CIRCULATING TUMOR CELLS: CLINICAL SIGNIFICANCE IN BREAST CANCER (REVIEW)

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Abstract

Circulating tumor cells (CTCs) constitute a heterogeneous population. Some tumor cells are cancer stem cells (CSCs), while others are in the process of the epithelial-mesenchymal transition (EMT); however, most CTCs are neither stem cells nor participants in the EMT. There is increasing interest in the study of the molecular biological characteristics of CTCs. Many researchers consider circulating tumor cells (CTC) as one of the variants of «liquid biopsy in real time». In this review, we discuss the clinical significance of CTCs in breast cancer and in particular the prognostic and predictive significance both in early stage and metastatic breast cancer, as well as the pathogenetic role of CTCs in venous thromboembolism. Evaluation of various characteristics of CTCs is promising for the study of new biomarkers and targets for targeted therapies. The clinical importance involves the determination of the heterogeneity of the CТC and in particular of the stem subpopulation of these cells, cells with signs of EMТ, with no evidence of stem cells, and with a combination of these features.

About the authors

E. V. Kaigorodova

Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Siberian State Medical University

Author for correspondence.
Email: zlobinae@mail.ru
ORCID iD: 0000-0003-4378-6915
Доктор медицинских наук, ведущий научный сотрудник отделения патологической анатомии и цитологии Томского НИИ онкологии; профессор кафедры биохимии и молекулярной биологии с курсом клинической лабораторной диагностики ГОУ ВПО СибГМУ Russian Federation

References

  1. Theodoropoulos PA, Polioudaki H, Agelaki S, et al. Circulating tumor cells with a putative stem cell phenotype in peripheral blood of patients with breast cancer. Cancer Lett. 2010;288(1):99–106. doi: 10.1016/j.canlet.2009.06.027.
  2. Scatena R, Bottoni P, Giardina B. Circulating tumour cells and cancer stem cells: a role for proteomics in defining the interrelationships between function, phenotype and differentiation with potential clinical applications. Biochim Biophys Acta. 2013;1835(2):129–143. doi: 10.1016/j.bbcan.2012.12.002.
  3. Kaigorodova EV, Tarabanovskaya NA, Staheeva MN, et al. Effect of small and radical surgical injury on the level of different populations of circulating tumor cells in the blood of breast cancer patients. Neoplasma. 2017;64(3):437–443. doi: 10.4149/neo_2017_315.
  4. Hermann PC, Huber SL, Herrler T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1(3):313–323. doi: 10.1016/j.stem.2007.06.002.
  5. Oskarsson T, Batlle E, Massague J. Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell. 2014;14(3):306–321. doi: 10.1016/j.stem.2014.02.002.
  6. Liao WT, Ye YP, Deng YJ, et al. Metastatic cancer stem cells: from the concept to therapeutics. Am J Stem Cells. 2014;3(2):46–62.
  7. Aktas B, Tewes M, Fehm T, et al. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res. 2009;11(4):R46. doi: 10.1186/bcr2333.
  8. Kasimir-Bauer S, Hoffmann O, Wallwiener D, et al. Expression of stem cell and epithelial-mesenchymal transition markers in primary breast cancer patients with circulating tumor cells. Breast Cancer Res. 2012;14(1):R15. doi: 10.1186/bcr3099.
  9. Chekhun SV, Zadvorny TV, Tymovska YO, et al. CD44+/CD24- markers of cancer stem cells in patients with breast cancer of different molecular subtypes. Exp Oncol. 2015;37(1):58–63.
  10. Balic M, Lin H, Young L, et al. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res. 2006;12(19):5615–5621. doi: 10.1158/1078-0432.Ccr-06-0169.
  11. Reuben JM, Lee BN, Gao H, et al. Primary breast cancer patients with high risk clinicopathologic features have high percentages of bone marrow epithelial cells with ALDH activity and CD44(+)CD24(lo) cancer stem cell phenotype. Eur J Cancer. 2011;47(10):1527–1536. doi: 10.1016/j.ejca.2011.01.011.
  12. Abraham BK, Fritz P, McClellan M, et al. Prevalence of CD44(+)/CD24(-/low) cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin Cancer Res. 2005;11(3):1154-1159.
  13. Mego M, Gao H, Lee BN, et al. Prognostic value of EMT-circulating tumor cells in metastatic breast cancer patients undergoing high-dose chemotherapy with autologous hematopoietic stem cell transplantation. J Cancer. 2012;3:369–380. doi: 10.7150/jca.5111.
  14. Kallergi G, Papadaki MA, Politaki E, et al. Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients. Breast Cancer Res. 2011;13(3):R59. doi: 10.1186/bcr2896.
  15. Raimondi C, Gradilone A, Naso G, et al. Epithelial-mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. Breast Cancer Res Treat. 2011;130(2):449–455. doi: 10.1007/s10549-011-1373-x.
  16. Liu F, Gu LN, Shan BE, et al. Biomarkers for EMT and MET in breast cancer: an update. Oncol Lett. 2016;12(6):4869–4876. doi: 10.3892/ol.2016.5369.
  17. Barriere G, Tartary M, Rigaud M. Epithelial mesenchymal transition: a new insight into the detection of circulating tumor cells. ISRN Oncol. 2012;2012:382010. doi: 10.5402/2012/382010.
  18. Armstrong AJ, Marengo MS, Oltean S, et al. Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Mol Cancer Res. 2011;9(8):997–1007. doi: 10.1158/1541-7786.MCR-10-0490.
  19. Chen K, Huang YH, Chen JL. Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol Sin. 2013;34(6):732–740. doi: 10.1038/aps.2013.27.
  20. Thiery JP, Acloque H, Huang RYJ, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–890. doi: 10.1016/j.cell.2009.11.007.
  21. Senbanjo LT, Chellaiah MA. CD44: a multifunctional cell surface adhesion receptor is a regulator of progression and metastasis of cancer cells. Front Cell Dev Biol. 2017;5:18. doi: 10.3389/fcell.2017.00018.
  22. Broersen LH, van Pelt GW, Tollenaar RA, Mesker WE. Clinical application of circulating tumor cells in breast cancer. Cell Oncol (Dordr). 2014;37(1):9–15. doi: 10.1007/s13402-013-0160-6.
  23. Bonnomet A, Syne L, Brysse A, et al. A dynamic in vivo model of epithelial-to-mesenchymal transitions in circulating tumor cells and metastases of breast cancer. Oncogene. 2012;31(33):3741–3753. doi: 10.1038/onc.2011.540.
  24. Alix-Panabieres C, Pantel K. Circulating tumor cells: liquid biopsy of cancer. Clin Chem. 2013;59(1):110–118. doi: 10.1373/clinchem.2012.194258.
  25. Gorges TM, Tinhofer I, Drosch M, et al. Circulating tumour cells escape from EpCAM-based detection due to epithelial-to-mesenchymal transition. BMC Cancer. 2012;12:178. doi: 10.1186/1471-2407-12-178.
  26. Thompson EW, Haviv I. The social aspects of EMT-MET plasticity. Nat Med. 2011;17(9):1048–1049. doi: 10.1038/nm.2437.
