Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Challenges in circulating tumour cell research

Nature Reviews Cancer volume 14, pages 623–631 (2014)Cite this article

Subjects

Abstract

During the past ten years, circulating tumour cells (CTCs) have received enormous attention as new biomarkers and the subject of basic research. Although CTCs are already used in numerous clinical trials, their clinical utility is still under investigation. Many issues regarding the detection and characterization of CTCs remain unknown. In this Opinion article, we propose a conceptual framework of CTC assays and point out current challenges of CTC research, which might structure this dynamic field of translational cancer research.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Circulating tumour cell (CTC) enrichment technologies.
Figure 2: Circulating tumour cell (CTC) detection technologies.
Figure 3: Current concept of cellular and molecular characteristics of circulating tumour cells CTCs).

Similar content being viewed by others

References

  1. Zhang, L. et al. Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin. Cancer Res. 18, 5701–5710 (2012).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hou, J. M. et al. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J. Clin. Oncol. 30, 525–532 (2012).

    Article  PubMed  Google Scholar 

  4. Krebs, M. G. et al. Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J. Clin. Oncol. 29, 1556–1563 (2011).

    Article  PubMed  Google Scholar 

  5. Aggarwal, C. et al. Relationship among circulating tumor cells, CEA and overall survival in patients with metastatic colorectal cancer. Ann. Oncol. 24, 420–428 (2013).

    Article  CAS  PubMed  Google Scholar 

  6. Deneve, E. et al. Capture of viable circulating tumor cells in the liver of colorectal cancer patients. Clin. Chem. 59, 1384–1392 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Bidard, F. C. et al. Clinical application of circulating tumor cells in breast cancer: overview of the current interventional trials. Cancer Metastasis Rev. 32, 179–188 (2013).

    Article  PubMed  Google Scholar 

  8. Pantel, K. & Alix-Panabieres, C. Real-time liquid biopsy in cancer patients: fact or fiction? Cancer Res. 73, 6384–6388 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Zippelius, A. et al. Limitations of reverse-transcriptase polymerase chain reaction analyses for detection of micrometastatic epithelial cancer cells in bone marrow. J. Clin. Oncol. 15, 2701–2708 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Pantel, K. & Alix-Panabieres, C. The clinical significance of circulating tumor cells. Nature Clin. Pract. Oncol. 4, 62–63 (2007).

    Article  Google Scholar 

  11. Pantel, K., Alix-Panabieres, C. & Riethdorf, S. Cancer micrometastases. Nature Rev. Clin. Oncol. 6, 339–351 (2009).

    Article  CAS  Google Scholar 

  12. Pantel, K. & Alix-Panabieres, C. Circulating tumour cells in cancer patients: challenges and perspectives. Trends Mol. Med. 16, 398–406 (2010).

    Article  PubMed  Google Scholar 

  13. Pantel, K. et al. Circulating epithelial cells in patients with benign colon diseases. Clin. Chem. 58, 936–940 (2012).

    Article  CAS  PubMed  Google Scholar 

  14. Rao, C. G. et al. Expression of epithelial cell adhesion molecule in carcinoma cells present in blood and primary and metastatic tumors. Int. J. Oncol. 27, 49–57 (2005).

    CAS  PubMed  Google Scholar 

  15. Bednarz, N. et al. BRCA1 loss preexisting in small subpopulations of prostate cancer is associated with advanced disease and metastatic spread to lymph nodes and peripheral blood. Clin. Cancer Res. 16, 3340–3348 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lee, J. M., Dedhar, S., Kalluri, R. & Thompson, E. W. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J. Cell Biol. 172, 973–981 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yu, M. et al. RNA sequencing of pancreatic circulating tumour cells implicates WNT signalling in metastasis. Nature 487, 510–513 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yu, M. et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339, 580–584 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yokobori, T. 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. 73, 2059–2069 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Riethdorf, S. et al. Detection and HER2 Expression of circulating tumor cells: prospective monitoring in breast cancer patients treated in the neoadjuvant geparquattro trial. Clin. Cancer Res. 16, 2634–2645 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Ignatiadis, M. et al. HER2-positive circulating tumor cells in breast cancer. PLoS ONE 6, e15624 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Miyamoto, D. T. et al. Androgen receptor signaling in circulating tumor cells as a marker of hormonally responsive prostate cancer. Cancer Discov. 2, 995–1003 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Markou, A., Strati, A., Malamos, N., Georgoulias, V. & Lianidou, E. S. Molecular characterization of circulating tumor cells in breast cancer by a liquid bead array hybridization assay. Clin. Chem. 57, 421–430 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Kufer, P. et al. Heterogeneous expression of MAGE-A genes in occult disseminated tumor cells: a novel multimarker reverse transcription-polymerase chain reaction for diagnosis of micrometastatic disease. Cancer Res. 62, 251–261 (2002).

