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Clinical relevance associated to the analysis of circulating tumour cells in patients with solid tumours

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Abstract

The distant growth of tumour cells escaping from primary tumours, a process termed metastasis, represents the leading cause of death among patients affected by malignant neoplasias from breast and colon. During the metastasis process, cancer cells liberated from primary tumour tissue, also termed circulating tumour cells (CTCs), travel through the circulatory and/or lymphatic systems to reach distant organs. The early detection and the genotypic and phenotypic characterisation of such CTCs could represent a powerful diagnostic tool of the disease, and could also be considered an important predictive and prognostic marker of disease progression and treatment response. In this article we discuss the potential relevance in the clinic of monitoring CTCs from patients suffering from solid epithelial tumours, with emphasis on the impact of such analyses as a predictive marker for treatment response.

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References

  1. López-Abente G, Pollán M, Aragonés N et al (2003) Plan Integral del Cáncer: Situación del Cáncer en España. Ministerio de Sanidad y Consumo, Madrid

    Google Scholar 

  2. Harris LN, Solomon N, Roberts L et al (2005) Detection and monitoring of circulating tumor cells (CTCs) by CK-19 mRNA in breast cancer patients treated with neoadjuvant chemotherapy: a marker of early recurrence [abstract]. Breast Cancer Res Treat 94[Suppl 1]:1021

    Google Scholar 

  3. Braun S, Vogl FD, Naume B et al (2005) International pooled analysis of prognostic significance of bone marrow micrometastasis in patients with stage I, II, or III breast cancer. N Engl J Med 353:79

    Article  Google Scholar 

  4. Campos M, Serrano MJ, Gaforio JJ (2006) Diagnóstico de enfermedad mínima residual en tumores sólidos de origen epitelial. En: Editorial Universidad de Granada, Granada, Spain. Diagnóstico y Pronóstico. Avances en oncología básica y aplicada 383–420

    Google Scholar 

  5. Weihrauch MR, Skibowski E, Draube A et al (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 

  6. Schindlbeck C, Kampik T, Janni W et al (2005) Prognostic relevance of disseminated tumor cells in the bone marrow and biological factors of 265 primary breast carcinomas. Breast Cancer Res 7:1174–1185

    Article  Google Scholar 

  7. Woelfle U, Breit E, Zafrakas K et al (2005) Bispecific immunomagnetic enrichment of micrometastatic tumour cell clusters from bone marrow of cancer patients. J Immunol Methods 300:136–145

    Article  CAS  PubMed  Google Scholar 

  8. Guo J, Xiao B, Zhang X et al (2004) Combined use of positive and negative immunomagnetic isolation followed by real-time RT-PCR for detection of the circulating tumor cells in patients with colorectal cancer. J Mol Med. 82:768–774

    Article  CAS  PubMed  Google Scholar 

  9. Muller V, Stahmann N, Riethdorf S et al (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 

  10. Kruger W, Datta C, Badbaran A et al (2000) Immunomagnetic tumor cell selection: implications for the detection of disseminated cancer cells. Transfusion 40:1489–1493

    Article  CAS  PubMed  Google Scholar 

  11. Molnar B, Ladanyi A, Tanko L et al (2001) Circulating tumor cell clusters in the peripheral blood of colorectal cancer patients. Clin Cancer Res 7:4080–4085

    CAS  PubMed  Google Scholar 

  12. Hardingham JE, Hewett PJ, Sage RE et al (2000) Molecular detection of blood-borne epithelial cells in colorectal cancer patients and in patients with benign bowel disease. Int J Cancer 89:8–13

    Article  CAS  PubMed  Google Scholar 

  13. Guo J (2005) Detection of cytokeratin 20 mRNA in the peripheral blood of patients with colorectal cancer by immunomagnetic bead enrichment and real-time reverse transcriptase-polymerase chain reaction. J Gastroenterol Hepatol 20:1279–1284

    Article  CAS  PubMed  Google Scholar 

  14. Fujita Y, Terashima M, Hishino Y et al (2006) Detection of cancer cells disseminated in bone marrow using real-time quantitative RT-PCR of CEA, CK19, and CK20 mRNA in patients with gastric cancer. Gastric Cancer 9:308–314

    Article  CAS  PubMed  Google Scholar 

  15. Zhang XW, Yang HY, Fan P et al (2005) Detection of micrometastasis in peripheral blood by multi-sampling in patients with colorectal cancer. World J Gastroenterol 11:436–438

