Skip to main content

Advertisement

Log in

Circulating tumour cells—a bona fide cause of metastatic cancer

  • NON-THEMATIC REVIEW
  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Circulating tumour cells (CTCs) are emerging as important prognostic markers and have potential clinical utility as tumour biomarkers for targeted cancer therapy. Although CTCs were proposed more than 100 years ago as potential precursors that may form metastatic lesions, formal evidence that CTCs are indeed capable of initiating metastases is limited. Moreover, the process of CTCs shedding into the circulation, relocating to distant organ sites and initiating metastatic foci is complex and intrinsically inefficient. To partially explain the metastatic process, the concepts of CTCs as metastatic precursors or pre-metastatic conditioners have been proposed; however, it is questionable as to whether these are both variable pathways to metastasis or just markers of metastatic burden. This review explores the evidence for CTCs in the initiation and progression of metastatic cancer and the data supporting these different concepts in an attempt to better understand the role of CTCs in metastasis. A greater understanding of the metastatic potential of CTCs will open new avenues for therapeutic interventions in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Cohen, S. J., Punt, C. J., Iannotti, N., Saidman, B. H., Sabbath, K. D., Gabrail, N. Y., et al. (2009). Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Annals of Oncology, 20(7), 1223–1229. doi:10.1093/annonc/mdn786.

    Article  CAS  PubMed  Google Scholar 

  2. Cristofanilli, M., Budd, G. T., Ellis, M. J., Stopeck, A., Matera, J., Miller, M. C., et al. (2004). Circulating tumor cells, disease progression, and survival in metastatic breast cancer. New England Journal of Medicine, 351(8), 781–791. doi:10.1056/NEJMoa040766.

    Article  CAS  PubMed  Google Scholar 

  3. Pierga, J. Y., Hajage, D., Bachelot, T., Delaloge, S., Brain, E., Campone, M., et al. (2012). High independent prognostic and predictive value of circulating tumor cells compared with serum tumor markers in a large prospective trial in first-line chemotherapy for metastatic breast cancer patients. Annals of Oncology, 23(3), 618–624. doi:10.1093/annonc/mdr263.

    Article  PubMed  Google Scholar 

  4. Thalgott, M., Rack, B., Maurer, T., Souvatzoglou, M., Eiber, M., Kress, V., et al. (2013). Detection of circulating tumor cells in different stages of prostate cancer. Journal of Cancer Research and Clinical Oncology, 139(5), 755–763. doi:10.1007/s00432-013-1377-5.

    Article  PubMed  Google Scholar 

  5. Hayes, D. F., Cristofanilli, M., Budd, G. T., Ellis, M. J., Stopeck, A., Miller, M. C., 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. Clinical Cancer Research, 12(14 Pt 1), 4218–4224. doi:10.1158/1078-0432.CCR-05-2821.

    Article  CAS  PubMed  Google Scholar 

  6. Scher, H. I., Jia, X., de Bono, J. S., Fleisher, M., Pienta, K. J., Raghavan, D., et al. (2009). Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data. Lancet Oncology, 10(3), 233–239. doi:10.1016/S1470-2045(08)70340-1.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Dong, X., Alpaugh, K. R., & Cristofanilli, M. (2012). Circulating tumor cells (CTCs) in breast cancer: a diagnostic tool for prognosis and molecular analysis. Chinese Journal of Cancer Research, 24(4), 388–398. doi:10.3978/j.issn.1000-9604.2012.11.03.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Khan, M. S., Kirkwood, A., Tsigani, T., Garcia-Hernandez, J., Hartley, J. A., Caplin, M. E., et al. (2013). Circulating tumor cells as prognostic markers in neuroendocrine tumors. Journal of Clinical Oncology, 31(3), 365–372. doi:10.1200/JCO.2012.44.2905.

    Article  CAS  PubMed  Google Scholar 

  9. Giuliano, M., Giordano, A., Jackson, S., Hess, K. R., De Giorgi, U., Mego, M., et al. (2011). Circulating tumor cells as prognostic and predictive markers in metastatic breast cancer patients receiving first-line systemic treatment. Breast Cancer Research, 13(3), R67. doi:10.1186/bcr2907.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Lucci, A., Hall, C. S., Lodhi, A. K., Bhattacharyya, A., Anderson, A. E., Xiao, L., et al. (2012). Circulating tumour cells in non-metastatic breast cancer: a prospective study. Lancet Oncology, 13(7), 688–695. doi:10.1016/S1470-2045(12)70209-7.

