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Home Archive 2021 № 4 CIRCULATING TUMOR CELLS: WHERE WE LEFT OFF? I. Kryvoshlyk, L. Skivka
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ISSN 2410-7751 (Print)
ISSN 2410-776X (Online)

Biotechnologia Acta V. 14, No 4, 2021
Р. 5-27, Bibliography 155, English
Universal Decimal Classification: 576.522; 576.523; 576.385.5; 571.27; 616-006


I. Kryvoshlyk, L. Skivka

ESC “Institute of Biology and Medicine” Taras Shevchenko National University of Kyiv, Ukraine

Cancer metastasis and recurrence are the leading causes of cancer-related death. Tumor cells which leave the primary or secondary tumors and shed into the bloodstream are called circulating tumor cells (CTC). These cells are the key drivers of cancer dissemination to surrounding tissues and to distant organs. The use of CTC in clinical practice necessitates the deep insight into their biology, as well as into their role in cancer evasion of immune surveillance, tumor resistance to chemo- radio- and immunotherapies and metastatic dormancy.

Aim. The purpose of the work was to review the current knowledge on the CTC biology, as well as the prospects for their use for the diagnosis and targeted treatment of metastatic disease.

Methods. The work proposed the integrative literature review using MEDLINE, Biological Abstracts and EMBASE databases.

Results. This review summarizes and discusses historical milestones and current data concerning СTС biology, the main stages of their life cycle, their role in metastatic cascade, clinical prospects for their use as markers for the diagnosis and prognostication of the disease course, as well as targets for cancer treatment.

Conclusions. Significant progress in the area of CTC biology and their use in cancer theranostics convincingly proved the attractiveness of these cells as targets for cancer prognosis and therapy. The effective use of liquid biopsy with quantitative and phenotypic characteristics of CTCs is impeded by the imperfection of the methodology for taking biological material and by the lack of reliable markers for assessing the metastatic potential of CTCs of various origins. The variety of mechanisms of tumor cells migration and invasion requires the development of complex therapeutic approaches for anti-metastatic therapy targeting CTCs. Efforts to address these key issues could help developing new and effective cancer treatment strategies.

Key words: circulating tumor cells; circulating tumor microembols; metastasis; epithelial mesenchymal transition; minimal residual disease.

© Palladin Institute of Biochemistry of National Academy of Sciences of Ukraine, 2021

  • References
    • 1. Bettio M., Carvalho R. N., Dimitrova N., Dyba T., Flego M., Giusti F., Martos C., Neamtiu L., Nicholson N., Randi G., Nicholl C. European Commission, Joint Research Centre (JRC), Ispra, Italy. EMJ Oncol. 2019, 7 (1), 48–49. Abstract No AR05.

      2. Siegel R. L., Miller K. D., Jemal A. Cancer statistics, 2020. CA: A Cancer Journal for Clinicians. 2020, 70 (1), 7–30.

      3. Galmarini C. M. Lessons from Hippocrates: Time to Change the Cancer Paradigm. International Journal of Chronic Diseases. 2020, V. 2020, P. 4715426.

      4. LeDran H. F. Mémoire avec un précis de plusieurs observations sur le cancer. Memories de l’academie royale de chirurgie. 1757, V. 3, P. 1–54.

      5. Récamier J. C. Recherchessurletraitement du cancer sur la compression methodique simple ou combinee et sur l'histoire generale de la meme maladie, 2nd ed.1829. Gabon, Paris.

      6. Thiersch K. Der Epithelial krebs, namentlich der Hand. 1865. Engelmann, Leipzig.

      7. Langenbeck B. On the development of cancer in the veins, and the transmission ofcancer from man to the lower animals. Edinb. Med. Surg. J. 1841, 55 (147), 251–253.

      8. Virchow R. Cellular pathologie. Nutr. Rev. 1858, P. 23–25.

      9. Ashworth T. R. A case of cancer in which cells similar to those in the tumors wereseen in the blood after death. Aust. Med. J. 1869, V. 14, P. 146–149.

      10. Engel H. C. Cancer cells in the blood; a five to nine year follow up study. Ann. Surg. 1959, 149 (4), 457–461.

      11. Pantel K., Schlimok G., Braun S., Kutter D., Lindemann F., Schalle, G., Funke I., Izbicki J. R., & Riethmüller G. Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl. Cancer Inst. 1993, 85 (17), 1419–1424.

      12. Pantel K., Izbicki J., Passlick B., Angstwurm M., Häussinger K., Thetter O., Riethmüller G. Frequency and prognostic significance of isolated tumour cells in bone marrow of patients with non-small-cell lung cancer without overt metastases. Lancet. 1996, 347 (9002), 649–653.

      13. Nowell P. C. The clonal evolution of tumor cell populations. Science. 1976, 194 (4260), 23–28.

      14. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl. J. Med. 1971, 285 (21), 1182–1186.

      15. Folkman J., Watson K., Ingber D., Hanahan D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature. 1989, 339 (6219), 58–61.

      16. Liotta L. A., Steeg P. S., Stetler-Stevenson W. G. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell. 1991, 64 (2), 327–336.