    PubMed  Google Scholar 

  16. Pinzani P, Salvadori B, Simi L et al (2006) Isolation by size of epithelial tumor cells in peripheral blood of patients with breast cancer: correlation with real-time reverse transcriptase-polymerase chain reaction results and feasibility of molecular analysis by laser microdissection. Hum Pathol 37:711–718

    Article  CAS  PubMed  Google Scholar 

  17. Jung R, Soondrum K, Kruger W et al (2001) Detection of micrometastasis through tissue-specific gene expression: its promise and problems. Recent Results Cancer Res 158:32–39

    CAS  PubMed  Google Scholar 

  18. Vlems F, Soong R, Diepstra H et al (2002) Effect of blood sample handling and reverse transcriptase-polymerase chain reaction assay sensitivity on detection of CK20 expression in healthy donor blood. Diagn Mol Pathol 11:90–97

    Article  PubMed  Google Scholar 

  19. Vlems FA, Diepstra JHS, Cornelissen IMHA et al (2002) Limitations of cytokeratin 20 RT-PCR to detect disseminated tumour cells in blood and bone marrow of patients with colorectal cancer: expression in controls and downregulation in tumour tissue. J Clin Pathol 55:156–163

    Article  CAS  Google Scholar 

  20. Dandachi N, Balic M, Stanzer S et al (2005) Critical evaluation of real-time reverse transcriptase-polymerase chain reaction for the quantitative detection of cytokeratin 20 mRNA in colorectal cancer patients. J Mol Diagn 7:631–637

    CAS  PubMed  Google Scholar 

  21. Ring A, Smith IE, Dowsett M (2004) Circulating tumour cells in breast cancer. Lancet Oncol 5:79–88

    Article  PubMed  Google Scholar 

  22. Ikeda S, Fujimori M, Shibata S (2006) Combined immunohistochemistry of ß-catenin, cytokeratin 7, and cytokeratin 20 is useful in discriminating primary lung adenocarcinomas from metastatic colorectal cancer. BMC Cancer 6:31–37

    Article  PubMed  CAS  Google Scholar 

  23. Angus B, Purvis J, Stock D et al (1987) NCL-5D3: a new monoclonal antibody recognizing low molecular weight cytokeratins effective for immunohistochemistry using fixed paraffin-embedded tissue. J Pathol 153:377–384

    Article  CAS  PubMed  Google Scholar 

  24. Zhong XY, Kaul S, Eichler A et al (1999) Evaluating GA7733-2 mRNA as a marker for the detection of micrometastatic breast cancer in peripheral blood and bone marrow. Arch Gynecol Obstet 263:2–6

    Article  CAS  PubMed  Google Scholar 

  25. Ciborowski P, Finn OJ (2002) Non-glycosylated tandem repeats of MUC1 facilitate attachment of breast tumor cells to normal human lung tissue and immobilized extracellular matrix proteins (ECM) in vitro: potential role in metastasis. Clin Exp Metastasis 19:339–345

    Article  CAS  PubMed  Google Scholar 

  26. Zieglschmid V, Hollman C, Bocher O (2005) Detection of disseminated tumor cells in peripheral blood. Crit Rev Clin Lab Sci 42:155–196

    Article  CAS  PubMed  Google Scholar 

  27. Silva HA, Abraul E, Raimundo D et al (2006) Molecular detection of EGFRvIII positive cells in the peripheral blood of breast cancer patients. Eur J Cancer 42:2617–2622

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  29. Braun S, Cevatli BS, Assemi C et al (2001) ErbB2 overexpression on occult metastatic cells in bone marrow predicts poor clinical outcome of stage I–III breast cancer patients. Cancer Res 61:1890–1895

    CAS  PubMed  Google Scholar 

  30. Gravalos C, Jimeno A (2008) Her2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol 19:1523–1529

    Article  CAS  PubMed  Google Scholar 

  31. Steinert R, Vietn M, Hantschick M et al (2005) Epithelial cells disseminate into the bone marrow of colorectal adenoma patients. Gut 54:1045–1046

    Article  CAS  PubMed  Google Scholar 

  32. Martin VM, Siewert C, Scharl A et al (1998) Immunomagnetic enrichment of disseminated epithelial tumor cells from peripheral blood by MACS. Exp Hematol 26:252–264

    CAS  PubMed  Google Scholar 

  33. Schardt JA, Meyer M, Hartman CH et al (2005) Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer. Cancer Cell 8:227–239