    Article  PubMed  Google Scholar 

  11. Aggarwal, C., Meropol, N. J., Punt, C. J., Iannotti, N., Saidman, B. H., Sabbath, K. D., et al. (2013). Relationship among circulating tumor cells, CEA and overall survival in patients with metastatic colorectal cancer. Annals of Oncology, 24(2), 420–428. doi:10.1093/annonc/mds336.

    Article  CAS  PubMed  Google Scholar 

  12. Miyamoto, D. T., Lee, R. J., Stott, S. L., Ting, D. T., Wittner, B. S., Ulman, M., et al. (2012). Androgen receptor signaling in circulating tumor cells as a marker of hormonally responsive prostate cancer. Cancer Discovery, 2(11), 995–1003. doi:10.1158/2159-8290.CD-12-0222.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Ashworth, T. R. (1869). A case of cancer in which cells similar to those in the tumours were seen in the blood after death. Australian Medical Journal, 14, 146–147.

    Google Scholar 

  14. Valastyan, S., & Weinberg, R. A. (2011). Tumor metastasis: molecular insights and evolving paradigms. Cell, 147(2), 275–292. doi:10.1016/j.cell.2011.09.024.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Fidler, I. J. (2002). The organ microenvironment and cancer metastasis. Differentiation, 70(9–10), 498–505. doi:10.1046/j.1432-0436.2002.700904.x.

    Article  PubMed  Google Scholar 

  16. Paget, S. (1889). The distribution of secondary growths in cancer of the breast. Lancet, 1, 571–573.

    Article  Google Scholar 

  17. Baccelli, I., Schneeweiss, A., Riethdorf, S., Stenzinger, A., Schillert, A., Vogel, V., et al. (2013). Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nature Biotechnology, 31(6), 539–544. doi:10.1038/nbt.2576.

    Article  CAS  PubMed  Google Scholar 

  18. Meng, S., Tripathy, D., Frenkel, E. P., Shete, S., Naftalis, E. Z., Huth, J. F., et al. (2004). Circulating tumor cells in patients with breast cancer dormancy. Clinical Cancer Research, 10(24), 8152–8162. doi:10.1158/1078-0432.CCR-04-1110.

    Article  PubMed  Google Scholar 

  19. Tiwari, N., Gheldof, A., Tatari, M., & Christofori, G. (2012). EMT as the ultimate survival mechanism of cancer cells. Seminars in Cancer Biology, 22(3), 194–207. doi:10.1016/j.semcancer.2012.02.013.

    Article  CAS  PubMed  Google Scholar 

  20. Nieto, M. A., & Cano, A. (2012). The epithelial-mesenchymal transition under control: global programs to regulate epithelial plasticity. Seminars in Cancer Biology, 22(5–6), 361–368. doi:10.1016/j.semcancer.2012.05.003.

    Article  CAS  PubMed  Google Scholar 

  21. Lindemann, F., Schlimok, G., Dirschedl, P., Witte, J., & Riethmuller, G. (1992). Prognostic significance of micrometastatic tumour cells in bone marrow of colorectal cancer patients. Lancet, 340(8821), 685–689.

    Article  CAS  PubMed  Google Scholar 

  22. Vogel, P., Ruschoff, J., Kummel, S., Zirngibl, H., Hofstadter, F., Hohenberger, W., et al. (2000). Prognostic value of microscopic peritoneal dissemination: comparison between colon and gastric cancer. Diseases of the Colon and Rectum, 43(1), 92–100.

    Article  CAS  PubMed  Google Scholar 

  23. de Bono, J. S., Scher, H. I., Montgomery, R. B., Parker, C., Miller, M. C., Tissing, H., et al. (2008). Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clinical Cancer Research, 14(19), 6302–6309. doi:10.1158/1078-0432.CCR-08-0872.

    Article  PubMed  Google Scholar 

  24. De Giorgi, U., Mego, M., Scarpi, E., Giuliano, M., Giordano, A., Reuben, J. M., et al. (2012). Relationship between lymphocytopenia and circulating tumor cells as prognostic factors for overall survival in metastatic breast cancer. Clinical Breast Cancer, 12(4), 264–269. doi:10.1016/j.clbc.2012.04.004.