      17. Liotta L. A., Kleinerman J., Saidel G. M. Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation. Cancer Res. 1974, 34 (5), 997–1004.

      18. Prasetyanti P. R., Medema J. P. Intra-tumor heterogeneity from a cancer stem cell perspective. Mol. Cancer. 2017, 16 (1), 41.

      19. Albini A., Bruno A., Gallo C., Pajardi G., Noonan D. M., Dallaglio K. Cancer stem cells and the tumor microenvironment: interplay in tumor heterogeneity. Connect. Tissue Res. 2015, 56 (5), 414–425.

      20. Fouad Y. A., Aanei C. Revisiting the hallmarks of cancer. Am. J. Cancer Res. 2017, 7 (5), 1016–1036.

      21. Greenburg G., Hay E. D. Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells. J. Cell Biol. 1982, 95 (1), 333–339.

      22. Jalal S., Shi S., Acharya V., Huang R. Y., Viasnoff V., Bershadsky A. D., Tee Y. H. Actin cytoskeleton self-organization in single epithelial cells and fibroblasts under isotropic confinement. J. Cell Sci. 2019, 132 (5), jcs220780.

      23. Karamanou K., Franchi M., Vynios D., Brézillon S. Epithelial-to-mesenchymal transition and invadopodia markers in breast cancer: Lumican a key regulator. Semin. Cancer Biol. 2020, V. 62, P. 125–133.

      24. Liao T. T., Yang M. H. Hybrid Epithelial/Mesenchymal State in Cancer Metastasis: Clinical Significance and Regulatory Mechanisms. Cells. 2020, 9 (3), 623.

      25. Nersesian S., Williams R., Newsted D., Shah K., Young S., Evans P. A., Allingham J. S., Craig, A. W. Effects of Modulating Actin Dynamics on HER2 Cancer Cell Motility and Metastasis. Sci Rep. 2018, 8 (1), 17243.

      26. Chaffer C. L., San Juan B. P., Lim E., Weinberg R. A. EMT, cell plasticity and metastasis. Cancer Metastasis Rev. 2016, 35 (4), 645–654.

      27. Peixoto P., Etcheverry A., Aubry M., Missey A., Lachat C., Perrard J., Hendrick E., Delage-Mourroux R., Mosser J., Borg C., Feugeas J. P., Herfs M., Boyer-Guittaut M., Hervouet E. EMT is associated with an epigenetic signature of ECM remodeling genes. Cell Death Dis. 2019, 10 (3), 205.

      28. Ridley A. J. Rho GTPase signalling in cell migration. Curr. Opin. Cell Biol. 2015, V. 36, P. 103–112. h

      29. Kazanietz M. G., Caloca M. J. The Rac GTPase in Cancer: From Old Concepts to New Paradigms. Cancer Res. 2017, 77 (20), 5445–5451.

      30. Gonzalez D. M., Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci. Signaling. 2014, 7 (344), re8.

      31. Nieszporek A., Skrzypek K., Adamek G., Majka M. Molecular mechanisms of epithelial to mesenchymal transition in tumor metastasis. Acta Biochim. Pol. 2019, 66 (4), 509–520.

      32. Ribatti D., Tamma R., Annese T. Epithelial-Mesenchymal Transition in Cancer: A Historical Overview. Transl. Oncol. 2020, 13 (6), 100773.

      33. Jolly M. K., Ware K. E., Gilja S., Somarelli J. A., Levine H. EMT and MET: necessary or permissive for metastasis? Mol. Oncol. 2017, 11 (7), 755–769.

      34. Pastushenko I., Brisebarre A., Sifrim A., Fioramonti M., Revenco T., Boumahdi S., Van Keymeulen A., Brown D., Moers V., Lemaire S., De Clercq S., Minguijón E., Balsat C., Sokolow Y., Dubois C., De Cock F., Scozzaro S., Sopena F., Lanas A., D'Haene N., Blanpain C. Identification of the tumour transition states occurring during EMT. Nature. 2018, 556 (7702), 463–468.

      35. Derynck R., Weinberg R. A. EMT and Cancer: More Than Meets the Eye. Dev. Cell. 2019, 49 (3), 313–316.

      36. Claudia Tanja Mierke. Physics of Cancer, Volume 1: Interplay between tumor biology, inflammation and cell mechanics. Published October 2018. Copyright © IOP Publishing Ltd. 2018. CHAPTER 1. Initiation of a neoplasm or tumor.

      37. Kim D. H., Xing T., Yang Z., Dudek R., Lu Q., Chen Y. H. Epithelial Mesenchymal Transition in Embryonic Development, Tissue Repair and Cancer: A Comprehensive Overview. J. Clin. Med. 2017, 7 (1), 1.

      38. Faheem M. M., Seligson N. D., Ahmad S. M., Rasool R. U., Gandhi S. G., Bhagat M., Goswami A. Convergence of therapy-induced senescence (TIS) and EMT in multistep carcinogenesis: current opinions and emerging perspectives. Cell Death. Discov. 2020, V. 6, P. 51.

      39. Jordan N. V., Johnson G. L., Abell A. N. Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer. Cell Cycle. 2011, 10 (17), 2865–2873.