    CAS  PubMed  Google Scholar 

  25. Riethdorf, S. et al. Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the CellSearch system. Clin. Cancer Res. 13, 920–928 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Coumans, F. A., van Dalum, G., Beck, M. & Terstappen, L. W. Filter characteristics influencing circulating tumor cell enrichment from whole blood. PLoS ONE 8, e61770 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lustberg, M. B. et al. Heterogeneous atypical cell populations are present in blood of metastatic breast cancer patients. Breast Cancer Res. 16, R23 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Yang, L. et al. Optimization of an enrichment process for circulating tumor cells from the blood of head and neck cancer patients through depletion of normal cells. Biotechnol. Bioeng. 102, 521–534 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shibata, K., Mori, M., Kitano, S. & Akiyoshi, T. Detection of ras gene mutations in peripheral blood of carcinoma patients using CD45 immunomagnetic separation and nested mutant allele specific amplification. Int. J. Oncol. 12, 1333–1338 (1998).

    CAS  PubMed  Google Scholar 

  30. Ramirez, J. M. et al. Prognostic relevance of viable circulating tumor cells detected by EPISPOT in metastatic breast cancer patients. Clin. Chem. 60, 214–221 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Lin, H. K. et al. Portable filter-based microdevice for detection and characterization of circulating tumor cells. Clin. Cancer Res. 16, 5011–5018 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hou, H. W. et al. Isolation and retrieval of circulating tumor cells using centrifugal forces. Sci. Rep. 3, 1259 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Sollier, E. et al. Size-selective collection of circulating tumor cells using Vortex technology. Lab. Chip 14, 63–77 (2014).

    Article  CAS  PubMed  Google Scholar 

  34. Nedosekin, D. A. et al. Photoacoustic and photothermal detection of circulating tumor cells, bacteria and nanoparticles in cerebrospinal fluid in vivo and ex vivo. J. Biophoton. 6, 523–533 (2013).

    Article  CAS  Google Scholar 

  35. Friedlander, T. W. et al. Detection and characterization of invasive circulating tumor cells (ictcs) derived from men with metastatic castration resistant prostate cancer (mCRPC). Int. J. Cancer 134, 2284–2293 (2013).

    Article  CAS  Google Scholar 

  36. Baccelli, I. et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nature Biotech. 31, 539–544 (2013).

    Article  CAS  Google Scholar 

  37. Hodgkinson, C. L. et al. Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Nature Med. http://dx.doi.org/10.1038/nm.3600 (2014).

  38. Rhim, A. D. et al. EMT and dissemination precede pancreatic tumor formation. Cell 148, 349–361 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Husemann, Y. et al. Systemic spread is an early step in breast cancer. Cancer Cell 13, 58–68 (2008).

    Article  PubMed  CAS  Google Scholar 

  40. Effenberger, K. E. et al. Disseminated tumor cells in pancreatic cancer-an independent prognosticator of disease progression and survival. Int. J. Cancer 131, E475–E483 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Stott, S. L. et al. Isolation of circulating tumor cells using a microvortex-generating herringbone-chip. Proc. Natl Acad. Sci. USA 107, 18392–18397 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ozkumur, E. et al. Inertial focusing for tumor antigen-dependent and -independent sorting of rare circulating tumor cells. Sci Transl. Med. 5, 179ra47 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Stott, S. L. et al. Isolation and characterization of circulating tumor cells from patients with localized and metastatic prostate cancer. Sci Transl. Med. 2, 25ra23 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Saucedo-Zeni, N. et al. 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 (2012).

    PubMed  PubMed Central  Google Scholar 

  46. Eifler, R. L. et al. Enrichment of circulating tumor cells from a large blood volume using leukapheresis and elutriation: proof of concept. Cytometry B Clin. Cytom. 80, 100–111 (2011).