    Article  PubMed  Google Scholar 

  25. Hiltermann, T. J., Pore, M. M., van den Berg, A., Timens, W., Boezen, H. M., Liesker, J. J., et al. (2012). Circulating tumor cells in small-cell lung cancer: a predictive and prognostic factor. Annals of Oncology, 23(11), 2937–2942. doi:10.1093/annonc/mds138.

    Article  CAS  PubMed  Google Scholar 

  26. Hou, J. M., Krebs, M. G., Lancashire, L., Sloane, R., Backen, A., Swain, R. K., et al. (2012). Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. Journal of Clinical Oncology, 30(5), 525–532. doi:10.1200/JCO.2010.33.3716.

    Article  PubMed  Google Scholar 

  27. Nieva, J., Wendel, M., Luttgen, M. S., Marrinucci, D., Bazhenova, L., Kolatkar, A., et al. (2012). High-definition imaging of circulating tumor cells and associated cellular events in non-small cell lung cancer patients: a longitudinal analysis. Physical Biology, 9(1), 016004. doi:10.1088/1478-3975/9/1/016004.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Luzzi, K. J., MacDonald, I. C., Schmidt, E. E., Kerkvliet, N., Morris, V. L., Chambers, A. F., et al. (1998). Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. American Journal of Pathology, 153(3), 865–873. doi:10.1016/S0002-9440(10)65628-3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Mervic, L. (2012). Time course and pattern of metastasis of cutaneous melanoma differ between men and women. PLoS ONE, 7(3), e32955. doi:10.1371/journal.pone.0032955.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Tas, F. (2012). Factors influencing the hormone receptor and HER2 levels in breast cancer: a population-based analysis. Onkologie, 35(3), 95–98. doi:10.1159/000336812.

    Article  CAS  PubMed  Google Scholar 

  31. Coumans, F. A., Siesling, S., & Terstappen, L. W. (2013). Detection of cancer before distant metastasis. BMC Cancer, 13(1), 283. doi:10.1186/1471-2407-13-283.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Ito, S., Nakanishi, H., Ikehara, Y., Kato, T., Kasai, Y., Ito, K., et al. (2001). Real-time observation of micrometastasis formation in the living mouse liver using a green fluorescent protein gene-tagged rat tongue carcinoma cell line. International Journal of Cancer, 93(2), 212–217. doi:10.1002/ijc.1318.

    Article  CAS  Google Scholar 

  33. Weiss, L. (2000). Metastasis of cancer: a conceptual history from antiquity to the 1990s. Cancer and Metastasis Reviews, 19(3-4), I–XI. 193-383.

    CAS  PubMed  Google Scholar 

  34. Becker, T. M., Caixeiro, N. J., Lim, S. H., Tognela, A., Kienzle, N., Scott, K. F., et al. (2014). New frontiers in circulating tumor cell analysis: a reference guide for biomolecular profiling toward translational clinical use. International Journal of Cancer, 134(11), 2523–2533. doi:10.1002/ijc.28516.

    Article  CAS  Google Scholar 

  35. Rossi, E., Basso, U., Celadin, R., Zilio, F., Pucciarelli, S., Aieta, M., et al. (2010). M30 neoepitope expression in epithelial cancer: quantification of apoptosis in circulating tumor cells by cell search analysis. Clinical Cancer Research, 16(21), 5233–5243. doi:10.1158/1078-0432.CCR-10-1449.

    Article  CAS  PubMed  Google Scholar 

  36. Larson, C. J., Moreno, J. G., Pienta, K. J., Gross, S., Repollet, M., & O’Hara, S. M. (2004). Apoptosis of circulating tumor cells in prostate cancer patients. Cytometry Part A, 62(1), 46–53. doi:10.1002/cyto.a.20073.

    Article  Google Scholar 

  37. Powell, A. A., Talasaz, A. H., Zhang, H., Coram, M. A., Reddy, A., Deng, G., et al. (2012). Single cell profiling of circulating tumor cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PLoS ONE, 7(5), e33788. doi:10.1371/journal.pone.0033788.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Duda, D. G., Duyverman, A. M., Kohno, M., Snuderl, M., Steller, E. J., Fukumura, D., et al. (2010). Malignant cells facilitate lung metastasis by bringing their own soil. Proceedings of the National Academy of Sciences of the United States of America, 107(50), 21677–21682. doi:10.1073/pnas.1016234107.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Joyce, J. A., & Pollard, J. W. (2009). Microenvironmental regulation of metastasis. Nature Reviews Cancer, 9(4), 239–252. doi:10.1038/nrc2618.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Honn, K. V., Tang, D. G., & Crissman, J. D. (1992). Platelets and cancer metastasis: a causal relationship? Cancer and Metastasis Reviews, 11(3–4), 325–351.

    Article  CAS  PubMed  Google Scholar 

  41. Palumbo, J. S., Talmage, K. E., Massari, J. V., La Jeunesse, C. M., Flick, M. J., Kombrinck, K. W., et al. (2005). Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood, 105(1), 178–185. doi:10.1182/blood-2004-06-2272.

    Article  CAS  PubMed  Google Scholar 

  42. Erpenbeck, L., Nieswandt, B., Schon, M., Pozgajova, M., & Schon, M. P. (2010). Inhibition of platelet GPIb alpha and promotion of melanoma metastasis. Journal of Investigative Dermatology, 130(2), 576–586. doi:10.1038/jid.2009.278.

    Article  CAS  PubMed  Google Scholar 

  43. Hafner, M., Orosz, P., Kruger, A., & Mannel, D. N. (1996). TNF promotes metastasis by impairing natural killer cell activity. International Journal of Cancer, 66(3), 388–392. doi:10.1002/(SICI)1097-0215(19960503)66:3<388::AID-IJC20>3.0.CO;2-6.

    Article  CAS  Google Scholar 

  44. Steinert, G., Scholch, S., Niemietz, T., Iwata, N., Garcia, S. A., Behrens, B., et al. (2014). Immune escape and survival mechanisms in circulating tumor cells of colorectal cancer. Cancer Research, 74(6), 1694–1704. doi:10.1158/0008-5472.CAN-13-1885.

    Article  CAS  PubMed  Google Scholar 

  45. Shao, B., Wahrenbrock, M. G., Yao, L., David, T., Coughlin, S. R., Xia, L., et al. (2011). Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of Trousseau syndrome. Blood, 118(15), 4015–4023. doi:10.1182/blood-2011-07-368514.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Letai, A., & Kuter, D. J. (1999). Cancer, coagulation, and anticoagulation. The Oncologist, 4(6), 443–449.

    CAS  PubMed  Google Scholar 

  47. Micalizzi, D. S., Farabaugh, S. M., & Ford, H. L. (2010). Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. Journal of Mammary Gland Biology and Neoplasia, 15(2), 117–134. doi:10.1007/s10911-010-9178-9.

    Article  PubMed Central  PubMed  Google Scholar 

  48. Cano, A., Perez-Moreno, M. A., Rodrigo, I., Locascio, A., Blanco, M. J., del Barrio, M. G., et al. (2000). The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nature Cell Biology, 2(2), 76–83. doi:10.1038/35000025.

    Article  CAS  PubMed  Google Scholar 

  49. Talbot, L. J., Bhattacharya, S. D., & Kuo, P. C. (2012). Epithelial-mesenchymal transition, the tumor microenvironment, and metastatic behavior of epithelial malignancies. International Journal of Biochemistry and Molecular Biology, 3(2), 117–136.

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Sieuwerts, A. M., Mostert, B., Bolt-de Vries, J., Peeters, D., de Jongh, F. E., Stouthard, J. M., et al. (2011). mRNA and microRNA expression profiles in circulating tumor cells and primary tumors of metastatic breast cancer patients. Clinical Cancer Research, 17(11), 3600–3618. doi:10.1158/1078-0432.CCR-11-0255.

    Article  CAS  PubMed  Google Scholar 

  51. Yokobori, T., Iinuma, H., Shimamura, T., Imoto, S., Sugimachi, K., Ishii, H., et al. (2013). Plastin3 is a novel marker for circulating tumor cells undergoing the epithelial-mesenchymal transition and is associated with colorectal cancer prognosis. Cancer Research, 73(7), 2059–2069. doi:10.1158/0008-5472.CAN-12-0326.

    Article  CAS  PubMed  Google Scholar 

  52. Kallergi, G., Papadaki, M. A., 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 Research, 13(3), R59. doi:10.1186/bcr2896.

    Article  PubMed Central  PubMed  Google Scholar 

  53. Balasubramanian, P., Lang, J. C., Jatana, K. R., Miller, B., Ozer, E., Old, M., et al. (2012). Multiparameter analysis, including EMT markers, on negatively enriched blood samples from patients with squamous cell carcinoma of the head and neck. PLoS ONE, 7(7), e42048. doi:10.1371/journal.pone.0042048.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Becker, T. M., Caixeiro, N. J., Lim, S. H., Tognela, A., Kienzle, N., Scott, K. F., et al. (2013). New frontiers in circulating tumor cell analysis—a reference guide for biomolecular profiling towards translational clinical use. International Journal of Cancer. doi:10.1002/ijc.28516.

    Google Scholar 

  55. Giordano, A., Gao, H., Anfossi, S., Cohen, E., Mego, M., Lee, B. N., et al. (2012). Epithelial-mesenchymal transition and stem cell markers in patients with HER2-positive metastatic breast cancer. Molecular Cancer Therapeutics, 11(11), 2526–2534. doi:10.1158/1535-7163.MCT-12-0460.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Mego, M., Mani, S. A., Lee, B. N., Li, C., Evans, K. W., Cohen, E. N., et al. (2012). Expression of epithelial-mesenchymal transition-inducing transcription factors in primary breast cancer: the effect of neoadjuvant therapy. International Journal of Cancer, 130(4), 808–816. doi:10.1002/ijc.26037.

    Article  CAS  Google Scholar 

  57. Satelli, A., Mitra, A., Cutrera, J. J., Devarie, M., Xia, X., Ingram, D. R., et al. (2014). Universal marker and detection tool for human sarcoma circulating tumor cells. Cancer Research, 74(6), 1645–1650. doi:10.1158/0008-5472.CAN-13-1739.

    Article  CAS  PubMed  Google Scholar 

  58. Muller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M. E., et al. (2001). Involvement of chemokine receptors in breast cancer metastasis. Nature, 410(6824), 50–56. doi:10.1038/35065016.

    Article  CAS  PubMed  Google Scholar 

  59. Craig, M. J., & Loberg, R. D. (2006). CCL2 (monocyte chemoattractant protein-1) in cancer bone metastases. Cancer and Metastasis Reviews, 25(4), 611–619. doi:10.1007/s10555-006-9027-x.

    Article  CAS  PubMed  Google Scholar 

  60. Thiery, J. P. (2003). Epithelial-mesenchymal transitions in development and pathologies. Current Opinion in Cell Biology, 15(6), 740–746.

    Article  CAS  PubMed  Google Scholar 

  61. Chambers, A. F., Groom, A. C., & MacDonald, I. C. (2002). Dissemination and growth of cancer cells in metastatic sites. Nature Reviews Cancer, 2(8), 563–572. doi:10.1038/nrc865.

    Article  CAS  PubMed  Google Scholar 

  62. Pantel, K., & Brakenhoff, R. H. (2004). Dissecting the metastatic cascade. Nature Reviews Cancer, 4(6), 448–456. doi:10.1038/nrc1370.

    Article  CAS  PubMed  Google Scholar 

  63. Chiang, A. C., & Massague, J. (2008). Molecular basis of metastasis. New England Journal of Medicine, 359(26), 2814–2823. doi:10.1056/NEJMra0805239.

    Article  CAS  PubMed  Google Scholar 

  64. Nierodzik, M. L., & Karpatkin, S. (2006). Thrombin induces tumor growth, metastasis, and angiogenesis: evidence for a thrombin-regulated dormant tumor phenotype. Cancer Cell, 10(5), 355–362. doi:10.1016/j.ccr.2006.10.002.

    Article  CAS  PubMed  Google Scholar 

  65. Gantus, M. A., Alves, L. M., Stipursky, J., Souza, E. C., Teodoro, A. J., Alves, T. R., et al. (2011). Estradiol modulates TGF-beta1 expression and its signaling pathway in thyroid stromal cells. Molecular and Cellular Endocrinology, 337(1–2), 71–79. doi:10.1016/j.mce.2011.02.001.

    Article  CAS  PubMed  Google Scholar 

  66. Heitzer, E., Auer, M., Gasch, C., Pichler, M., Ulz, P., Hoffmann, E. M., et al. (2013). Complex tumor genomes inferred from single circulating tumor cells by array-CGH and next-generation sequencing. Cancer Research, 73(10), 2965–2975. doi:10.1158/0008-5472.CAN-12-4140.

    Article  CAS  PubMed  Google Scholar 

  67. Smirnov, D. A., Zweitzig, D. R., Foulk, B. W., Miller, M. C., Doyle, G. V., Pienta, K. J., et al. (2005). Global gene expression profiling of circulating tumor cells. Cancer Research, 65(12), 4993–4997. doi:10.1158/0008-5472.CAN-04-4330.

    Article  CAS  PubMed  Google Scholar 

  68. Shaikhibrahim, Z., Lindstrot, A., Ellinger, J., Rogenhofer, S., Buettner, R., & Wernert, N. (2012). Genes differentially expressed in the peripheral zone compared to the transitional zone of the normal human prostate and their potential regulation by ETS factors. Molecular Medicine Reports, 5(1), 32–36. doi:10.3892/mmr.2011.628.

    CAS  PubMed  Google Scholar 

  69. Raja, S. B., Murali, M. R., Devaraj, H., & Devaraj, S. N. (2012). Differential expression of gastric MUC5AC in colonic epithelial cells: TFF3-wired IL1 beta/Akt crosstalk-induced mucosal immune response against Shigella dysenteriae infection. Journal of Cell Science, 125(Pt 3), 703–713. doi:10.1242/jcs.092148.

    Article  CAS  PubMed  Google Scholar 

  70. Bidard, F. C., Pierga, J. Y., Vincent-Salomon, A., & Poupon, M. F. (2008). A “class action” against the microenvironment: do cancer cells cooperate in metastasis? Cancer and Metastasis Reviews, 27(1), 5–10. doi:10.1007/s10555-007-9103-x.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646–674. doi:10.1016/j.cell.2011.02.013.

    Article  CAS  PubMed  Google Scholar 

  72. Vanderlaag, K. E., Hudak, S., Bald, L., Fayadat-Dilman, L., Sathe, M., Grein, J., et al. (2010). Anterior gradient-2 plays a critical role in breast cancer cell growth and survival by modulating cyclin D1, estrogen receptor-alpha and survivin. Breast Cancer Research, 12(3), R32. doi:10.1186/bcr2586.

    Article  PubMed Central  PubMed  Google Scholar 

  73. Khatib, A. M., Auguste, P., Fallavollita, L., Wang, N., Samani, A., Kontogiannea, M., et al. (2005). Characterization of the host proinflammatory response to tumor cells during the initial stages of liver metastasis. American Journal of Pathology, 167(3), 749–759. doi:10.1016/S0002-9440(10)62048-2.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Auguste, P., Fallavollita, L., Wang, N., Burnier, J., Bikfalvi, A., & Brodt, P. (2007). The host inflammatory response promotes liver metastasis by increasing tumor cell arrest and extravasation. American Journal of Pathology, 170(5), 1781–1792. doi:10.2353/ajpath.2007.060886.

    Article  PubMed Central  PubMed  Google Scholar 

  75. Liotta, L. A., & Kohn, E. C. (2001). The microenvironment of the tumour-host interface. Nature, 411(6835), 375–379. doi:10.1038/35077241.

    Article  CAS  PubMed  Google Scholar 

  76. Obermayr, E., Castillo-Tong, D. C., Pils, D., Speiser, P., Braicu, I., Van Gorp, T., et al. (2013). Molecular characterization of circulating tumor cells in patients with ovarian cancer improves their prognostic significance—a study of the OVCAD consortium. Gynecologic Oncology, 128(1), 15–21. doi:10.1016/j.ygyno.2012.09.021.

    Article  CAS  PubMed  Google Scholar 

  77. Bidard, F. C., Pierga, J. Y., Soria, J. C., & Thiery, J. P. (2013). Translating metastasis-related biomarkers to the clinic–progress and pitfalls. Nature Reviews Clinical Oncology, 10(3), 169–179. doi:10.1038/nrclinonc.2013.4.

    Article  CAS  PubMed  Google Scholar 

  78. Zhe, X., Cher, M. L., & Bonfil, R. D. (2011). Circulating tumor cells: finding the needle in the haystack. American Journal of Cancer Research, 1(6), 740–751.

    PubMed Central  PubMed  Google Scholar 

  79. Braun, S., Vogl, F. D., Naume, B., Janni, W., Osborne, M. P., Coombes, R. C., et al. (2005). A pooled analysis of bone marrow micrometastasis in breast cancer. New England Journal of Medicine, 353(8), 793–802. doi:10.1056/NEJMoa050434.

    Article  CAS  PubMed  Google Scholar 

  80. Peinado, H., Aleckovic, M., Lavotshkin, S., Matei, I., Costa-Silva, B., Moreno-Bueno, G., et al. (2012). Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nature Medicine, 18(6), 883–891. doi:10.1038/nm.2753.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Pantel, K., Schlimok, G., Kutter, D., Schaller, G., Genz, T., Wiebecke, B., et al. (1991). Frequent down-regulation of major histocompatibility class I antigen expression on individual micrometastatic carcinoma cells. Cancer Research, 51(17), 4712–4715.

    CAS  PubMed  Google Scholar 

  82. Schlimok, G., & Riethmuller, G. (1990). Detection, characterization and tumorigenicity of disseminated tumor cells in human bone marrow. Seminars in Cancer Biology, 1(3), 207–215.

    CAS  PubMed  Google Scholar 

  83. Pantel, K., Schlimok, G., Angstwurm, M., Passlick, B., Izbicki, J. R., Johnson, J. P., et al. (1995). Early metastasis of human solid tumours: expression of cell adhesion molecules. Ciba Foundation Symposium, 189, 157–170. discussion 170-153, 174-156.

    CAS  PubMed  Google Scholar 

  84. Dawson, M. R., Duda, D. G., Fukumura, D., & Jain, R. K. (2009). VEGFR1-activity-independent metastasis formation. Nature, 461(7262), E4. doi:10.1038/nature08254. discussion E5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Brandt, B., Junker, R., Griwatz, C., Heidl, S., Brinkmann, O., Semjonow, A., et al. (1996). Isolation of prostate-derived single cells and cell clusters from human peripheral blood. Cancer Research, 56(20), 4556–4561.

    CAS  PubMed  Google Scholar 

  86. Al-Mehdi, A. B., Tozawa, K., Fisher, A. B., Shientag, L., Lee, A., & Muschel, R. J. (2000). Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nature Medicine, 6(1), 100–102. doi:10.1038/71429.

    Article  CAS  PubMed  Google Scholar 

  87. Gerlinger, M., Rowan, A. J., Horswell, S., Larkin, J., Endesfelder, D., Gronroos, E., et al. (2012). Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. New England Journal of Medicine, 366(10), 883–892. doi:10.1056/NEJMoa1113205.

    Article  CAS  PubMed  Google Scholar 

  88. Gasch, C., Bauernhofer, T., Pichler, M., Langer-Freitag, S., Reeh, M., Seifert, A. M., et al. (2013). Heterogeneity of epidermal growth factor receptor status and mutations of KRAS/PIK3CA in circulating tumor cells of patients with colorectal cancer. Clinical Chemistry, 59(1), 252–260. doi:10.1373/clinchem.2012.188557.

    Article  CAS  PubMed  Google Scholar 

  89. Niikura, N., Liu, J., Hayashi, N., Mittendorf, E. A., Gong, Y., Palla, S. L., et al. (2012). Loss of human epidermal growth factor receptor 2 (HER2) expression in metastatic sites of HER2-overexpressing primary breast tumors. Journal of Clinical Oncology, 30(6), 593–599. doi:10.1200/JCO.2010.33.8889.

    Article  PubMed Central  PubMed  Google Scholar 

  90. Dupont Jensen, J., Laenkholm, A. V., Knoop, A., Ewertz, M., Bandaru, R., Liu, W., et al. (2011). PIK3CA mutations may be discordant between primary and corresponding metastatic disease in breast cancer. Clinical Cancer Research, 17(4), 667–677. doi:10.1158/1078-0432.CCR-10-1133.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the University of Western Sydney and the University of New South Wales. Funding sources include the Cancer Institute New South Wales for the South West Sydney Translational Cancer Research Unit, University of New South Wales Equipment Grant and Prostate Cancer Foundation of Australia.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to N. J. Caixeiro.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Caixeiro, N.J., Kienzle, N., Lim, S.H. et al. Circulating tumour cells—a bona fide cause of metastatic cancer. Cancer Metastasis Rev 33, 747–756 (2014). https://doi.org/10.1007/s10555-014-9502-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-014-9502-8

Keywords

Navigation