      40. Cao Z., Livas T., Kyprianou N. Anoikis and EMT: Lethal "Liaisons" during Cancer Progression. Crit. Rev. Oncog. 2016, 21 (3–4), 155–168.

      41. Wei C., Yang C., Wang S., Shi D., Zhang C., Lin X., Liu Q., Dou R., Xiong B. Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol. Cancer. 2019, 18 (1), 64.

      42. Yang C., Dou R., Wei C., Liu K., Shi D., Zhang C., Liu Q., Wang S., Xiong B. Tumor-derived exosomal microRNA-106b-5p activates EMT-cancer cell and M2-subtype TAM interaction to facilitate CRC metastasis. Mol. Ther. 2021, 29 (6), 2088–2107.

      43. Cortés M., Sanchez-Moral L., de Barrios O., Fernández-Aceñero M. J., Martínez-Campanario M. C., Esteve-Codina A., Darling D. S., Győrffy B., Lawrence T., Dean D. C., Postigo A. Tumor-associated macrophages (TAMs) depend on ZEB1 for their cancer-promoting roles. EMBO J. 2017, 36 (22), 3336–3355.

      44. Xu R., Won J. Y., Kim C. H., Kim D. E., Yim H. Roles of the Phosphorylation of Transcriptional Factors in Epithelial-Mesenchymal Transition. J. Oncol. 2019, V. 2019, P. 5810465.

      45. Alidadiani N., Ghaderi S., Dilaver N., Bakhshamin S., Bayat M. Epithelial mesenchymal transition Transcription Factor (TF): The structure, function and microRNA feedback loop. Gene. 2018, V. 674, P. 115–120.

      46. Mohammed S. I., Torres-Luquis O., Walls E., Lloyd F. Lymph-circulating tumor cells show distinct properties to blood-circulating tumor cells and are efficient metastatic precursors. Mol. Oncol. 2019, 13 (6), 1400–1418.

      47. Kolostova K., Pospisilova E., Pavlickova V., Bartos R., Sames M., Pawlak I., Bobek V. Next generation sequencing of glioblastoma circulating tumor cells: non-invasive solution for disease monitoring. Am. J. Transl. Res. 2021, 13 (5), 4489–4499.

      48. Kowalik A., Kowalewska M., Góźdź S. Current approaches for avoiding the limitations of circulating tumor cells detection methods-implications for diagnosis and treatment of patients with solid tumors. Transl. Res. 2017, V. 185, P. 58–84.e15.

      49. Christou N., Meyer J., Popeskou S., David V., Toso C., Buchs N., Liot E., Robert J., Ris F., Mathonnet M. Circulating Tumour Cells, Circulating Tumour DNA and Circulating Tumour miRNA in Blood Assays in the Different Steps of Colorectal Cancer Management, a Review of the Evidence in 2019. Biomed. Res. Int. 2019, V. 2019, P. 5953036.

      50. Millner L. M., Linder M. W., Valdes R. Jr. Circulating tumor cells: a review of present methods and the need to identify heterogeneous phenotypes. Ann. Clin. Lab. Sci. 2013, 43 (3), 295–304.

      51. Plaks V., Kong N., Werb Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem. Cell. 2015, 16 (3), 225–238.

      52. Agnoletto C., Corrà F., Minotti L., Baldassari F., Crudele F., Cook W. J. J., Di Leva G., d'Adamo A. P., Gasparini P., Volinia S. Heterogeneity in Circulating Tumor Cells: The Relevance of the Stem-Cell Subset. Cancers (Basel). 2019, 11 (4), 483.

      53. Wang W. C., Zhang X. F., Peng J., Li X. F., Wang A. L., Bie Y. Q., Shi L. H., Lin M. B., Zhang X. F. Survival Mechanisms and Influence Factors of Circulating Tumor Cells. Biomed. Res. Int. 2018, V. 2018, P. 6304701.

      54. Krog B. L., Henry M. D. Biomechanics of the Circulating Tumor Cell Microenvironment. Adv. Exp. Med. Biol. 2018, V. 1092, P. 209–233.

      55. Sprouse M. L., Welte T., Boral D., Liu H. N., Yin W., Vishnoi M., Goswami-Sewell D., Li L., Pei G., Jia P., Glitza-Oliva I. C., Marchetti D. PMN-MDSCs Enhance CTC Metastatic Properties through Reciprocal Interactions via ROS/Notch/Nodal Signaling. Int. J. Mol. Sci. 2019, 20 (8), 1916.

      56. Choi H. Y., Yang G. M., Dayem A. A., Saha S. K., Kim K., Yoo Y., Hong K., Kim J. H., Yee C., Lee K. M., Cho S. G. Hydrodynamic shear stress promotes epithelial-mesenchymal transition by downregulating ERK and GSK3β activities. Breast Cancer Res. 2019, 21 (1), 6.

      57. Dianat-Moghadam H., Azizi M., Eslami-S Z., Cortés-Hernández L. E., Heidarifard M., Nouri M., Alix-Panabières C. The Role of Circulating Tumor Cells in the Metastatic Cascade: Biology, Technical Challenges, and Clinical Relevance. Cancers (Basel). 2020, 12 (4), 86.