    Article  PubMed  Google Scholar 

  47. Fischer, J. C. et al. Diagnostic leukapheresis enables reliable detection of circulating tumor cells of nonmetastatic cancer patients. Proc. Natl Acad. Sci. USA 110, 16580–16585 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  49. Meng, S. et al. Circulating tumor cells in patients with breast cancer dormancy. Clin. Cancer Res. 10, 8152–8162 (2004).

    Article  PubMed  Google Scholar 

  50. Bellahcene, A. et al. Transcriptome analysis reveals an osteoblast-like phenotype for human osteotropic breast cancer cells. Breast Cancer Res. Treat. 101, 135–148 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Garcia, T. et al. A convenient clinically relevant model of human breast cancer bone metastasis. Clin. Exp. Metastasis 25, 33–42 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Le Gall, C. et al. A cathepsin K inhibitor reduces breast cancer induced osteolysis and skeletal tumor burden. Cancer Res. 67, 9894–9902 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Bos, P. D. et al. Genes that mediate breast cancer metastasis to the brain. Nature 459, 1005–1009 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wan, L., Pantel, K. & Kang, Y. Tumor metastasis: moving new biological insights into the clinic. Nature Med. 19, 1450–1464 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Zhang, L. et al. The identification and characterization of breast cancer CTCs competent for brain metastasis. Sci Transl. Med. 5, 180ra48 (2013).

    Article  PubMed  CAS  Google Scholar 

  56. Labelle, M., Begum, S. & Hynes, R. O. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 20, 576–590 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kang, Y. & Pantel, K. Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell 23, 573–581 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ocana, O. H. et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22, 709–724 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Tsai, J. H., Donaher, J. L., Murphy, D. A., Chau, S. & Yang, J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22, 725–736 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Tsuji, T. et al. Epithelial-mesenchymal transition induced by growth suppressor p12CDK2-AP1 promotes tumor cell local invasion but suppresses distant colony growth. Cancer Res. 68, 10377–10386 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tam, W. L. & Weinberg, R. A. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nature Med. 19, 1438–1449 (2013).

    Article  CAS  PubMed  Google Scholar 

  62. Punnoose, E. A. et al. Molecular biomarker analyses using circulating tumor cells. PLoS ONE 5, e12517 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Giordano, A. et al. Epithelial-mesenchymal transition and stem cell markers in patients with HER2-positive metastatic breast cancer. Mol. Cancer Ther. 11, 2526–2534 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  65. Smerage, J. B. et al. Monitoring apoptosis and Bcl-2 on circulating tumor cells in patients with metastatic breast cancer. Mol. Oncol. 7, 680–692 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Fusi, A. et al. Expression of chemokine receptors on circulating tumor cells in patients with solid tumors. J. Transl. Med. 10, 52 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kaifi, J. T. et al. Tumor-cell homing to lymph nodes and bone marrow and CXCR4 expression in esophageal cancer. J. Natl Cancer Inst. 97, 1840–1847 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Shiozawa, Y. et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J. Clin. Invest. 121, 1298–1312 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Brugger, W. et al. Mobilization of tumor cells and hematopoietic progenitor cells into peripheral blood of patients with solid tumors. Blood 83, 636–640 (1994).

    Article  CAS  PubMed  Google Scholar 

  71. Joseph, J. et al. Disseminated prostate cancer cells can instruct hematopoietic stem and progenitor cells to regulate bone phenotype. Mol. Cancer Res. 10, 282–292 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Pantel, K. & Brakenhoff, R. H. Dissecting the metastatic cascade. Nature Rev. Cancer 4, 448–456 (2004).

    Article  CAS  Google Scholar 

  73. Aguirre-Ghiso, J. A. Models, mechanisms and clinical evidence for cancer dormancy. Nature Rev. Cancer 7, 834–846 (2007).

    Article  CAS  Google Scholar 

  74. Wicha, M. S. & Hayes, D. F. Circulating tumor cells: not all detected cells are bad and not all bad cells are detected. J. Clin. Oncol. 29, 1508–1511 (2011).