  27. Wang KH, Kao AP, Lin TC, et al. Promotion of epithelial-mesenchymal transition and tumor growth by 17 beta-estradiol in an ER+/HER2(+) cell line derived from human breast epithelial stem cells. Biotechnol Appl Biochem. 2012;59(3):262–267. doi: 10.1002/bab.1022.
  28. Bhat-Nakshatri P, Goswami CP, Badve S, et al. Identification of FDA-approved drugs targeting breast cancer stem cells along with biomarkers of sensitivity. Sci Rep. 2013;3:2530. doi: 10.1038/srep02530.
  29. Klefstrom J, Morel A-P, Lièvre M, et al. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One. 2008;3(8):e2888. doi: 10.1371/journal.pone.0002888.
  30. Creighton CJ, Li XX, Landis M, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci U S A. 2009;106(33):13820–13825. doi: 10.1073/pnas.0905718106.
  31. Yamashita N, Tokunaga E, Kitao H, et al. Vimentin as a poor prognostic factor for triple-negative breast cancer. J Cancer Res Clin Oncol. 2013;139(5):739–746. doi: 10.1007/s00432-013-1376-6.
  32. Mani SA, Guo W, Liao MJ, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133(4):704–715. doi: 10.1016/j.cell.2008.03.027.
  33. Asiedu MK, Ingle JN, Behrens MD, et al. TGFbeta/TNF(alpha)-mediated epithelial-mesenchymal transition generates breast cancer stem cells with a claudin-low phenotype. Cancer Res. 2011;71(13):4707–4719. doi: 10.1158/0008-5472.CAN-10-4554.
  34. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. doi: 10.1016/j.cell.2011.02.013.
  35. Schindlbeck C, Andergassen U, Hofmann S, et al. Comparison of circulating tumor cells (CTC) in peripheral blood and disseminated tumor cells in the bone marrow (DTC-BM) of breast cancer patients. J Cancer Res Clin Oncol. 2013;139(6):1055–1062. doi: 10.1007/s00432-013-1418-0.
  36. Bidard FC, Proudhon C, Pierga JY. Circulating tumor cells in breast cancer. Mol Oncol. 2016;10(3):418–430. doi: 10.1016/j.molonc.2016.01.001.
  37. Uhr JW, Pantel K. Controversies in clinical cancer dormancy. Proc Natl Acad Sci U S A. 2011;108(30):12396–12400. doi: 10.1073/pnas.1106613108.
  38. Kim MY, Oskarsson T, Acharyya S, et al. Tumor self-seeding by circulating cancer cells. Cell. 2009;139(7):1315–1326. doi: 10.1016/j.cell.2009.11.025.
  39. Blanco MJ, Moreno-Bueno G, Sarrio D, et al. Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene. 2002;21(20):3241–3246. doi: 10.1038/sj.onc.1205416.
  40. Bock C, Rack B, Huober J, et al. Distinct expression of cytokeratin, N-cadherin and CD133 in circulating tumor cells of metastatic breast cancer patients. Future Oncol. 2014;10(10):1751–1765. doi: 10.2217/fon.14.58.
  41. Bednarz-Knoll N, Alix-Panabieres C, Pantel K. Plasticity of disseminating cancer cells in patients with epithelial malignancies. Cancer Metastasis Rev. 2012;31(3−4):673–687. doi: 10.1007/s10555-012-9370-z.
  42. Yang MH, Imrali A, Heeschen C. Circulating cancer stem cells: the importance to select. Chin J Cancer Res. 2015;27(5):437–449. doi: 10.3978/j.issn.1000-9604.2015.04.08.
  43. Hall C, Karhade M, Laubacher B, et al. Circulating tumor cells after neoadjuvant chemotherapy in stage I-III triple-negative breast cancer. Ann Surg Oncol. 2015;22 Suppl 3:552–558. doi: 10.1245/s10434-015-4600-6.
  44. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351(8):781–791. doi: 10.1056/NEJMoa040766.
  45. Pierga JY, Petit T, Lévy C, et al. Pathological response and circulating tumor cell count identifies treated HER2+ inflammatory breast cancer patients with excellent prognosis: BEVERLY-2 survival data. Clin Cancer Res. 2015;21(6):1298–1304. doi: 10.1158/1078-0432.CCR-14-1705.
  46. Dawood S, Broglio K, Valero V, et al. Circulating tumor cells in metastatic breast cancer: from prognostic stratification to modification of the staging system? Cancer. 2008;113(9):2422–2430. doi: 10.1002/cncr.23852.
  47. Bidard FC, Belin L, Delaloge S, et al. Time-dependent prognostic impact of circulating tumor cells detection in non-metastatic breast cancer: 70-month analysis of the REMAGUS02 study. Int J Breast Cancer. 2013;2013:130470. doi: 10.1155/2013/130470.
  48. Wallwiener M, Hartkopf AD, Baccelli I, et al. The prognostic impact of circulating tumor cells in subtypes of metastatic breast cancer. Breast Cancer Res Treat. 2013;137(2):503–510. doi: 10.1007/s10549-012-2382-0.
  49. Hall CS, Karhade M, Laubacher BA, et al. Circulating tumor cells and recurrence after primary systemic therapy in stage III inflammatory breast cancer. J Natl Cancer Inst. 2015;107(11):djv250. doi: 10.1093/jnci/djv250.
  50. Giordano A, Egleston BL, Hajage D, et al. Establishment and validation of circulating tumor cell-based prognostic nomograms in first-line metastatic breast cancer patients. Clin Cancer Res. 2013;19(6):1596–1602. doi: 10.1158/1078-0432.CCR-12-3137.
  51. Horiguchi J, Takata D, Rokutanda N, et al. Change of circulating tumor cells before and after neoadjuvant chemotherapy in patients with primary breast cancer. Cancer Res. 2012;72(24 Suppl):P3-06-29. doi: 10.1158/0008-5472.SABCS12-P3-06-29.