      58. Alexandrova A. Y., Chikina A. S., Svitkina T. M. Actin cytoskeleton in mesenchymal-to-amoeboid transition of cancer cells. Int. Rev. Cell. Mol. Biol. 2020, V. 356, P. 197–256.

      59. Wu J. S., Jiang J., Chen B. J., Wang K., Tang Y. L., Liang X. H. Plasticity of cancer cell invasion: Patterns and mechanisms. Transl. oncol. 2021, 14 (1), 100899.

      60. Chen L., Bode A. M., Dong Z. Circulating Tumor Cells: Moving Biological Insights into Detection. Theranostics. 2017, 7 (10), 2606–2619. ttps://

      61. Jones B. C., Kelley L. C., Loskutov Y. V., Marinak K. M., Kozyreva V. K., Smolkin M. B., Pugacheva E. N. Dual Targeting of Mesenchymal and Amoeboid Motility Hinders Metastatic Behavior. Mol. Cancer Res. 2017, 15 (6), 670–682.

      62. Yu M. Metastasis Stemming from Circulating Tumor Cell Clusters. Trends Cell Biol. 2019, 29 (4), 275–276.

      63. Giuliano M., Shaikh A., Lo H. C., Arpino G., De Placido S., Zhang X. H., Cristofanilli M., Schiff R., Trivedi M. V. Perspective on Circulating Tumor Cell Clusters: Why It Takes a Village to Metastasize. Cancer Res. 2018, 78 (4), 845–852.

      64. Aktary Z., Alaee M., Pasdar M. Beyond cell-cell adhesion: Plakoglobin and the regulation of tumorigenesis and metastasis. Oncotarget. 2017, 8 (19), 32270–32291.

      65. Lim S. B., Yeo T., Lee W. D., Bhagat A. A. S., Tan S. J., Tan D. S. W., Lim W. T., Lim C. T. Addressing cellular heterogeneity in tumor and circulation for refined prognostication. Proc. Natl. Acad. Sci. USA. 2019, 116 (36), 17957–17962.

      66. Amintas S., Bedel A., Moreau-Gaudry F., Boutin J., Buscail L., Merlio J. P., Vendrely V., Dabernat S., Buscail E. Circulating Tumor Cell Clusters: United We Stand Divided We Fall. Int. J. Mol. Sci. 2020, 21 (7), 2653.

      67. Castro-Giner F., Aceto N. Tracking cancer progression: from circulating tumor cells to metastasis. Genome Med. 2020, 12 (1), 31.

      68. Mentis A. A., Grivas P. D., Dardiotis E., Romas N. A., Papavassiliou A. G. Circulating tumor cells as Trojan Horse for understanding, preventing, and treating cancer: a critical appraisal. Cell Mol. Life Sci. 2020, 77 (18), 3671–3690.

      69. Micalizzi D. S., Maheswaran S., Haber D. A. A conduit to metastasis: circulating tumor cell biology. Genes. Dev. 2017, 31 (18), 1827–1840.

      70. Anvari S., Osei E., Maftoon N. Interactions of platelets with circulating tumor cells contribute to cancer metastasis. Sci. Rep. 2021, 11 (1), 15477.

      71. Jiang X., Wong K. H. K., Khankhel A. H., Zeinali M., Reategui E., Phillips M. J., Luo X., Aceto N., Fachin F., Hoang A. N., Kim W., Jensen A. E.,. Sequist L. V., Maheswaran S., Haber D. A., Stott S. L., Toner M. Microfluidic isolation of platelet-covered circulating tumor cells. Lab. Chip. 2017, 17 (20), 3498‒3503.

      72. Yang L., Shi P., Zhao G., Xu J., Peng W., Zhang J., Zhang G., Wang X., Dong Z., Chen F., Cui H. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct. Target. Ther. 2020, 5 (1), 8.

      73. Gkountela S., Castro-Giner F., Szczerba B. M., Vetter M., Landin J., Scherrer R., Krol I., Scheidmann M. C., Beisel C., Stirnimann C. U., Kurzeder C., Heinzelmann-Schwarz V., Rochlitz C., Weber W. P., Aceto N. Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding. Cell. 2019, 176 (1‒2), 98‒112.e14.

      74. Lei M. M. L., Lee T. K. W. Cancer Stem Cells: Emerging Key Players in Immune Evasion of Cancers. Front. Cell Dev. Biol. 2021, V. 9, P. 692940.

      75. Nicolini A., Rossi G., Ferrari P., Carpi A. Minimal residual disease in advanced or metastatic solid cancers: The G0-G1 state and immunotherapy are key to unwinding cancer complexity. Semin. Cancer Biol. 2020, S1044-579X(20)30075-4.

      76. Tjensvoll K., Nordgård O., Skjæveland M., Oltedal S., Janssen E. A. M., Gilje B. Detection of disseminated tumor cells in bone marrow predict late recurrences in operable breast cancer patients. BMC Cancer. 2019, 19 (1), 1131.

