Deutsche Zeitschrift für Onkologie 2012; 44(1): 11-16
DOI: 10.1055/s-0031-1298684
© Karl F. Haug Verlag MVS Medizinverlage Stuttgart GmbH & Co. KG

Die Bedeutung der im Blut zirkulierenden Tumorzellen in der Metastasierungskaskade

Katharina Pachmann
Further Information

Publication History

Publication Date:
28 March 2012 (online)


Obgleich für die meisten Patienten die Diagnose eines bösartigen Tumors der größte Schock ist, ist der Primärtumor selten lebensbedrohlich, vielmehr sind Metastasen in lebenswichtige Organe wie Leber und Lunge die bedrohlichsten Folgen. Solche Absiedelungen können nur durch Zellen entstehen, die den Primärtumor verlassen haben und die Fähigkeit haben, an anderen Stellen wieder anzuwachsen. Die vorliegende Übersicht fasst ältere und neuere Daten darüber zusammen, welche Faktoren dazu beitragen, dass Zellen den Primärtumor verlassen können, geht der Frage nach, wie diese freigesetzten Zellen es bewerkstelligen, im Kreislauf zu überleben, dass der Nachweis solcher zirkulierender Tumorzellen zwar eine wichtige Momentaufnahme im Ablauf der Metastasierung darstellt, aber auch, dass zu einer erfolgreiche Absiedelung weitere, noch wenig verstandene Schritte gehören, die nur ein Bruchteil der freigesetzten Zellen vollbringen. Es wird die Hypothese diskutiert, dass weniger die komplette Elimination dieser Zellen als vielmehr Strategien, die es verhindern, dass diese Zellen sich absiedeln können, in Zukunft am erfolgreichsten im Kampf gegen die Metastasenbildung sein könnten.


It is rarely the primary malignant tumor but rather cells released from the primary tumor, settling in distant organs and growing into metastases, that determine the fate of the patient. In the present review older and more recent data on cell release from the primary tumor are discussed, revealing that probably many more cells than previously thought can be released into the circulation not only due to natural development but also due to diagnostic and therapeutic manipulations. Such cells circulating in peripheral blood must be the origin of metastases but circulating tumor cells by definition are not micro metastases themselves and only a minor fraction of these cells seems to be capable of settling and growing in distant loci. For this purpose cells must have strategies to survive in the circulation and although a wealth of research has been devoted to clarify the ways by which cells can resettle and re-grow in distant organs these steps have not been well understood until now. Since, however, approaches to eliminate these cells in order to prevent metastasis formation have been only partly successful, strategies to prevent them from settling such as hormone blocking therapies empirically known to be effective or metronomic therapies should in the future more closely be investigated.