  52. Бжадуг О.Б., Тюляндин С.А., Гривцова Л.Ю., и др. Клиническое значение определения циркулирующих опухолевых клеток в крови больных распространенным раком молочной железы // Иммунология гемопоэза. — 2007. — №2 — С. 72–101. [Bzhadug OB, Tyulyandin SA, Grivtsova LYu, et al. Die klinische bedeutung derbestimmung von den zierkulierendentumorzellen bei den patienten mit demdisseminierten mammakarzinom. Immunologiya gemopoeza. 2007;(2):72–101. (In Russ).]
  53. Mego M, Giordano A, De Giorgi U, et al. Circulating tumor cells in newly diagnosed inflammatory breast cancer. Breast Cancer Res. 2015;17:2. doi: 10.1186/s13058-014-0507-6.
  54. Sandri MT, Zorzino L, Cassatella MC, et al. Changes in circulating tumor cell detection in patients with localized breast cancer before and after surgery. Ann Surg Oncol. 2010;17(6):1539–1545. doi: 10.1245/s10434-010-0918-2.
  55. Lucci A, Hall CS, Lodhi AK, et al. Circulating tumour cells in non-metastatic breast cancer: a prospective study. Lancet Oncol. 2012;13(7):688–695 doi: 10.1016/S1470-2045(12)70209-7.
  56. Pachmann K, Camara O, Kavallaris A, et al. Monitoring the response of circulating epithelial tumor cells to adjuvant chemotherapy in breast cancer allows detection of patients at risk of early relapse. J Clin Oncol. 2008;26(8):1208–1215. doi: 10.1200/JCO.2007.13.6523.
  57. Fischer JC, Niederacher D, Topp SA, et al. Diagnostic leukapheresis enables reliable detection of circulating tumor cells of nonmetastatic cancer patients. Proc Natl Acad Sci U S A. 2013;110(41):16580–16585. doi: 10.1073/pnas.1313594110.
  58. Bidard FC, Mathiot C, Delaloge S, et al. Single circulating tumor cell detection and overall survival in nonmetastatic breast cancer. Ann Oncol. 2010;21(4):729–733. doi: 10.1093/annonc/mdp391.
  59. Pierga JY, Bidard FC, Mathiot C, et al. Circulating tumor cell detection predicts early metastatic relapse after neoadjuvant chemotherapy in large operable and locally advanced breast cancer in a phase II randomized trial. Clin Cancer Res. 2008;14(21):7004–7010. doi: 10.1158/1078-0432.CCR-08-0030.
  60. Onstenk W, Kraan J, Mostert B, et al. Improved circulating tumor cell detection by a combined EpCAM and MCAM CellSearch enrichment approach in patients with breast cancer undergoing neoadjuvant chemotherapy. Mol Cancer Ther. 2015;14(3):821–827. doi: 10.1158/1535-7163.MCT-14-0653.
  61. Rack B, Schindlbeck C, Jückstock J, et al. Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst. 2014;106(5):dju066. doi: 10.1093/jnci/dju066.
  62. Liu MC, Shields PG, Warren RD, et al. Circulating tumor cells: a useful predictor of treatment efficacy in metastatic breast cancer. J Clin Oncol. 2009;27(31):5153–5159. doi: 10.1200/JCO.2008.20.6664.
  63. Giuliano M, Giordano A, Jackson S, et al. Circulating tumor cells as prognostic and predictive markers in metastatic breast cancer patients receiving first-line systemic treatment. Breast Cancer Res. 2011;13(3):R67. doi: 10.1186/bcr2907.
  64. Ansieau S. EMT in breast cancer stem cell generation. Cancer Lett. 2013;338(1):63–68. doi: 10.1016/j.canlet.2012.05.014.
  65. Dave B, Mittal V, Tan NM, Chang JC. Epithelial-mesenchymal transition, cancer stem cells and treatment resistance. Breast Cancer Res. 2012;14(1):202. doi: 10.1186/bcr2938.
  66. Zhang L, Ridgway LD, Wetzel MD, et al. The identification and characterization of breast cancer CTCs competent for brain metastasis. Sci Transl Med. 2013;5(180):180ra48. doi: 10.1126/scitranslmed.3005109.
  67. Baccelli I, Schneeweiss A, Riethdorf S, et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol. 2013;31(6):539–544. doi: 10.1038/nbt.2576.
  68. Yu M, Bardia A, Wittner BS, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013;339(6119):580–584. doi: 10.1126/science.1228522.
  69. Khoury JD, Adcock DM, Chan F, et al. Increases in quantitative D-dimer levels correlate with progressive disease better than circulating tumor cell counts in patients with refractory prostate cancer. Am J Clin Pathol. 2010;134(6):964–969. doi: 10.1309/AJCPH92SXYLIKKTS.
  70. Zhong YC, Zhang T, Di W, Li WP. Thrombin promotes epithelial ovarian cancer cell invasion by inducing epithelial-mesenchymal transition. J Gynecol Oncol. 2013;24(3):265–272. doi: 10.3802/jgo.2013.24.3.265.
  71. Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nat Rev Cancer. 2011;11(2):123–134. doi: 10.1038/nrc3004.
  72. Palumbo JS, Talmage KE, Massari JV, et al. Tumor cell-associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-dependent and-independent mechanisms. Blood. 2007;110(1):133–141. doi: 10.1182/blood-2007-01-065995.
  73. Defeo K, Hayes C, Chernick M, Ryn JV, Gilmour SK. Use of dabigatran etexilate to reduce breast cancer progression. Cancer Biol Ther. 2010;10(10):1001–1008. doi: 10.4161/cbt.10.10.13236.
  74. Hong H, Zhang Y, Nayak TR, et al. Immuno-PET of tissue factor in pancreatic cancer. J Nucl Med. 2012;53(11):1748–1754. doi: 10.2967/jnumed.112.105460.
  75. Lustberg MB, Balasubramanian P, Miller B, et al. Heterogeneous atypical cell populations are present in blood of metastatic breast cancer patients. Breast Cancer Res. 2014;16(2):R23. doi: 10.1186/bcr3622.

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