vestibИзвестия Национальной академии наук Беларуси. Серия биологических наукProceedings of the National Academy of Sciences of Belarus, Biological Series1029-89402524-230XThe Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"10.29235/1029-8940-2021-66-3-370-384vestib-767Research ArticleОБЗОРЫREVIEWSЦиркулирующие опухолевые клетки и циркулирующие раковые стволовые клетки и их детекция методом проточной цитофлуориметрииCirculating tumor cells and circulating cancer stem cells and their detection by the method of flow cytometryПознякТ. А.PozniakT. A.

Позняк Татьяна Анатольевна - кандидат биологических наук, старший научный сотрудник.

ул. Академическая, 27, 220072, Минск.

Tatyana A. Pozniak - Ph. D. (Biol.), Senior Researcher. Institute of Biophysics and Cell Engineering of the National Academy of Sciences of Belarus.

27, Akademicheskaya Str., 220072, Minsk.

tatyana.pozniak@gmail.comГончаровА. Е.HancharouA. Y.

Гончаров Андрей Евгеньевич - кандидат медицинских наук, доцент, директор.

ул. Академическая, 27, 220072, Минск.

Andrei E. Hancharou - Ph. D. (Med.), Associate Professor, Director, Institute of Biophysics and Cell Engineering of the National Academy of Sciences of Belarus.

27, Akademicheskaya Str., 220072, Minsk.

andrei.hancharou@gmail.comАбашкинВ. М.AbashkinV. M.

Абашкин Виктор Михайлович - младший научный сотрудник.

ул. Академическая, 27, 220072, Минск.

Viktar М. Abashkin - Junior Researcher, Institute of Biophysics and Cell Engineering of the National Academy of Sciences of Belarus.

27, Akademicheskaya Str., 220072, Minsk.

viktar.abashkin@gmail.comСтановаяА. И.StanovayaA. I.

Становая Алеся Игоревна - младший научный сотрудник.

ул. Академическая, 27, 220072, Минск.

Alesia I. Stanovaya - Junior Researcher, Institute of Biophysics and Cell Engineering of the National Academy of Sciences of Belarus.

27, Akademicheskaya Str., 220072, Minsk.

alesiastanovaya@gmail.comПрохоровА. В.ProkhorovA. V.

Прохоров Александр Викторович - доктор медицинских наук, профессор, заведующий кафедрой.

пр. Дзержинского, 83, 220116, Минск.

Alexander V. Prokhorov - D. Sc. (Med.), Professor, Head of the Department, Belarusian State Medical University.

83, Dzerzhinski Ave., 220116, Minsk.

aprokharau@gmail.comЩербинД. Г.ShcharbinD. G.

Щербин Дмитрий Григорьевич - доктор биологических наук, доцент, заведующий лабораторией.

ул. Академическая, 27, 220072, Минск.

Dzmitry G. Shcharbin - D. Sc. (Biol.), Associate Professor, Head of the Laboratory, Institute of Biophysics and Cell Engineering of the National Academy of Sciences of Belarus.

27, Akademicheskaya Str., 220072, Minsk.

shcharbin@gmail.comИнститут биофизики и клеточной инженерии НАН БеларусиInstitute of Biophysics and Cell Engineering of the National Academy of Sciences of BelarusБелорусский государственный медицинский университетBelarusian State Medical University202104082021663370384Copyright © Позняк Т.А., Гончаров А.Е., Абашкин В.М., Становая А.И., Прохоров А.В., Щербин Д.Г., 20212021Позняк Т.А., Гончаров А.Е., Абашкин В.М., Становая А.И., Прохоров А.В., Щербин Д.Г.Pozniak T.A., Hancharou A.Y., Abashkin V.M., Stanovaya A.I., Prokhorov A.V., Shcharbin D.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestibio.belnauka.by/jour/article/view/767

В обзоре приведено описание циркулирующих раковых стволовых клеток (цРСК) и циркулирующих опухолевых клеток (ЦОК) в крови человека и методов их определения. цРСК являются одними из главных инициаторов рецидива онкологических заболеваний, что делает их основной мишенью для разработки новых методов лечения. ЦОК являются относительно новыми биомаркерами для ранней диагностики метастазирования, мониторинг содержания которых дает ценную информацию на всех этапах ведения онкопациентов, включая раннюю диагностику заболевания, оценку риска рецидива болезни, определение эффективности химиотерапии с возможностью последующей ее коррекции.

This review describes the circulating cancer stem cells (CCSCs) and circulating tumor cells (CTCs). CCSCs are one of the main initiators of recurrent cancer and thus make them an important target for the development of new treatment methods. CTCs are relatively new biomarkers for the early diagnosis of metastasis. CTCs provide doctors with valuable information about each stages of cancer treatments: diagnostic of early-stage disease, early detection of recurrent cancer, the efficiency of chemotherapy, and makes it possible to select an individual sensitive drug.

The most informative and frequently used markers for the detection of CSCs and CSCs were described. The mechanism of two models of tumor formation is considered: clonal and hierarchical. The known mechanisms of epithelial-mesenchymal transition of tumor cells are described. The most widely used specific cell surface markers for the detection and isolation of CTCs and CCSCs are described. The efficiency of a sensitive high-precision method of multicolor flow cytometry using specific fluorescent dye-labeled monoclonal antibodies for the detection of CCSCs and CTCs in the blood of cancer patients is analyzed. Detection of CTCs and CCSCs provides important information for the early diagnosis of metastasis and open a possibility to personalized treatment, and to monitoring of all stages cancers.

циркулирующие опухолевые клеткициркулирующие раковые стволовые клеткимаркерыклональная и иерархическая модели образования опухолимногоцветная проточная цитофлуориметрияcirculating tumor cellscirculating cancer stem cellsepithelial-mesenchymal transitionmarkersclonal and hierarchical models of tumor formationmulticolor flow cytometryReferencesРак (онкологические заболевания) [Electronic resource] // Zdrav. Expert. - Mode of access: http://zdrav.expert/index.php/Ctat'ya:Rak_(onkologicheckiye_zabolevaniya). - Date of access: 14.03.2021.Cancer (oncological diseases). Zdrav. Expert. Available at: http://zdrav.expert/index.php/Ctat'ya:Rak_(onkologicheckiye_zabolevaniya). (accessed 14.03.2021).Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406) / S. Kopetz [et al.] // J. Clin. Oncol. - 2017. - Vol. 35, N 4. - P. 285-294. https://doi.org/10.1200/jco.20.01994Kopetz S., Guthrie K. A., Morris V. K., