberg F, Cortesi E, Gazzaniga P (2011) Epithelial-mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. Breast Cancer Res Treat 130:449–455

    Article  CAS  PubMed  Google Scholar 

  • Redding WH, Coombes RC, Monaghan P, Clink HM, Imrie SF, Dearnaley DP, Ormerod MG, Sloane JP, Gazet JC, Powles TJ et al (1983) Detection of micrometastases in patients with primary breast cancer. Lancet 2:1271–1274

    Article  CAS  PubMed  Google Scholar 

  • Riethdorf S, Fritsche H, Muller V, Rau T, Schindlbeck C, Rack B, Janni W, Coith C, Beck K, Janicke F, Jackson S, Gornet T, Cristofanilli M, Pantel K (2007) Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the Cell Search system. Clin Cancer Res Off J Am Assoc Cancer Res 13:920–928

    Article  CAS  Google Scholar 

  • Riethdorf S, Wikman H, Pantel K (2008) Review: biological relevance of disseminated tumor cells in cancer patients. Int J Cancer 123:1991–2006

    Article  CAS  PubMed  Google Scholar 

  • Ring AE, Zabaglo L, Ormerod MG, Smith IE, Dowsett M (2005) Detection of circulating epithelial cells in the blood of patients with breast cancer: comparison of three techniques. Br J Cancer 92:906–912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salmanzadeh A, Sano MB, Shafiee H, Stremler MA, Davalos RV (2012) Isolation of rare cancer cells from blood cells using dielectrophoresis. Conf Proc IEEE Eng Med Biol Soc 2012:590–593

    PubMed  Google Scholar 

  • Saucedo-Zeni N, Mewes S, Niestroj R, Gasiorowski L, Murawa D, Nowaczyk P, Tomasi T, Weber E, Dworacki G, Morgenthaler NG, Jansen H, Propping C, Sterzynska K, Dyszkiewicz W, Zabel M, Kiechle M, Reuning U, Schmitt M, Lucke K (2012) A novel method for the in vivo isolation of circulating tumor cells from peripheral blood of cancer patients using a functionalized and structured medical wire. Int J Oncol 41:1241–1250

    PubMed  PubMed Central  Google Scholar 

  • Schindlbeck C, Jeschke U, Schulze S, Karsten U, Janni W, Rack B, Sommer H, Friese K (2005) Characterisation of disseminated tumor cells in the bone marrow of breast cancer patients by the Thomsen-Friedenreich tumor antigen. Histochem Cell Biol 123:631–637

    Article  CAS  PubMed  Google Scholar 

  • Schindlbeck C, Jeschke U, Schulze S, Karsten U, Janni W, Rack B, Krajewski S, Sommer H, Friese K (2007) Prognostic impact of Thomsen-Friedenreich tumor antigen and disseminated tumor cells in the bone marrow of breast cancer patients. Breast Cancer Res Treat 101:17–25

    Article  CAS  PubMed  Google Scholar 

  • Schindlbeck C, Stellwagen J, Jeschke U, Karsten U, Rack B, Janni W, Juckstock J, Tulusan A, Sommer H, Friese K (2008) Immunomagnetic enrichment of disseminated tumor cells in bone marrow and blood of breast cancer patients by the Thomsen-Friedenreich-antigen. Clin Exp Metastasis 25:233–240

    Article  PubMed  Google Scholar 

  • Schindlbeck C, Pfab G, Jueckstock J, Andergassen U, Sommer H, Janni W, Friese K, Rack B (2011) Prognostic relevance of disseminated tumor cells in the bone marrow of patients with primary breast cancer—results of a standardized follow-up. Anticancer Res 31:2749–2755

    CAS  PubMed  Google Scholar 

  • Schindlbeck C, Andergassen U, Hofmann S, Juckstock J, Jeschke U, Sommer H, Friese K, Janni W, Rack B (2013) Comparison of circulating tumor cells (CTC) in peripheral blood and disseminated tumor cells in the bone marrow (DTC-BM) of breast cancer patients. J Cancer Res Clin Oncol 139:1055–1062

    Article  PubMed  Google Scholar 

  • Shigeoka H, Karsten U, Okuno K, Yasutomi M (1999) Inhibition of liver metastases from neuraminidase-treated colon 26 cells by an anti-Thomsen-Friedenreich-specific monoclonal antibody. Tumour Biol 20:139–146

    Article  CAS  PubMed  Google Scholar 

  • Sloane JP, Ormerod MG, Neville AM (1980) Potential pathological application of immunocytochemical methods to the detection of micrometastases. Cancer Res 40:3079–3082

    CAS  PubMed  Google Scholar 

  • Smerage JB, Barlow WE, Hortobagyi GN, Winer EP, Leyland-Jones B, Srkalovic G, Tejwani S, Schott AF, O’Rourke MA, Lew DL, Doyle GV, Gralow JR, Livingston RB, Hayes DF (2014) Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol 32:3483–3489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Solomayer EF, Gebauer G, Hirnle P, Janni W, Luck HJ, Becker S, Huober J, Kramer B, Wackwitz B, Wallwiener D, Fehm T (2012) Influence of zoledronic acid on disseminated tumor cells in primary breast cancer patients. Ann Oncol 23:2271–2277

    Article  PubMed  Google Scholar 

  • Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lonning PE, Borresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Strauss DC, Thomas JM (2010) Transmission of donor melanoma by organ transplantation. Lancet Oncol 11:790–796

    Article  PubMed  Google Scholar 

  • Taubert H, Blumke K, Bilkenroth U, Meye A, Kutz A, Bartel F, Lautenschlager C, Ulbrich EJ, Nass N, Holzhausen HJ, Koelbl H, Lebrecht A (2004) Detection of disseminated tumor cells in peripheral blood of patients with breast cancer: correlation to nodal status and occurrence of metastases. Gynecol Oncol 92:256–261

    Article  PubMed  Google Scholar 

  • Weihrauch MR, Skibowski E, Draube A, Geller A, Tesch H, Diehl V, Bohlen H (2002) Immunomagnetic enrichment and detection of isolated tumor cells in bone marrow of patients with epithelial malignancies. Clin Exp Metastasis 19:617–621

    Article  CAS  PubMed  Google Scholar 

  • Wiedswang G, Borgen E, Karesen R, Kvalheim G, Nesland JM, Qvist H, Schlichting E, Sauer T, Janbu J, Harbitz T, Naume B (2003) Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer. J Clin Oncol Off J Am Soc Clin Oncol 21:3469–3478

    Article  CAS  Google Scholar 

  • Xenidis N, Ignatiadis M, Apostolaki S, Perraki M, Kalbakis K, Agelaki S, Stathopoulos EN, Chlouverakis G, Lianidou E, Kakolyris S, Georgoulias V, Mavroudis D (2009) Cytokeratin-19 mRNA-positive circulating tumor cells after adjuvant chemotherapy in patients with early breast cancer. J Clin Oncol 27:2177–2184

    Article  CAS  PubMed  Google Scholar 

  • Xue P, Wu Y, Guo J, Kang Y (2015) Highly efficient capture and harvest of circulating tumor cells on a microfluidic chip integrated with herringbone and micropost arrays. Biomed Microdevices 17:9945

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Klinikum Traunstein, Cuno-Niggl-Str. 3, 83278, Traunstein, Germany

    C. Schindlbeck

  2. Department of Obstetrics and Gynecology, Campus Innenstadt, Ludwig-Maximilians-University, Maistr. 11, 80337, Munich, Germany

    U. Andergassen, J. Jueckstock, B. Rack & U. Jeschke

  3. Department of Obstetrics and Gynecology, University of Ulm, Prittwitzstr. 43, 89075, Ulm, Germany

    W. Janni

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  1. C. Schindlbeck
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  2. U. Andergassen
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  3. J. Jueckstock
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  4. B. Rack
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  5. W. Janni
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  6. U. Jeschke
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Correspondence to U. Jeschke.

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Schindlbeck, C., Andergassen, U., Jueckstock, J. et al. Disseminated and circulating tumor cells in bone marrow and blood of breast cancer patients: properties, enrichment, and potential targets. J Cancer Res Clin Oncol 142, 1883–1895 (2016). https://doi.org/10.1007/s00432-016-2118-3

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  • DOI: https://doi.org/10.1007/s00432-016-2118-3

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