  • Literatur

  • 1 Banys M, Gruber I, Krawczyk N et al. Hematogenous and lymphatic tumor cell dissemination may be detected in patients diagnosed with ductal carcinoma in situ of the breast. Breast Cancer Res Treat 2011; Apr 1. [Epub ahead of print]
  • 2 Bedard PL, Cardoso F. Can some patients avoid adjuvant chemotherapy for early-stage breast cancer?. Nat Rev Clin Oncol 2011; 8: 272-279
  • 3 Bockhorn M, Jain RK, Nunn LL. Active versus passive mechanisms in metastasis: do cancer cells crawl into vessels, or are they pushed?. Lancet Oncol 2007; 8: 444-448
  • 4 Bonadonna G, Moliterni A, Zambetti M et al. 30 years' follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study. BMJ 2005; 330: 217-220
  • 5 Bos PD, Nguyen DX, Massagué J. Modeling metastasis in the mouse. Curr Opin Pharmacol 2010; 10: 571-577
  • 6 Braun S, Marth C. Circulating tumor cells in metastatic breast cancer. Toward individualized treatment?. N Engl J Med 2004; 351: 824-826
  • 7 Camara O, Rengsberger M, Egbe A et al. The relevance of circulating epithelial tumor cells (CETC) for therapy monitoring during neoadjuvant (primary systemic) chemotherapy in breast cancer. Ann Oncol 2007; 18: 1484-1492
  • 8 Camara O, Kavallaris A, Nöschel H et al. Seeding of epithelial cells into circulation during surgery for breast cancer: the fate of malignant and benign mobilized cells. World J Surg Oncol 2006; 4: 67
  • 9 Cameron MD, Schmidt EE, Kerkvliet N et al. Temporal progression of metastasis in lung: cell survival, dormancy, and location dependence of metastatic inefficiency. Cancer Res 2000; 60: 2541-2546
  • 10 Chambers AF, Naumov GN, Vantyghem AS, Tuck AB. Molecular biology of breast cancer metastasis Clinical implications of experimental studies on metastatic inefficiency. Breast Cancer Res 2000; 2: 400-407
  • 11 Choy A, McCulloch P. Induction of tumour cell shedding into effluent venous blood breast cancer surgery. Br J Cancer 1996; 73: 79-82
  • 12 Comen E, Norton L, Massagué J. Clinical implications of cancer self-seeding. Nat Rev Clin Oncol 2011; 8: 369-377
  • 13 Criscitiello C, Fumagalli D, Saini KS, Loi S. Tamoxifen in early-stage estrogen receptor positive breast cancer: overview of clinical use and molecular biomarkers for patient selection. OncoTargets and Therapy 2011; 4: 1-11
  • 14 Cristofanilli M, Budd GT, Ellis MJ et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 2004; 351: 781-791
  • 15 De Bono JS, Scher HI, Montgomery RB et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res 2008; 14: 6302-6309
  • 16 Demicheli R, Retsky MW, Hrushesky WJM et al. The effects of surgery on tumor growth: a century of investigations. Ann Oncol 2008; 19: 1821-1828
  • 17 Dhakal HP, Naume B, Synnestvedt M et al. Vascularization in primary breast carcinomas: its prognostic significance and relationship with tumor cell dissemination. Clin Caner Res 2008; 14: 2341-2350
  • 18 Epstein RJ. Maintenance therapy to suppress micrometastasis: the new challenge for adjuvant cancer treatment. Clin Cancer Res 2005; 11: 5337-5341
  • 19 Fidler IJ. The relationship of embolic homogeneity, number, size and viability to the incidence of experimental metastasis. Eur J Cancer 1973; 9: 223-227
  • 20 Fisher B, Fisher E. Transmigration of lymph nodes by tumor cells. Science 1966; 152: 1397-1398
  • 21 Fisher B, Jeong JH, Bryant J et al. National Surgical Adjuvant Breast and Bowel Project randomised clinical trials: Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet 2004; 364: 858-868
  • 22 Gajda M, Camara O, Oppel S, Kroll T et al. Monitoring circulating epithelial tumor cells (CETC) during primary systemic chemotherapy including trastuzumab for early prediction of outcome in patients with Her2/neu-positive tumors. Ann Oncol 2008; 19: 2090-2091
  • 23 Glaves D, Huben RP, Weiss L. Haematogenous dissemination of cells from human renal adenocarcinomas. Br J Cancer 1988; 57: 32-35
  • 24 Griffon-Etienne G, Boucher Y, Brekken C et al. Taxane-induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure in solid tumors: clinical implications. Cancer Res 1999; 67: 2729-2735
  • 25 Hadfield G. The dormant cancer cell. Br Med J 1954; 2(4888): 607-610
  • 26 Hansen E, Wolff N, Knuechel R et al. Tumor cells in blood shed from the surgical field. Arch Surg 1995; 130: 387-393
  • 27 Helmlinger G, Netti PA, Lichtenbeld HC et al. Solid stress inhibits the growth of multicellular tumor spheroids. Nat Biotechnol 1997; 15: 778-783
  • 28 Hoshida T, Isaka N, Hagendoorn J et al. Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. Cancer Res 2006; 66: 8065-8075
  • 29 Hunter KW. Host genetics and tumour metastasis. Br J Cancer 2004; 90: 752-755
  • 30 Jain RK, Tong RT, Munn LL. Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model. Cancer Res 2007; 67: 2729-2735
  • 31 Kennedy CR, Gao F, Margenthaler JA. Neoadjuvant versus adjuvant chemotherapy for triple negative breast cancer. J Surg Res 2010; 163: 52-57
  • 32 Kim MY, Oskarsson T, Acharyya S et al. Tumor self-seeding by circulating cancer cells. Cell 2009; 139: 1315-1326
  • 33 Kouros-Mehr H, Bechis SK, Slorach EM et al. GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell 2008; 13: 141-152
  • 34 Leung CT, Brugge JS. Tumor self-seeding: bidirectional flow of tumor cells. Cell 2009; 139: 1226-1228
  • 35 Liotta LA, Saidel MG, Kleinerman J. The significance of hematogenous tumor cell clumps in the metastatic process. Cancer Res 1976; 36: 889-894
  • 36 Loddo M, Kingsbury SR, Rashid M et al. Cell-cycle-phase progression analysis identifies unique phenotypes of major prognostic and predictive significance in breast cancer. Br J Cancer 2009; 100: 959-970
  • 37 Meng S, Tripathy D, Frenkel EP et al. Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 2004; 10: 8152-8162
  • 38 Miller MC, Doyle GV, Terstappen LWMM. Significance of circulating tumor cells detected by the CellSearch System in patients with metastatic breast colorectal and prostate cancer. J Oncol 2010; DOI: 10.1155/2010/617421 (Epub ahead of print)
  • 39 Nagy P, Friedländer E, Tanner M et al. Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a Herceptinresistant, MUC4-expressing breast cancer cell line. Cancer Res 2005; 65: 473-482
  • 40 Nguyen DX, Bos PD, Massagué J. Metastasis: from dissemination to organ-specific colonization. Nature Reviews Cancer 2009; 9: 274-284
  • 41 Norton L, Massagué J. Is cancer a disease of self-seeding?. Nat Med 2006; 12: 875-878
  • 42 Pachmann K. Longtime recirculating tumor cells in breast cancer patients. Clin Cancer Res 2005; 11: 5657-5658
  • 43 Pachmann K, Camara O, Kavallaris A et al. Monitoring the response of circulating epithelial tumor cells (CETC) to adjuvant chemotherapy in breast cancer allows detection of patients at risk of early relapse. J Clin Oncol 2008; 26: 1208-1215
  • 44 Pachmann K, Camara O, Kohlhase A et al. Assessing the efficacy of targeted therapy using circulating epithelial tumor cells (CETC): the example of SERM therapy monitoring as a unique tool to individualize therapy. J Cancer Res Clin Oncol 2011; 137: 821-828
  • 45 Pachmann K, Camara O, Kroll T et al. Efficacy control of therapy using circulating epithelial tumor cells (CETC) as „liquid biopsy“: Trastuzumab in HER2/neu-positive breast carcinoma. J Cancer Res Clin Oncol 2011; DOI: 10.1007/s00432–011–1000–6
  • 46 Pályi-Krekk Z, Barok M, Isola J et al. Hyaluronan-induced masking of ErbB2 and CD44-enhanced trastuzumab internalisation in trastuzumab resistant breast cancer. Eur J Cancer 2007; 43: 2423-2433
  • 47 Podsypanina K, Du YC, Jechlinger M et al. Seeding and propagation of untransformed mouse mammary cells in the lung. Science 2008; 321: 1841-1844
  • 48 Rack B, Schindlbeck C, Andergassen U et al. Prognostic role of circulating tumor cells in the peripheral blood of primary breast cancer patients. Cancer Res 2010; 70: 93 (suppl 24; abstr S6–5)
  • 49 Retsky MW, Hrushesky WJM, Gukas ID. Hypothesis: primary antiangiogenic method proposed to treat early stage breast cancer. BMC Cancer 2009; 9: 7
  • 50 Ring AI, Zabaglo L, Ormerod MG et al. Detection of circulating epithelial cells in the blood of patients with breast cancer: comparison of three techniques. Br J Cancer 2005; 92: 906-912
  • 51 Rolle A, Günzel R, Pachmann U et al. Increase in number of circulating disseminated epithelial cells after surgery for non-small cell lung cancer monitored by MAINTRAC® is a predictor for relapse: A preliminary report. World J Surg Oncol 2005; 3: 18
  • 52 Sahai E. Illuminating the metastatic process. Nat Rev 2007; 7: 737-749
  • 53 Townson JL, Chambers AF. Dormancy of solitary metastatic cells. Cell Cycle 2006; 5: 1744-1750
  • 54 Salsbury AJ. The significance of the circulating cancer cell. Cancer Treat Rev 1975; 2: 55-72
  • 55 Trzpis M, McLaughlin PMJ, de Leij LMFH, Harmsen MC. Epithelial cell adhesion molecule more than a carcinoma marker and adhesion molecule. Am J Pathol 2007; 171: 386-395
  • 56 Turnbull RB, Kyle K, Watson FR, Spratt J. Cancer of the colon: The influence of the no-touch isolation technic on survival rates. Ann Surgery 1967; 166: 420-425
  • 57 Vogelaar FJ, Mesker WE, Rijken AM et al. Clinical impact of different detection methods for disseminated tumor cells in bone marrow of patients undergoing surgical resection of colorectal liver metastases: a prospective follow-up study. BMC Cancer 2010; 10: 153
  • 58 Weaver DL, Ashikaga T, Krag DN et al. Effect of occult metastases on survival in node-negative breast cancer. N Engl J Med 2011; 364: 412-421
  • 59 Weis L. Cancer cell traffic from the lungs to the liver: an example of metastatic inefficiency. Int J Cancer 1980; 25: 385-392
  • 60 Wicha MS, Hayes DF. Circulating tumor cells. Not all detected cells are bad and not all bad cells are detected. J Clin Oncol 2011; DOI: 10.1200/JCO.2010.34.0026
  • 61 Wiedswang G, Borgen E, Kåresen R et al. Isolated tumor cells in bone marrow three years after diagnosis in disease-free breast cancer patients predict unfavorable clinical outcome. Clin Cancer Res 2004; 10: 5342-5348
  • 62 Wong CW, Song C, Grimes MM et al. Intravascular location of breast cancer cells after spontaneous metastasis to the lung. Am J Pathol 2002; 161: 749-753