    Article  CAS  PubMed  Google Scholar 

  34. Zach O, Lutz D (2006) Tumor cell detection in peripheral blood and bone marrow. Curr Opin Oncol 18:48–56

    Article  PubMed  Google Scholar 

  35. Brugger W, Buhring HJ, Grunebach F et al (1999) Expression of MUC 1 epitopes normal bone marrow implications for the detection of micrometastatic tumor cells. J Clin Oncol 17:1535–1544

    CAS  PubMed  Google Scholar 

  36. Findeisen P, Rockel M, Nees 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 33:1001–1010

    CAS  PubMed  Google Scholar 

  37. Muller V, Hayes DF, Pantel K (2006) Recent translational research: circulating tumor cells in breast cancer patients. Breast Cancer Res 8:110–120

    Article  PubMed  CAS  Google Scholar 

  38. Mehes G, Witt A, Kubista E, Ambros PF (2001) Circulating breast cancer cells are frequently apoptotic. Am J Pathol 159:17–20

    CAS  PubMed  Google Scholar 

  39. Pierga JY, Bonnenton C, Vincent-Salomon A et al (2004) Clinical significance of immunocytochemical detection of tumor cells using digital microscopy in peripheral blood and bone marrow of breast cancer patients. Clin Cancer Res 10:1392–1400

    Article  CAS  PubMed  Google Scholar 

  40. Pantel K, Muller V, Auer M et al (2003) Detection and clinical implications of early systemic tumor cell dissemination in breast cancer. Clin Cancer Res 9:6326–6334

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  42. Gaforio JJ, Serrano MJ, Sanchez-Rovira P et al (2003) Detection of breast cancer cells in the peripheral blood is positively correlated with estrogen-receptor status and predicts for poor prognosis. Int J Cancer 107:984–990

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  44. Patriarca F, Sacco C, Sperotto A et al (2003) Prognostic significance of the detection of tumour cells in peripheral blood stem cell collections in stage II and III breast cancer patients treated with high-dose therapy. Bone Marrow Transplant 31:789–794

    Article  CAS  PubMed  Google Scholar 

  45. Gradilone A, Gazzaniga P, Silvestri I et al (2003) Detection of CK19, CK20 and EGFR mRNAs in peripheral blood of carcinoma patients: correlation with clinical stage of disease. Oncol Rep 10:217–222

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  47. Hawes D, Neville AM, Cote RJ (2003) Prognosis of minimal residual disease in bone marrow, blood and lymph nodes in breast cancer. Micrometastasis 4:67–85

    Google Scholar 

  48. Stathopoulou A, Vlachonikolis I, Mavroudis D et al (2002) Molecular detection of cytokeratin-19-positive cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic significance. J Clin Oncol 20:3404–3412

    Article  CAS  PubMed  Google Scholar 

  49. Smith BM, Slade MJ, English J et al (2000) Response of circulating tumor cells to systemic therapy in patients with metastatic breast cancer: comparison of quantitative polymerase chain reaction and immunocytochemical techniques. J Clin Oncol 18:1432–1439

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  51. Hiraiwa K, Takeuchi H, Hasegawa H et al (2008) Clinical significance of circulating tumor cells in blood from patients with gastrointestinal cancers. Ann Surg Oncol 15:3092–3100

    Article  PubMed  Google Scholar 

  52. Cohen SJ, Alpaugh RK, Gross S et al (2006) Isolation and characterization of circulating tumor cells in patients with metastatic colorectal cancer. Clin Colorectal Cancer 6:125–132

    Article  CAS  PubMed  Google Scholar 

  53. Bessa X, Piñol V, Castellví-Bel S et al (2003) Prognostic value of postoperative detection of blood circulating tumor cells in patients with colorectal cancer operated on for cure. Ann Surg 237:368–375

    Article  PubMed  Google Scholar 

  54. Uen YH, Lu CY, Tsai HL 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 15:2120–2128

    Article  PubMed  Google Scholar 

  55. Hauch S, Zimmermann S, Lankiewicz S et al (2008) The clinical significance of circulating tumour cells in breast cancer and colorectal cancer patients. Anticancer Res 27:1337–1341

    Google Scholar 

  56. Pantel K, Riethmuller G (1996) Micrometastasis detection and treatment with monoclonal antibodies. Curr Top Microbiol Immunol 213:1–18

    CAS  PubMed  Google Scholar 

  57. Lankiewicz S, Rother E, Zimmermann S et al (2008) Tumour-associated transcripts and EGFR deletion variants in colorectal cancer in primary tumour, metastases and circulating tumour cells. Cell Oncol 30:463–471

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  59. Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2:563–572