    Article  PubMed  Google Scholar 

  75. Krebs, M. G. et al. Molecular analysis of circulating tumour cells-biology and biomarkers. Nat. Rev. Clin. Oncol. 11, 129–144 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Wels, J., Kaplan, R. N., Rafii, S. & Lyden, D. Migratory neighbors and distant invaders: tumor-associated niche cells. Genes Dev. 22, 559–574 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Psaila, B. & Lyden, D. The metastatic niche: adapting the foreign soil. Nature Rev. Cancer 9, 285–293 (2009).

    Article  CAS  Google Scholar 

  78. Heitzer, E. et al. Complex tumor genomes inferred from single circulating tumor cells by array-CGH and next-generation sequencing. Cancer Res. 73, 2965–2975 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Lohr, J. G. et al. Whole-exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer. Nature Biotech. 32, 479–484 (2014).

    Article  CAS  Google Scholar 

  80. Klein, C. A. Parallel progression of primary tumours and metastases. Nat. Rev. Cancer 9, 302–312 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Gasch, C. 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. 59, 252–260 (2013).

    Article  CAS  PubMed  Google Scholar 

  83. Mostert, B. et al. KRAS and BRAF mutation status in circulating colorectal tumor cells and their correlation with primary and metastatic tumor tissue. Int. J. Cancer 133, 130–141 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Fehm, T. et al. HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial. Breast Cancer Res. Treat. 124, 403–412 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Babayan, A. et al. Heterogeneity of estrogen receptor expression in circulating tumor cells from metastatic breast cancer patients. PLoS ONE 8, e75038 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Shaffer, D. R. et al. Circulating tumor cell analysis in patients with progressive castration-resistant prostate cancer. Clin. Cancer Res. 13, 2023–2029 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Leversha, M. A. et al. Fluorescence in situ hybridization analysis of circulating tumor cells in metastatic prostate cancer. Clin. Cancer Res. 15, 2091–2097 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Jiang, Y., Palma, J. F., Agus, D. B., Wang, Y. & Gross, M. E. Detection of androgen receptor mutations in circulating tumor cells in castration-resistant prostate cancer. Clin. Chem. 56, 1492–1495 (2010).

    Article  PubMed  Google Scholar 

  89. Sridhar, S. S. et al. Castration-resistant prostate cancer: from new pathophysiology to new treatment. Eur. Urol. 65, 289–299 (2014).

    Article  PubMed  Google Scholar 

  90. Thorban, S. et al. Immunocytochemical detection of disseminated tumor cells in the bone marrow of patients with esophageal carcinoma. J. Natl Cancer Inst. 88, 1222–1227 (1996).

    Article  CAS  PubMed  Google Scholar 

  91. Pantel, K. & Alix-Panabieres, C. The potential of circulating tumor cells as a liquid biopsy to guide therapy in prostate cancer. Cancer Discov. 2, 974–975 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Smerage, J. B. et al. Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J. Clin. Oncol. http://dx.doi.org/10.1200/JCO.2014.56.2561 (2014).

  93. Scher, H. I., Morris, M. J., Larson, S. & Heller, G. Validation and clinical utility of prostate cancer biomarkers. Nat. Rev. Clin. Oncol. 10, 225–234 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Sieuwerts, A. M. et al. mRNA and microRNA expression profiles in circulating tumor cells and primary tumors of metastatic breast cancer patients. Clin. Cancer Res. 17, 3600–3618 (2011).

    Article  CAS  PubMed  Google Scholar 

  95. Powell, A. A. et al. Single cell profiling of circulating tumor cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PLoS ONE 7, e33788 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Dawson, S. J. et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N. Engl. J. Med. 368, 1199–1209 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. Diaz, L. A. Jr & Bardelli, A. Liquid biopsies: genotyping circulating tumor DNA. J. Clin. Oncol. 32, 579–586 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Kidess, E. & Jeffrey, S. S. Circulating tumor cells versus tumor-derived cell-free DNA: rivals or partners in cancer care in the era of single-cell analysis? Genome Med. 5, 70 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Bidard, F. C. et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol. 15, 406–414 (2014).

    Article  PubMed  Google Scholar 

  100. Murtaza, M. et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497, 108–112 (2013).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

C.A.-P. is supported by Grant “INCa-DGOS-Inserm 6045”, Institut National du Cancer (INCa) national grants; K.P. is supported by European Research Council Investigator Grant “DISSECT” (no. 269081); K.P. and C.A.-P. are both supported by the ERA-NET on Translational Cancer Research (TRANSCAN) grant “CTC-SCAN”.