      77. Risson E., Nobre A. R., Maguer-Satta V., Aguirre-Ghiso J. A. The current paradigm and challenges ahead for the dormancy of disseminated tumor cells. Nat. Cancer. 2020, 1 (7), 672‒680.

      78. Marconato L., Facchinetti A., Zanardello C., Rossi E., Vidotto R., Capello K., Melchiotti E., Laganga P., Zamarchi R., Vascellari M. Detection and Prognostic Relevance of Circulating and Disseminated Tumour Cell in Dogs with Metastatic Mammary Carcinoma: A Pilot Study. Cancers (Basel). 2019, 11 (2), 163.

      79. O'Sullivan B., Brierley J., Byrd D., Bosman F., Kehoe S., Kossary C., Piñeros M., Van Eycken E., Weir H. K., Gospodarowicz M. The TNM classification of malignant tumours-towards common understanding and reasonable expectations. Lancet Oncol. 2017, 18 (7), 849‒851.

      80. Aguirre-Ghiso J., Sosa M. Emerging Topics on Disseminated Cancer Cell Dormancy and the Paradigm of Metastasis. Ann. Rev. Cancer Biol. 2018, V. 2, Р. 377–393.

      81. Kilickap S., Aktas B. Y., Ozisik Y. Y. (2019) Bone Marrow Micrometastases and Circulating Tumor Cells. In: Aydiner A., Igci A., Soran A. (eds). Breast Disease. Springer, Cham.

      82. Piranlioglu R., Lee E., Ouzounova M., Bollag R. J., Vinyard A. H., Arbab A. S., Marasco D., Guzel M., Cowell J. K., Thangaraju M., Chadli A., Hassan K. A., Wicha M. S., Celis E., Korkaya H. Primary tumor-induced immunity eradicates disseminated tumor cells in syngeneic mouse model. Nat. Commun. 2019, 10 (1), 1430.

      83. Marcuzzi E., Angioni R., Molon B., Calì B. Chemokines and Chemokine Receptors: Orchestrating Tumor Metastasization. Int. J. Mol. Sci. 2019, 20 (1), 96.

      84. Rafii S., Butler J. M., Ding B. S. Angiocrine functions of organ-specific endothelial cells. Nature. 2016, 529 (7586), 316–325.

      85. Rycaj K., Li H., Zhou J., Chen X., Tang D. G. Cellular determinants and microenvironmental regulation of prostate cancer metastasis. Semin. Cancer Biol. 2017, V. 44, P. 83‒97.

      86. Dasgupta A., Lim A. R., Ghajar C. M. Circulating and disseminated tumor cells: harbingers or initiators of metastasis? Mol. Oncol. 2017, 11 (1), 40–61.

      87. Zhang W., Bado I., Wang H., Lo H. C., Zhang X. H. Bone Metastasis: Find Your Niche and Fit in. Trends in Cancer. 2019, 5 (2), 95–110.

      88. Sowder M. E., Johnson R. W. Bone as a Preferential Site for Metastasis. JBMR Plus. 2019, 3 (3), e10126.

      89. Esposito M., Guise T., Kang Y. The Biology of Bone Metastasis. Cold Spring Harb. Perspect. Med. 2018, 8 (6), a031252.

      90. Haider M. T., Smit D. J., Taipaleenmäki H. The Endosteal Niche in Breast Cancer Bone Metastasis. Front. Oncol. 2020, V. 10, P. 335.

      91. Liu C., Zhao Q., Yu X. Bone Marrow Adipocytes, Adipocytokines, and Breast Cancer Cells: Novel Implications in Bone Metastasis of Breast Cancer. Front. Oncol. 2020, V. 10, P. 561595.

      92. Carvalho R., Paredes J., Ribeiro A. S. Impact of breast cancer cells´ secretome on the brain metastatic niche remodeling. Semin. Cancer Biol. 2020, V. 60, P. 294‒301.

      93. Seano G. Targeting the perivascular niche in brain tumors. Curr. Opin. Oncol. 2018, 30 (1), 54–60.

      94. Maru Y. The lung metastatic niche. J. Mol. Med. (Berl). 2015, 93 (11), 1185–1192.

      95. Sharma S. K., Chintala N. K., Vadrevu S. K., Patel J., Karbowniczek M., Markiewski M. M. Pulmonary alveolar macrophages contribute to the premetastatic niche by suppressing antitumor T cell responses in the lungs. J. Immunol. 2015, 194 (11), 5529–5538.

      96. Kai F., Drain A. P., Weaver V. M. The Extracellular Matrix Modulates the Metastatic Journey. Dev. Cell. 2019, 49 (3), 332–346.

      97. Lee Y. C., Kurtova A. V., Xiao J., Nikolos F., Hayashi K., Tramel Z., Jain A., Chen F., Chokshi M., Lee C., Bao G., Zhang X., Shen J., Mo Q., Jung S. Y., Rowley D., Chan K. S. Collagen-rich airway smooth muscle cells are a metastatic niche for tumor colonization in the lung. Nat. Commun. 2019, 10 (1), 2131.

      98. Zhuyan J., Chen M., Zhu T., Bao X., Zhen T., Xing K., Wang Q., Zhu S. Critical steps to tumor metastasis: alterations of tumor microenvironment and extracellular matrix in the formation of pre-metastatic and metastatic niche. Cell Biosci. 2020, V. 10, P. 89.

      99. Ren G., Esposito M., Kang Y. Bone metastasis and the metastatic niche. J. Mol. Med. (Berl). 2015, 93 (11), 1203–1212.

      100. Melzer C., von der Ohe J., Hass R. Breast Carcinoma: From Initial Tumor Cell Detachment to Settlement at Secondary Sites. Biomed. Res. Int. 2017, V. 2017, P. 8534371.

      101. Manjili M. H. Tumor Dormancy and Relapse: From a Natural Byproduct of Evolution to a Disease State. Cancer Res. 2017, 77 (10), 2564–2569.

      102. Meléndez-Rodríguez F., Urrutia A. A., Lorendeau D., Rinaldi G., Roche O., Böğürcü-Seidel N., Ortega Muelas M., Mesa-Ciller C., Turiel G., Bouthelier A., Hernansanz-Agustín P., Elorza A., Escasany E., Li Q., Torres-Capelli M., Tello D., Fuertes E., Fraga E., Martínez-Ruiz A., Pérez B., Aragonés J. HIF1α Suppresses Tumor Cell Proliferation through Inhibition of Aspartate Biosynthesis. Cell Rep. 2019, 26 (9), 2257–2265.e4.

      103. Vinay D. S., Ryan E. P., Pawelec G., Talib W. H., Stagg J., Elkord E., Lichtor T., Decker W. K., Whelan R. L., Kumara H., Signori E., Honoki K., Georgakilas A. G., Amin A., Helferich W. G., Boosani C. S., Guha G., Ciriolo M. R., Chen, S, Mohammed S. I., Kwon B. S. Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Semin. Cancer Biol. 2015, 35 (l), S185–S198.

      104. Pein M., Oskarsson T. Microenvironment in metastasis: roadblocks and supportive niches. Am. J. Physiol. Cell Physiol. 2015, 309 (10), C627–C638.

      105. Pascual G., Avgustinova A., Mejetta S., Martín M., Castellanos A., Attolini C. S., Berenguer A., Prats N., Toll A., Hueto J. A., Bescós C., Di Croce L., Benitah S. A. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature. 2017, 541 (7635), 41–45.

      106. Phan T. G., Croucher P. I. The dormant cancer cell life cycle. Nature Rev. Cancer. 2020, 20 (7), 398–411.

      107. Masucci M. T., Minopoli M., Del Vecchio S., Carriero M. V. The Emerging Role of Neutrophil Extracellular Traps (NETs) in Tumor Progression and Metastasis. Front. Immunol. 2020, V. 11, P. 1749.

      108. Tayoun T., Faugeroux V., Oulhen M., Aberlenc A., Pawlikowska P., Farace F. CTC-Derived Models: A Window into the Seeding Capacity of Circulating Tumor Cells (CTCs). Cells. 2019, 8 (10), 1145.

      109. Kitz J., Lowes L. E., Goodale D., Allan A. L. Circulating Tumor Cell Analysis in Preclinical Mouse Models of Metastasis. Diagnostics (Basel). 2018, 8 (2), 30.

      110. Sobral-Filho R. G., DeVorkin L., Macpherson S., Jirasek A., Lum J. J., Brolo A. G. Ex Vivo Detection of Circulating Tumor Cells from Whole Blood by Direct Nanoparticle Visualization. ACS Nano. 2018, 12 (2), 1902–1909.

      111. Qiao Y., Li J., Shi C., Wang W., Qu X., Xiong M., Sun Y., Li D., Zhao X., Zhang D. Prognostic value of circulating tumor cells in the peripheral blood of patients with esophageal squamous cell carcinoma. OncoTargets and Therapy. 2017, V. 10, P. 1363–1373.

      112. Shen Z., Wu A., Chen X. Current detection technologies for circulating tumor cells. Chemical Society Reviews. 2017, 46 (8), 2038–2056.

      113. Van der Toom E. E., Verdone J. E., Gorin M. A., Pienta K. J. Technical challenges in the isolation and analysis of circulating tumor cells. Oncotarget. 2016, 7 (38), 62754–62766.

      114. Li S., Plouffe B. D., Belov A. M., Ray S., Wang X., Murthy S. K., Karger B. L., Ivanov A. R. An Integrated Platform for Isolation, Processing, and Mass Spectrometry-based Proteomic Profiling of Rare Cells in Whole Blood. MCP. 2015, 14 (6), 1672–1683.

      115. Keller L., Pantel K. Unravelling tumour heterogeneity by single-cell profiling of circulating tumour cells. Nat. Rev. Cancer. 2019, 19 (10), 553–567.

      116. Campos-Carrillo A., Weitzel J. N., Sahoo P., Rockne R., Mokhnatkin J. V., Murtaza M., Gray S. W., Goetz L., Goel A., Schork N., Slavin T. P. Circulating tumor DNA as an early cancer detection tool. Pharmacology & Therapeutics. 2020, V. 207, P. 107458.

      117. Kelley S. O., Pantel K. A. New Era in Liquid Biopsy: From Genotype to Phenotype. Clin. Chem. 2020, 66 (1), 89–96.

      118. Ferreira M. M., Ramani V. C., Jeffrey S. S. Circulating tumor cell technologies. Mol. Oncol. 2016, 10 (3), 374–394.

      119. Cho H., Kim J., Song H., Sohn K. Y., Jeon M., Han K. H. Microfluidic technologies for circulating tumor cell isolation. The Analyst. 2018, 143 (13), 2936–2970.

      120. Sharma S., Zhuang R., Long M., Pavlovic M., Kang Y., Ilyas A., Asghar W. Circulating tumor cell isolation, culture, and downstream molecular analysis. Biotechnology Advances. 2018, 36 (4), 1063–1078.

      121. Guerin M. V., Finisguerra V., Van den Eynde B. J., Bercovici N., Trautmann A. Preclinical murine tumor models: a structural and functional perspective. eLife. 2020, V. 9, e50740.

      122. Kerbel R. S. A Decade of Experience in Developing Preclinical Models of Advanced- or Early-Stage Spontaneous Metastasis to Study Antiangiogenic Drugs, Metronomic Chemotherapy, and the Tumor Microenvironment. Cancer J. 2015, 21 (4), 274–283.

      123. Welch D. R. Technical considerations for studying cancer metastasis in vivo. Clin. Exp. Metastasis. 1997, 15 (3), 272–306.

      124. Goodale D., Phay C., Postenka C. O., Keeney M., Allan A. L. Characterization of tumor cell dissemination patterns in preclinical models of cancer metastasis using flow cytometry and laser scanning cytometry. Cytometry A. 2009, 75 (4), 344–355.

      125. Allan A. L., Vantyghem S. A., Tuck A. B., Chambers A. F., Chin-Yee I. H., Keeney M. Detection and quantification of circulating tumor cells in mouse models of human breast cancer using immunomagnetic enrichment and multiparameter flow cytometry. Cytometry A. 2005, 65 (1), 4–14.

      126. Kersten K., de Visser K. E., van Miltenburg M. H., Jonkers J. Genetically engineered mouse models in oncology research and cancer medicine. EMBO Mol. Med. 2017, 9 (2), 137–153.

      127. Olive K. P., Politi K. Translational therapeutics in genetically engineered mouse models of cancer. Cold Spring Harb. Protoc. 2014, 2014 (2), 131–143.

      128. Hashizume R., Gupta N. Patient-derived Tumor Models for Diffuse Intrinsic Pontine Gliomas. Curr. Neuropharmacol. 2017, 15 (1), 98–103.

      129. Rebecca V. W., Somasundaram R., Herlyn M. Pre-clinical modeling of cutaneous melanoma. Nat. Commun. 2020, 11 (1), 2858.

      130. Lee T. W., Lai A., Harms J. K., Singleton D. C., Dickson B. D., Macann A., Hay M. P., Jamieson S. Patient-Derived Xenograft and Organoid Models for Precision Medicine Targeting of the Tumour Microenvironment in Head and Neck Cancer. Cancers. 2020, 12 (12), 3743.

      131. Lallo A., Schenk M. W., Frese K. K., Blackhall F., Dive C. Circulating tumor cells and CDX models as a tool for preclinical drug development. Transl. Lung Cancer Res. 2017, 6 (4), 397–408.

      132. Tellez-Gabriel M., Cochonneau D., Cadé M., Jubellin C., Heymann M. F., Heymann D. Circulating Tumor Cell-Derived Pre-Clinical Models for Personalized Medicine. Cancers. 2018, 11 (1), 19.

      133. Alimirzaie S., Bagherzadeh M., Akbari M. R. Liquid biopsy in breast cancer: A comprehensive review. Clin. Genet. 2019, 95 (6), 643–660.

      134. Schwarzenbach H., Hoon D. S., Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat. Rev.  Cancer. 2011, 11 (6), 426–437.

      135. Schwarzenbach H., Nishida N., Calin G. A., Pantel K. Clinical relevance of circulating cell-free microRNAs in cancer. Nat. Rev. Clin. Ooncol. 2014, 11 (3), 145–156.

      136. Pardini B., Sabo A. A., Birolo G., Calin G. A. Noncoding RNAs in Extracellular Fluids as Cancer Biomarkers: The New Frontier of Liquid Biopsies. Cancers. 2019, 11 (8), 1170.

      137. Eslami-S Z., Cortés-Hernández L. E., Cayrefourcq L., Alix-Panabières C. The Different Facets of Liquid Biopsy: A Kaleidoscopic View. Cold Spring Harb. Perspect. Med. 2020, 10 (6), a037333.

      138. Fici P. Cell-Free DNA in the Liquid Biopsy Context: Role and Differences Between ctDNA and CTC Marker in Cancer Management. Methods Mol. Biol. 2019, V. 1909, P. 47–73.

      139. Maly V., Maly O., Kolostova K., Bobek V. Circulating Tumor Cells in Diagnosis and Treatment of Lung Cancer. In Vivo. 2019, 33 (4), 1027–1037.

      140. Liang D. H., Hall C., Lucci A. Circulating Tumor Cells in Breast Cancer. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer. 2020, V. 215, P. 127–145.

      141. Cortés-Hernández L. E., Eslami-S Z., Alix-Panabières C. Circulating tumor cell as the functional aspect of liquid biopsy to understand the metastatic cascade in solid cancer. Mol. Aspects Med. 2020, V. 72, P. 100816.

      142. Mushtaq M., Kovalevska L., Darekar S., Abramsson A., Zetterberg H., Kashuba V., Klein G., Arsenian-Henriksson M., Kashuba E. Cell stemness is maintained upon concurrent expression of RB and the mitochondrial ribosomal protein S18-2. Proc. Natl. Acad. Sci. USA. 2020, 117 (27).

      143. Liu T., Xu H., Huang M., Ma W., Saxena D., Lustig R. A., Alonso-Basanta M., Zhang Z., O'Rourke D. M., Zhang L., Gong Y., Kao G. D., Dorsey J. F., Fan Y. Circulating Glioma Cells Exhibit Stem Cell-like Properties. Cancer Res. 2018, 78 (23), 6632–6642.

      144. Okabe T., Togo S., Fujimoto Y., Watanabe J., Sumiyoshi I., Orimo A., Takahashi K. Mesenchymal Characteristics and Predictive Biomarkers on Circulating Tumor Cells for Therapeutic Strategy. Cancers. 2020, 12 (12), 3588.

      145. Guan X., Ma F., Li C., Wu S., Hu S., Huang J., Sun X., Wang J., Luo Y., Cai R., Fan Y., Li Q., Chen S., Zhang P., Li Q., Xu B. The prognostic and therapeutic implications of circulating tumor cell phenotype detection based on epithelial-mesenchymal transition markers in the first-line chemotherapy of HER2-negative metastatic breast cancer. Cancer Commun. (Lond). 2019, 39 (1), 1.

      146. Chen Y., Li S., Li W., Yang R., Zhang X., Ye Y., Yu J., Ye L., Tang W. Circulating tumor cells undergoing EMT are poorly correlated with clinical stages or predictive of recurrence in hepatocellular carcinoma. Sci. Rep. 2019, 9 (1), 7084.

      147. Sun Y. F., Guo W., Xu Y., Shi Y. H., Gong Z. J., Ji Y., Du M., Zhang X., Hu B., Huang A., Chen G. G., Lai P., Cao Y., Qiu S. J., Zhou J., Yang X. R., Fan J. Circulating Tumor Cells from Different Vascular Sites Exhibit Spatial Heterogeneity in Epithelial and Mesenchymal Composition and Distinct Clinical Significance in Hepatocellular Carcinoma. Clin. Cancer Res. 2018, 24 (3), 547–559.

      148. Lin P. P. Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis. Cells. 2020, 9 (6), 1539.

      149. Galanzha E. I., Menyaev Y. A., Yadem A. C., Sarimollaoglu M., Juratli M. A., Nedosekin D. A., Foster S. R., Jamshidi-Parsian A., Siegel E. R., Makhoul I., Hutchins L. F., Suen J. Y., Zharov V. P. In vivo liquid biopsy using Cytophone platform for photoacoustic detection of circulating tumor cells in patients with melanoma. Sci. Transl. Med. 2019, 11 (496), eaat5857.

      150. Han Y., Liu D., Li L. PD-1/PD-L1 pathway: current researches in cancer. Am. J. Cancer Res. 2020, 10 (3), 727–742.

      151. Zhang W., Huang Q., Xiao W., Zhao Y., Pi J., Xu H., Zhao H., Xu J., Evans C. E., Jin H. Advances in Anti-Tumor Treatments Targeting the CD47/SIRPα Axis. Front. Immunol. 2020, V. 11, P. 18.

      152. Lian S., Xie R., Ye Y., Lu Y., Cheng Y., Xie X., Li S., Jia L. Dual blockage of both PD-L1 and CD47 enhances immunotherapy against circulating tumor cells. Sci. Rep. 2019, 9 (1), 4532.

      153. Chen C., Zhao S., Karnad A., Freeman J. W. The biology and role of CD44 in cancer progression: therapeutic implications. J. Hematol. Oncol. 2018, 11 (1), 64.

      154. Leone K., Poggiana C., Zamarchi R. The Interplay between Circulating Tumor Cells and the Immune System: From Immune Escape to Cancer Immunotherapy. Diagnostics (Basel). 2018, 8 (3), 59.

      155. Zhong X., Zhang H., Zhu Y., Liang Y., Yuan Z., Li J., Li J., Li X., Jia Y., He T., Zhu J., Sun Y., Jiang W., Zhang H., Wang C., Ke Z. Circulating tumor cells in cancer patients: developments and clinical applications for immunotherapy. Mol. Cancer. 2020, 19 (1), 15.


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Home Archive 2021 № 4 CIRCULATING TUMOR CELLS: WHERE WE LEFT OFF? I. Kryvoshlyk, L. Skivka

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