    Article  CAS  PubMed  Google Scholar 

  60. Dawood S, Broglio K, Valero V et al (2008) Circulating tumor cells in metastatic breast cancer: from prognostic stratification to modification of the staging system? Cancer 113:2422–2430

    Article  PubMed  Google Scholar 

  61. Hayes DF, Cristofanilli M, Budd GT 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 12:4218–4224

    Article  CAS  PubMed  Google Scholar 

  62. Fisher ER, Anderson S, Tan-Chiu E et al (2002) Fifteen-year prognostic discriminants for invasive breast carcinoma: National Surgical Adjuvant. 2001. Breast and Bowel Project Protocol-06. Cancer 91:1679–1687

    Article  Google Scholar 

  63. Bosma AJ, Weigelt B, Lambrechts AC et al (2002) Detection of circulating breast tumor cells by differential expression of marker genes. Clin Cancer Res 8:1871–1878

    CAS  PubMed  Google Scholar 

  64. Zehentner BK, Secrist H, Hayes DC et al (2002) Detection of circulating tumor cells in peripheral blood of breast cancer patients during or after therapy using a multigene real-time RT-PCR assay. Mol Diagn Ther 10:41–47

    Article  Google Scholar 

  65. Bidard F-C, Vincent-Salomon A, Sigal-Zafrani B et al (2008) Prognosis of women with stage IV breast cancer depends on detection of circulating tumor cells rather than disseminated tumor cells. Ann Oncology 19:496–500

    Article  Google Scholar 

  66. Janni W, Gastroph S, Hepp F et al (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 

  67. Pierga JY, Bonneton C, Magdelenat H et al (2003) Clinical significance of proliferative potential of occult metastatic cells in bone marrow of patients with breast cancer. Br J Cancer 89:539–545

    Article  PubMed  Google Scholar 

  68. Serrano MJ, Sánchez-Rovira P, Delgado-Rodríguez M, Gaforio JJ (2009) Detection of circulating tumor cells in the context of treatment. Cancer Biol Ther 8:671–675

    Article  PubMed  Google Scholar 

  69. Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorogenesis. Cell 61:759–767

    Article  CAS  PubMed  Google Scholar 

  70. Bernards R, Weinberg RA (2002) A progression puzzle. Nature 418:823

    Article  CAS  PubMed  Google Scholar 

  71. Pantel K, Brakenhoff RH (2004) Dissecting the metastatic cascade. Nature 4:448–456

    CAS  Google Scholar 

  72. Harris AL (2002) Hypoxia: a key regulatory factor in tumor growth. Nat Rev Cancer 2:38–47

    Article  CAS  PubMed  Google Scholar 

  73. Kang Y, Siegel PM, Shu W et al (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 89:35–67

    Google Scholar 

  74. Engel J, Eckel R, Kerr J et al (2003) The process of metastasisation for breast cancer. Eur J Cancer 39:1794–1806

    Article  CAS  PubMed  Google Scholar 

  75. Minn AJ, Gupta GP, Siegel PM et al (2005) Genes that mediate breast cancer metastasis to lung. Nature 436:518–524

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Center GENYO (Pfizer-University of Granada-Andalucian Goverment Center for Genomics and Oncological Research), Avda. del Conocimiento, s/n, ES-18100, Armilla, Granada, Spain

    Ma. José Serrano Fernández, Juan Carlos Álvarez Merino, Ana Fernández García & José Antonio Lorente Acosta

  2. Department of Legal Medicine, University of Granada, Granada, Spain

    Juan Carlos Álvarez Merino & José Antonio Lorente Acosta

  3. Institute of Clinical Medicine Medicine Faculty, University of Tromsø, Tromsø, Norway

    Iñigo Martínez Zubiaurre

  4. Medical Oncology Department, University Hospital, Jaén, Spain

    Pedro Sánchez Rovira

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  1. Ma. José Serrano Fernández
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  2. Juan Carlos Álvarez Merino
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  3. Iñigo Martínez Zubiaurre
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  4. Ana Fernández García
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  5. Pedro Sánchez Rovira
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  6. José Antonio Lorente Acosta
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Correspondence to Ma. José Serrano Fernández.

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Serrano Fernández, M.J., Álvarez Merino, J.C., Martínez Zubiaurre, I. et al. Clinical relevance associated to the analysis of circulating tumour cells in patients with solid tumours. Clin Transl Oncol 11, 659–668 (2009). https://doi.org/10.1007/s12094-009-0421-z

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  • DOI: https://doi.org/10.1007/s12094-009-0421-z

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