Author information

Authors and Affiliations

  1. Department of Cellular and Tissular Biopathology of Tumors, University Medical Centre, Saint-Eloi Hospital, Institute of Medicine Regenerative & Biotherapy, Laboratory of Rare Human Circulating Cells, 80 Avenue Augustin Fliche 34295 Montpellier Cedex 5, Montpellier, France

    Catherine Alix-Panabières

  2. University Institute of Clinical Research UM1 - EA2415 - Epidemiology, Biostatistics & Public Health, 641, Avenue du Doyen Gaston GIRAUD 34093 Montpellier Cedex 5, Montpellier, France

    Catherine Alix-Panabières

  3. Department of Tumor Biology, University Medical Center, Hamburg-Eppendorf, Martinistrasse 52, Hamburg, 20246, Germany

    Klaus Pantel

Authors
  1. Catherine Alix-Panabières
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Klaus Pantel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Klaus Pantel.

Ethics declarations

Competing interests

C.A.P. received honoraria from Sanofi and grants from Janssen and Roche; K.P. received honoraria from Janssen, Alere and Gilupi.

Related links

PowerPoint slides

Glossary

BEAMing PCR

A combination of emulsion digital PCR and flow cytometry: beads, emulsions, amplification and magnetics (BEAMing) are combined to achieve the necessary level of sensitivity.

Cancer stem cells

Cancer cells with self-renewing capacity and the ability to create or sustain a tumour cell population.

Castration-resistant prostate cancer

(CRPC). Prostate cancer that no longer responds to androgen deprivation therapy.

CellSearch® system

US Food and Drug Administration (FDA)-cleared technology that allows a sensitive positive capture of CTCs by antibodies against epithelial cell adhesion molecule (EPCAM) coated with ferrofluids: tumour cells are identified by positive immunostaining for antibodies against cytokeratins (CK8, CK18 and CK19), negative immunostaining for the common leukocyte antigen CD45 to exclude leukocytes, and positive DAPI staining as a measure of nuclear integrity.

Clinical utility

The capacity to diagnose and to facilitate a decision to adopt or reject a therapeutic action: the risks and benefits result from test use.

Clinical validity

The predictive value of a test for a given clinical outcome (for example, in cancer, a primary tumour or metastasis will develop in a patient with a positive test): a test identifies the clinical status of a patient.

Dielectrophoresis

(DEP). A phenomenon in which a force is exerted on a dielectric particle when it is subjected to a non-uniform electric field. As biological cells have diverse dielectric properties, DEP can be used to manipulate, transport, separate and sort different types of particles (for example, circulating tumour cells).

Digital PCR

A refinement of conventional PCR methods that can be used to directly quantify and clonally amplify nucleic acids, including DNA, cDNA or RNA that occur at very low frequencies.

Epithelial-to-mesenchymal transition

(EMT). Conversion from an epithelial to a mesenchymal phenotype, which is a normal component of embryonic development. In carcinomas, this transformation results in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.

Leukapheresis

A process by which a large amount of blood is withdrawn from a vein, white blood cells and circulating tumour cells are selectively removed, and the remaining blood (red blood cells in platelet- and leukocyte-poor plasma) is transfused back into the donor.

Microfluidic devices

The integration of one or different laboratory functions on a single chip of only millimetres to a few square centimetres in size, in which extremely small fluid volumes (down to <picolitres) are handled.

Parallel progression

Tumour cells leave the primary tumour and home to secondary sites many years before the diagnosis and surgical resection of the primary tumour. These disseminated tumour cells can develop mutations that are independent from the mutational landscape of the primary tumour.

Photoacoustic flow cytometry

The irradiation of individual cells in blood and lymph flow with one or a few focused laser beams operating at different wavelengths, followed by the use of an ultrasound transducer attached to the skin to record laser-induced acoustic waves.

Tumour, node, metastasis cancer staging

(TNM cancer staging). A staging system for classifying cancers that was originally developed by the American Joint Committee on Cancer (AJCC) and that grades cancer by tumour, lymph node and metastatic status.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alix-Panabières, C., Pantel, K. Challenges in circulating tumour cell research. Nat Rev Cancer 14, 623–631 (2014). https://doi.org/10.1038/nrc3820

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3820

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer