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Relevance of CTC Clusters in Breast Cancer Metastasis

Chapter
First Online:
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1220)

Abstract

Metastasis is the major cause of mortality in patients with breast cancer; however, the mechanisms of tumor cell dissemination and metastasis formation are not well established yet. The study of circulating tumour cells (CTCs), the metastatic precursors of distant disease, may help in this search. CTCs can be found in the blood of cancer patients as single cells or as tumor cell aggregates, known as CTC clusters. CTC clusters have differential biological features such as an enhanced survival and metastatic potential, and they hold great promises for the evaluation of prognosis, diagnosis and therapy of the metastatic cancer. The analysis of CTC clusters offers new insights into the mechanism of metastasis and can guide towards the development of new diagnostic and therapeutic strategies to suppress cancer metastasis. This has become possible thanks to the development of improved technologies for detection of CTCs and CTC clusters. However, more efficient methods are needed in order to address important questions regarding the metastatic potential of CTC and future clinical applications. In this chapter, we explore the current knowledge on the role of CTC clusters in breast cancer metastasis, their origin, metastatic advantages and clinical importance.

Keywords

Breast cancer Circulating tumor cells (CTCs) CTC clusters Metastatic potential Homotypic CTC clusters Heterotypic CTC clusters 
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Notes

Acknowledgements

The work of the authors is supported by Roche-Chus Joint Unit (IN853B 2018/03) funded by GAIN, “Consellería de Economía, Emprego e Industria”. IMP is funded by the Training Programme for Academic Staff (FPU) fellowship, from the Ministry of Education and Vocational Training, Spanish Government.

References

  1. 1.
    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.  https://doi.org/10.3322/caac.21492.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277–300.  https://doi.org/10.3322/caac.20073.PubMedCrossRefGoogle Scholar
  3. 3.
    Brandt B, Junker R, Griwatz C, Heidl S, Brinkmann O, Semjonow A, et al. Isolation of prostate-derived single cells and cell clusters from human peripheral blood. Cancer Res. 1996;56(20):4556–61.PubMedGoogle Scholar
  4. 4.
    Cho EH, Wendel M, Luttgen M, Yoshioka C, Marrinucci D, Lazar D, et al. Characterization of circulating tumor cell aggregates identified in patients with epithelial tumors. Phys Biol. 2012;9(1):016001.  https://doi.org/10.1088/1478-3975/9/1/016001.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Hou JM, Krebs MG, Lancashire L, Sloane R, Backen A, Swain RK, 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. 2012;30(5):525–32.  https://doi.org/10.1200/JCO.2010.33.3716.PubMedCrossRefGoogle Scholar
  6. 6.
    Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014;158:1110–22.  https://doi.org/10.1016/j.cell.2014.07.013.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Langenbeck B. On the development of cancer in the vein s, and the transmission of cancer from man to the lower animals. Edinb Med Surg J. 1841;55(147):251–3.Google Scholar
  8. 8.
    Ashworth TR. A case of cancer in which cells similar to those in the Tumours were seen in the blood after death. Aust Med J. 1869;  https://doi.org/10.1111/j.1528-1167.2011.03138.x.
  9. 9.
    Denis MG, Tessier MH, Dreno B, Lustenberger P. Circulating micrometastases following oncological surgery. Lancet. 1996;347(9005):913.  https://doi.org/10.1016/s0140-6736(96)91402-6.PubMedCrossRefGoogle Scholar
  10. 10.
    Liotta LA, Kleinerman J, Saidel GM. The significance of hematogenous tumor cell clumps in the metastatic process. Cancer Res. 1976;  https://doi.org/10.1097/INF.0b013e31818ec288.
  11. 11.
    Virchow R. Cellular pathology. As based upon physiological and pathological histology. Philadelphia: J B Lippincott; 1863.  https://doi.org/10.5962/bhl.title.32770.CrossRefGoogle Scholar
  12. 12.
    Coman DR, Delong RP, McCutcheon M. Studies on the mechanisms of metastasis. The distribution of tumors in various organs in relation to the distribution of arterial emboli. Cancer Res. 1951;11(8):648–51.PubMedGoogle Scholar
  13. 13.
    Zeidman I. Metastasis: a review of recent advances. Cancer Res. 1957;17(3):157–62.PubMedGoogle Scholar
  14. 14.
    Watanabe S. The metastasizability of tumor cells. Cancer. 1954;7(2):215–23.  https://doi.org/10.1002/1097-0142(195403)7:2<215::aid-cncr2820070203>3.0.co;2-6.PubMedCrossRefGoogle Scholar
  15. 15.
    Fidler IJ. The relationship of embolic homogeneity, number, size and viability to the incidence of experimental metastasis. Eur J Cancer. 1973;  https://doi.org/10.1016/S0014-2964(73)80022-2.
  16. 16.
    Thompson SC. The colony forming efficiency of single cells and cell aggregates from a spontaneous mouse mammary tumour using the lung colony assay. Br J Cancer. 1974;  https://doi.org/10.1038/bjc.1974.201.
  17. 17.
    Liotta LA, Kleinerman J, Saidel GM. Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Res. 1974;34(5):997–1004.PubMedGoogle Scholar
  18. 18.
    Knisely WH, Mahaley MS. Relationship between size and distribution of “spontaneous” metastases and three sizes of intravenously injected particles of VX2 carcinoma. Cancer Res. 1958;18(8 Part 1):900–5.PubMedGoogle Scholar
  19. 19.
    Zeidman I, Buss JM. Transpulmonary passage of tumor cell emboli. Cancer Res. 1952;12(10):731–3.PubMedGoogle Scholar
  20. 20.
    Lione A, Bosmann HB. Quantitative relationship between volume of tumour cell units and their intravascular survival. Br J Cancer. 1978;  https://doi.org/10.1038/bjc.1978.33.
  21. 21.
    Tsoi DT, Rowsell C, McGregor C, Kelly CM, Verma S, Pritchard KI. Disseminated tumor embolism from breast cancer leading to multiorgan failure. J Clin Oncol. 2010;  https://doi.org/10.1200/JCO.2009.25.1009.
  22. 22.
    Peeters DJE, Brouwer A, Van den Eynden GG, Rutten A, Onstenk W, Sieuwerts AM, et al. Circulating tumour cells and lung microvascular tumour cell retention in patients with metastatic breast and cervical cancer. Cancer Lett. 2015;  https://doi.org/10.1016/j.canlet.2014.10.039.
  23. 23.
    Yu M, Stott S, Toner M, Maheswaran S, Haber DA. Circulating tumor cells: approaches to isolation and characterization. J Cell Biol. 2011;192(3):373–82.  https://doi.org/10.1083/jcb.201010021.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Au SH, Edd J, Haber DA, Maheswaran S, Stott SL, Toner M. Clusters of circulating tumor cells: a biophysical and technological perspective. Curr Opin Biomed Eng. 2017;3:13–9.  https://doi.org/10.1016/j.cobme.2017.08.001.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;  https://doi.org/10.1126/science.959840.
  26. 26.
    Poste G, Fidler IJ. The pathogenesis of cancer metastasis. Nature. 1980;283(5743):139–46.  https://doi.org/10.1038/283139a0.PubMedCrossRefGoogle Scholar
  27. 27.
    Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3(6):453–8.  https://doi.org/10.1038/nrc1098.CrossRefGoogle Scholar
  28. 28.
    Molnar B, Ladanyi A, Tanko L, Sreter L, Tulassay Z. Circulating tumor cell clusters in the peripheral blood of colorectal cancer patients. Clin Cancer Res. 2001;7(12):4080–5.PubMedGoogle Scholar
  29. 29.
    Brandt B, Roetger A, Heidl S, Jackisch C, Lelle RJ, Assmann G, et al. Isolation of blood-borne epithelium-derived c-erbB-2 oncoprotein-positive clustered cells from the peripheral blood of breast cancer patients. Int J Cancer. 1998;76(6):824–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Hou JM, Krebs M, Ward T, Sloane R, Priest L, Hughes A, et al. Circulating tumor cells as a window on metastasis biology in lung cancer. Am J Pathol. 2011;178(3):989–96.  https://doi.org/10.1016/j.ajpath.2010.12.003.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Kats-Ugurlu G, Roodink I, De Weijert M, Tiemessen D, Maass C, Verrijp K, et al. Circulating tumour tissue fragments in patients with pulmonary metastasis of clear cell renal cell carcinoma. J Pathol. 2009;  https://doi.org/10.1002/path.2613.
  32. 32.
    Vona G, Estepa L, Béroud C, Damotte D, Capron F, Nalpas B, et al. Impact of cytomorphological detection of circulating tumor cells in patients with liver cancer. Hepatology. 2004;  https://doi.org/10.1002/hep.20091.
  33. 33.
    Stott SL, Hsu CH, Tsukrov DI, Yu M, Miyamoto DT, Waltman BA, et al. Isolation of circulating tumor cells using a microvortex-generating herringbone-chip. Proc Natl Acad Sci. 2010;107(43):18392–7.  https://doi.org/10.1073/pnas.1012539107.PubMedCrossRefGoogle Scholar
  34. 34.
    Mascalchi M, Falchini M, Maddau C, Salvianti F, Nistri M, Bertelli E, et al. Prevalence and number of circulating tumour cells and microemboli at diagnosis of advanced NSCLC. J Cancer Res Clin Oncol. 2016;  https://doi.org/10.1007/s00432-015-2021-3.
  35. 35.
    Krebs MG, J-m H, Sloane R, Lancashire L, Priest L, Nonaka D, et al. Analysis of circulating tumor cells in patients with non-small cell lung cancer using epithelial marker-dependent and -independent approaches. J Thorac Oncol. 2012;7(2):306–15.  https://doi.org/10.1097/JTO.0b013e31823c5c16.PubMedCrossRefGoogle Scholar
  36. 36.
    Khoja L, Backen A, Sloane R, Menasce L, Ryder D, Krebs M, et al. A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarker. Br J Cancer. 2012;106(3):508–16.  https://doi.org/10.1038/bjc.2011.545.PubMedCrossRefGoogle Scholar
  37. 37.
    Wendel M, Bazhenova L, Boshuizen R, Kolatkar A, Honnatti M, Cho EH, et al. Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology. Phys Biol. 2012;  https://doi.org/10.1088/1478-3967/9/1/016005.
  38. 38.
    Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013;339:580–4.  https://doi.org/10.1126/science.1228522.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Hosokawa M, Kenmotsu H, Koh Y, Yoshino T, Yoshikawa T, Naito T, et al. Size-based isolation of circulating tumor cells in lung cancer patients using a microcavity array system. PLoS One. 2013;8(6)  https://doi.org/10.1371/journal.pone.0067466.
  40. 40.
    Warkiani ME, Guan G, Luan KB, Lee WC, Bhagat AAS, Kant Chaudhuri P, et al. Slanted spiral microfluidics for the ultra-fast, label-free isolation of circulating tumor cells. Lab Chip. 2014;  https://doi.org/10.1039/c3lc50617g.
  41. 41.
    Harouaka RA, Zhou MD, Yeh YT, Khan WJ, Das A, Liu X, et al. Flexible micro spring array device for high-throughput enrichment of viable circulating tumor cells. Clin Chem. 2014;60(2):323–33.  https://doi.org/10.1373/clinchem.2013.206805.PubMedCrossRefGoogle Scholar
  42. 42.
    Mu Z, Wang C, Ye Z, Austin L, Civan J, Hyslop T, et al. Prospective assessment of the prognostic value of circulating tumor cells and their clusters in patients with advanced-stage breast cancer. Breast Cancer Res Treat. 2015;154(3):563–71.  https://doi.org/10.1007/s10549-015-3636-4.PubMedCrossRefGoogle Scholar
  43. 43.
    Paoletti C, Li Y, Muñiz MC, Kidwell KM, Aung K, Thomas DG, et al. Significance of circulating tumor cells in metastatic triple-negative breast cancer patients within a randomized, phase II trial: TBCRC 019. Clin Cancer Res. 2015;  https://doi.org/10.1158/1078-0432.CCR-14-2781.
  44. 44.
    Sarioglu AF, Aceto N, Kojic N, Donaldson MC, Zeinali M, Hamza B, et al. A microfluidic device for label-free, physical capture of circulating tumor cell clusters. Nat Methods. 2015;12:685–91.  https://doi.org/10.1038/nmeth.3404.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Maddipati R, Stanger BZ. Pancreatic cancer metastases harbor evidence of polyclonality. Cancer Discov. 2015;5(10):1086–97.  https://doi.org/10.1158/2159-8290.CD-15-0120.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Cheung KJ, Padmanaban V, Silvestri V, Schipper K, Cohen JD, Fairchild AN, et al. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters. Proc Natl Acad Sci U S A. 2016;113(7):E854–63.  https://doi.org/10.1073/pnas.1508541113.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Long E, Ilie M, Bence C, Butori C, Selva E, Lalvée S, et al. High expression of TRF2, SOX10, and CD10 in circulating tumor microemboli detected in metastatic melanoma patients. A potential impact for the assessment of disease aggressiveness. Cancer Med. 2016;5:1022–33.  https://doi.org/10.1002/cam4.661.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Chen JY, Tsai WS, Shao HJ, Wu JC, Lai M, Lu SH, et al. Sensitive and specific biomimetic lipid coated microfluidics to isolate viable circulating tumor cells and microemboli for cancer detection. PLoS One. 2016;11(3):e0149633.  https://doi.org/10.1371/journal.pone.0149633.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Kulasinghe A, Tran THP, Blick T, O’Byrne K, Thompson EW, Warkiani ME, et al. Enrichment of circulating head and neck tumour cells using spiral microfluidic technology. Sci Rep. 2017;  https://doi.org/10.1038/srep42517.
  50. 50.
    Wang C, Mu Z, Chervoneva I, Austin L, Ye Z, Rossi G, et al. Longitudinally collected CTCs and CTC-clusters and clinical outcomes of metastatic breast cancer. Breast Cancer Res Treat. 2017;161(1):83–94.  https://doi.org/10.1007/s10549-016-4026-2.PubMedCrossRefGoogle Scholar
  51. 51.
    Jansson S, Bendahl PO, Larsson AM, Aaltonen KE, Rydén L. Prognostic impact of circulating tumor cell apoptosis and clusters in serial blood samples from patients with metastatic breast cancer in a prospective observational cohort. BMC Cancer. 2016;16(1):1–15.  https://doi.org/10.1186/s12885-016-2406-y.CrossRefGoogle Scholar
  52. 52.
    Reddy RM, Murlidhar V, Zhao L, Grabauskiene S, Zhang Z, Ramnath N et al. Basic science: lung cancer Pulmonary venous blood sampling significantly increases the yield of circulating tumor cells in early-stage lung cancer. 2016 March;  https://doi.org/10.1016/j.jtcvs.2015.09.126.
  53. 53.
    Chang MC, Chang YT, Chen JY, Jeng YM, Yang CY, Tien YW, et al. Clinical significance of circulating tumor microemboli as a prognostic marker in patients with pancreatic ductal adenocarcinoma. Clin Chem. 2016;62(3):505–13.  https://doi.org/10.1373/clinchem.2015.248260.PubMedCrossRefGoogle Scholar
  54. 54.
    Zhang D, Zhao L, Zhou P, Ma H, Huang F, Jin M, et al. Circulating tumor microemboli (CTM) and vimentin+ circulating tumor cells (CTCs) detected by a size-based platform predict worse prognosis in advanced colorectal cancer patients during chemotherapy. Cancer Cell Int. 2017;17:6.  https://doi.org/10.1186/s12935-016-0373-7.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Zheng X, Fan L, Zhou P, Ma H, Huang S, Yu D, et al. Detection of circulating tumor cells and circulating tumor microemboli in gastric cancer. Transl Oncol. 2017;10(3):431–41.  https://doi.org/10.1016/j.tranon.2017.02.007.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Lee M, Kim EJ, Cho Y, Kim S, Chung HH, Park NH, et al. Predictive value of circulating tumor cells (CTCs) captured by microfluidic device in patients with epithelial ovarian cancer. Gynecol Oncol. 2017;145(2):361–5.  https://doi.org/10.1016/j.ygyno.2017.02.042.PubMedCrossRefGoogle Scholar
  57. 57.
    Fanelli MF, Oliveira TB, Braun AC, Corassa M, Abdallah EA, Nicolau UR, et al. Evaluation of incidence, significance, and prognostic role of circulating tumor microemboli and transforming growth factor-β receptor I in head and neck cancer. Head Neck. 2017;39(11):2283–92.  https://doi.org/10.1002/hed.24899.PubMedCrossRefGoogle Scholar
  58. 58.
    Hayashi M, Zhu P, McCarty G, Meyer CF, Pratilas CA, Levin A, et al. Size-based detection of sarcoma circulating tumor cells and cell clusters. Oncotarget. 2017;8(45):78965–77.  https://doi.org/10.18632/oncotarget.20697.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Murlidhar V, Reddy RM, Fouladdel S, Zhao L, Ishikawa MK, Grabauskiene S, et al. Poor prognosis indicated by venous circulating tumor cell clusters in early-stage lung cancers. Cancer Res. 2017;77(18):5194–206.  https://doi.org/10.1158/0008-5472.CAN-16-2072.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Xu Y, Qin T, Li J, Wang X, Gao C, Xu C, et al. Detection of circulating tumor cells using negative enrichment immunofluorescence and an in situ hybridization system in pancreatic cancer. Int J Mol Sci. 2017;18(4)  https://doi.org/10.3390/ijms18040622.
  61. 61.
    Gkountela S, Castro-Giner F, Szczerba BM, Vetter M, Landin J, Scherrer R, et al. Circulating tumor cell clustering shapes DNA methylation to enable metastasis seeding. Cell. 2019;176(1–2):98–112.e14.  https://doi.org/10.1016/j.cell.2018.11.046.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Krol I, Castro-Giner F, Maurer M, Gkountela S, Szczerba BM, Scherrer R, et al. Detection of circulating tumour cell clusters in human glioblastoma. Br J Cancer. 2018;114(4):487–91.  https://doi.org/10.1038/s41416-018-0186-7.CrossRefGoogle Scholar
  63. 63.
    Liu X, Taftaf R, Kawaguchi M, Chang YF, Chen W, Entenberg D, et al. Homophilic CD44 interactions mediate tumor cell aggregation and polyclonal metastasis in patient-derived breast cancer models. Cancer Discov. 2019;9(1):96–113.  https://doi.org/10.1158/2159-8290.CD-18-0065.PubMedCrossRefGoogle Scholar
  64. 64.
    Kulasinghe A, Zhou J, Kenny L, Papautsky I, Punyadeera C. Capture of circulating tumour cell clusters using straight microfluidic chips. Cancers. 2019;  https://doi.org/10.3390/cancers11010089.
  65. 65.
    Abdallah EA, Braun AC, Flores BCTCP, Senda L, Urvanegia AC, Calsavara V, et al. The potential clinical implications of circulating tumor cells and circulating tumor microemboli in gastric cancer. Oncologist. 2019;  https://doi.org/10.1634/theoncologist.2018-0741.
  66. 66.
    McFadden DG, Papagiannakopoulos T, Taylor-Weiner A, Stewart C, Carter SL, Cibulskis K, et al. Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing. Cell. 2014;  https://doi.org/10.1016/j.cell.2014.02.031.
  67. 67.
    Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JMC, Papaemmanuil E, et al. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015;520(7547):353–7.  https://doi.org/10.1038/nature14347.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Marusyk A, Tabassum DP, Altrock PM, Almendro V, Michor F, Polyak K. Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. Nature. 2014;514(7520):54–8.  https://doi.org/10.1038/nature13556.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Tabassum DP, Polyak K. Tumorigenesis: it takes a village. Nat Rev Cancer. 2015;15(8):473–83.  https://doi.org/10.1038/nrc3971.PubMedCrossRefGoogle Scholar
  70. 70.
    Cleary AS, Leonard TL, Gestl SA, Gunther EJ. Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers. Nature. 2014;  https://doi.org/10.1038/nature13187.
  71. 71.
    Küsters B, Kats G, Roodink I, Verrijp K, Wesseling P, Ruiter DJ, et al. Micronodular transformation as a novel mechanism of VEGF-A-induced metastasis. Oncogene. 2007;  https://doi.org/10.1038/sj.onc.1210360.
  72. 72.
    Hong Y, Fang F, Zhang Q. Circulating tumor cell clusters: what we know and what we expect (review). Int J Oncol. 2016;49(6):2206–16.  https://doi.org/10.3892/ijo.2016.3747.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Glinsky VV, Glinsky GV, Glinskii OV, Huxley VH, Turk JR, Mossine VV, et al. Intravascular metastatic cancer cell homotypic aggregation at the sites of primary attachment to the endothelium. Cancer Res. 2003;63(13):3805–11.Google Scholar
  74. 74.
    Al-Mehdi AB, Tozawa K, Fisher AB, Shientag L, Lee A, Muschel RJ. Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat Med. 2000;6(1):100–2.  https://doi.org/10.1038/71429.PubMedCrossRefGoogle Scholar
  75. 75.
    Giuliano M, Shaikh A, Lo HC, Arpino G, De Placido S, Zhang XH, et al. Perspective on circulating tumor cell clusters: why it takes a village to metastasize. Cancer Res. 2018;78:845–52.PubMedCrossRefGoogle Scholar
  76. 76.
    Haeger A, Krause M, Wolf K, Friedl P. Cell jamming: collective invasion of mesenchymal tumor cells imposed by tissue confinement. Biochim Biophys Acta Gen Subj. 2014;  https://doi.org/10.1016/j.bbagen.2014.03.020.
  77. 77.
    Au SH, Edd J, Stoddard AE, Wong KHK, Fachin F, Maheswaran S, et al. Microfluidic isolation of circulating tumor cell clusters by size and asymmetry. Sci Rep. 2017;7:2433.  https://doi.org/10.1038/s41598-017-01150-3.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Marrinucci D, Bethel K, Kolatkar A, Luttgen MS, Malchiodi M, Baehring F, et al. Fluid biopsy in patients with metastatic prostate, pancreatic and breast cancers. Phys Biol. 2012;9(1):016003.  https://doi.org/10.1088/1478-3975/9/1/016003.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Desitter I, Guerrouahen BS, Benali-Furet N, Wechsler J, Jänne PA, Kuang Y, et al. A new device for rapid isolation by size and characterization of rare circulating tumor cells. Anticancer Res. 2011;31(2):427–41.PubMedGoogle Scholar
  80. 80.
    Larsson AM, Jansson S, Bendahl PO, Levin Tykjaer Jörgensen C, Loman N, Graffman C, et al. Longitudinal enumeration and cluster evaluation of circulating tumor cells improve prognostication for patients with newly diagnosed metastatic breast cancer in a prospective observational trial. Breast Cancer Res. 2018;20(1):48.  https://doi.org/10.1186/s13058-018-0976-0.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Ozkumur E, Shah AM, Ciciliano JC, Emmink BL, Miyamoto DT, Brachtel E, et al. Inertial focusing for tumor antigen-dependent and -independent sorting of rare circulating tumor cells. Sci Transl Med. 2013;5(179):179–47.  https://doi.org/10.1126/scitranslmed.3005616.CrossRefGoogle Scholar
  82. 82.
    Karabacak NM, Spuhler PS, Fachin F, Lim EJ, Pai V, Ozkumur E, et al. Microfluidic, marker-free isolation of circulating tumor cells from blood samples. Nat Protoc. 2014;9(3):694–710.  https://doi.org/10.1038/nprot.2014.044.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Friedlander TW, Ngo VT, Dong H, Premasekharan G, Weinberg V, Doty S, et al. Detection and characterization of invasive circulating tumor cells derived from men with metastatic castration-resistant prostate cancer. Int J Cancer. 2014;134(10):2284–93.  https://doi.org/10.1002/ijc.28561.PubMedCrossRefGoogle Scholar
  84. 84.
    Szczerba BM, Castro-Giner F, Vetter M, Krol I, Gkountela S, Landin J, et al. Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature. 2019;  https://doi.org/10.1038/s41586-019-0915-y.
  85. 85.
    Bhagwat N, Dulmage K, Pletcher CH, Wang L, DeMuth W, Sen M, et al. An integrated flow cytometry-based platform for isolation and molecular characterization of circulating tumor single cells and clusters. Sci Rep. 2018;8(1):5035.  https://doi.org/10.1038/s41598-018-23217-5.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Cheng SB, Xie M, Xu JQ, Wang J, Lv SW, Guo S, et al. High-efficiency capture of individual and cluster of circulating tumor cells by a microchip embedded with three-dimensional poly(dimethylsiloxane) scaffold. Anal Chem. 2016;88(13):6773–80.  https://doi.org/10.1021/acs.analchem.6b01130.PubMedCrossRefGoogle Scholar
  87. 87.
    Cheng SB, Xie M, Chen Y, Xiong J, Liu Y, Chen Z, et al. Three-dimensional scaffold chip with thermosensitive coating for capture and reversible release of individual and cluster of circulating tumor cells. Anal Chem. 2017;89(15):7924–32.  https://doi.org/10.1021/acs.analchem.7b00905.PubMedCrossRefGoogle Scholar
  88. 88.
    Zhou J, Kulasinghe A, Bogseth A, O’Byrne K, Punyadeera C, Papautsky I. Isolation of circulating tumor cells in non-small-cell-lung-cancer patients using a multi-flow microfluidic channel. Microsyst Nanoeng. 2019;5:8.  https://doi.org/10.1038/s41378-019-0045-6.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Topal B, Roskams T, Fevery J, Penninckx F. Aggregated colon cancer cells have a higher metastatic efficiency in the liver compared with nonaggregated cells: an experimental study. J Surg Res. 2003;112(1):31–7.  https://doi.org/10.1016/S0022-4804(03)00140-9.PubMedCrossRefGoogle Scholar
  90. 90.
    Fidler IJ, Talmadge JE. Evidence that intravenously derived murine pulmonary melanoma metastases can originate from the expansion of a single tumor cell. Cancer Res. 1986;  https://doi.org/10.1158/0008-5472.CAN-09-0167.Glioma.
  91. 91.
    Chen JF, Ho H, Lichterman J, Lu YT, Zhang Y, Garcia MA, et al. Subclassification of prostate cancer circulating tumor cells by nuclear size reveals very small nuclear circulating tumor cells in patients with visceral metastases. Cancer. 2015;121(18):3240–51.  https://doi.org/10.1002/cncr.29455.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    de Wit S, van Dalum G, Lenferink ATM, Tibbe AGJ, Hiltermann TJN, Groen HJM, et al. The detection of EpCAM+ and EpCAM– circulating tumor cells. Sci Rep. 2015;5(1):12270.  https://doi.org/10.1038/srep12270.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Bulfoni M, Turetta M, Del Ben F, Di Loreto C, Beltrami AP, Cesselli D. Dissecting the heterogeneity of circulating tumor cells in metastatic breast cancer: going far beyond the needle in the haystack. Int J Mol Sci. 2016;17(10):1–25.  https://doi.org/10.3390/ijms17101775.CrossRefGoogle Scholar
  94. 94.
    Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015;  https://doi.org/10.1038/nature16064.
  95. 95.
    Fabisiewicz A, Grzybowska E. CTC clusters in cancer progression and metastasis. Med Oncol. 2017;34(1):1–10.  https://doi.org/10.1007/s12032-016-0875-0.CrossRefGoogle Scholar
  96. 96.
    Yao X, Choudhury AD, Yamanaka YJ, Adalsteinsson VA, Gierahn TM, Williamson CA, et al. Functional analysis of single cells identifies a rare subset of circulating tumor cells with malignant traits. Integr Biol (United Kingdom). 2014;  https://doi.org/10.1039/c3ib40264a.
  97. 97.
    Paoli P, Giannoni E, Chiarugi P. Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta. 2013;1833(12):3481–98.PubMedCrossRefGoogle Scholar
  98. 98.
    Zhao Q, Barclay M, Hilkens J, Guo X, Barrow H, Rhodes JM, et al. Interaction between circulating galectin-3 and cancer-associated MUC1 enhances tumour cell homotypic aggregation and prevents anoikis. Mol Cancer. 2010;9:1–12.  https://doi.org/10.1186/1476-4598-9-154.CrossRefGoogle Scholar
  99. 99.
    Micalizzi DS, Maheswaran S, Haber DA. A conduit to metastasis: circulating tumor cell biology. Genes Dev. 2017;31(18):1827–40.  https://doi.org/10.1101/gad.305805.117.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Aceto N, Toner M, Maheswaran S, Haber DA. En route to metastasis: circulating tumor cell clusters and epithelial-to-mesenchymal transition. Trends Cancer. 2015;1(1):44–52.  https://doi.org/10.1016/j.trecan.2015.07.006.PubMedCrossRefGoogle Scholar
  101. 101.
    Dasgupta A, Lim AR, Ghajar CM. Circulating and disseminated tumor cells: harbingers or initiators of metastasis? Mol Oncol. 2017;11(1):40–61.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Sharma D, Brummel-Ziedins KE, Bouchard BA, Holmes CE. Platelets in tumor progression: a host factor that offers multiple potential targets in the treatment of cancer. J Cell Physiol. 2014;229(8):1005–15.  https://doi.org/10.1002/jcp.24539.PubMedCrossRefGoogle Scholar
  103. 103.
    Olivier De W, Mieke Van B, Marc M, An H, Marc B. Carcinoma-associated fibroblasts provide operational flexibility in metastasis. Semin Cancer Biol. 2014;25:33–46.  https://doi.org/10.1016/j.semcancer.2013.12.009.CrossRefGoogle Scholar
  104. 104.
    Duda DG, Duyverman AMMJ, Kohno M, Snuderl M, Steller EJA, Fukumura D, et al. Malignant cells facilitate lung metastasis by bringing their own soil. Proc Natl Acad Sci U S A. 2010;107(50):21677–82.  https://doi.org/10.1073/pnas.1016234107.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351(8):781–91.  https://doi.org/10.1056/NEJMoa040766.PubMedCrossRefGoogle Scholar
  106. 106.
    Bidard FC, Peeters DJ, Fehm T, Nolé F, Gisbert-Criado R, Mavroudis D, et al. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol. 2014;  https://doi.org/10.1016/S1470-2045(14)70069-5.
  107. 107.
    Zhang L, Riethdorf S, Wu G, Wang T, Yang K, Peng G, et al. Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin Cancer Res. 2012;  https://doi.org/10.1158/1078-0432.CCR-12-1587.
  108. 108.
    Choi JW, Kim JK, Yang YJ, Kim P, Yoon KH, Yun SH. Urokinase exerts antimetastatic effects by dissociating clusters of circulating tumor cells. Cancer Res. 2015;75(21):4474–82.  https://doi.org/10.1158/0008-5472.CAN-15-0684.PubMedCrossRefGoogle Scholar
  109. 109.
    Mirshahi S, Pujade-Lauraine E, Soria C, Pocard M, Mirshahi M, Soria J. Urokinase antimetastatic effects-letter. Cancer Res. 2016;76(16):4909.  https://doi.org/10.1158/0008-5472.CAN-16-0138.PubMedCrossRefGoogle Scholar
  110. 110.
    Bithi SS, Vanapalli SA. Microfluidic cell isolation technology for drug testing of single tumor cells and their clusters. Sci Rep. 2017;7:41707.  https://doi.org/10.1038/srep41707.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Cheung KJ, Ewald AJ. A collective route to metastasis: seeding by tumor cell clusters. Science (New York, NY). 2016;352:167–9.  https://doi.org/10.1126/science.aaf6546.CrossRefGoogle Scholar
  112. 112.
    Balakrishnan A, Koppaka D, Anand A, Deb B, Grenci G, Viasnoff V, et al. Circulating tumor cell cluster phenotype allows monitoring response to treatment and predicts survival. Sci Rep. 2019;9(1):7933.  https://doi.org/10.1038/s41598-019-44404-y.PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Roche-Chus Joint Unit, Translational Medical Oncology Group (Oncomet)Health Research Institute of Santiago de CompostelaSantiago de CompostelaSpain
  2. 2.Translational Medical Oncology Group (Oncomet)Health Research Institute of Santiago de Compostela, University Clinical Hospital of Santiago de Compostela (CHUS/SERGAS)Santiago de CompostelaSpain
  3. 3.Centro de Investigación Biomédica en Red Cáncer (CIBERONC)MadridSpain

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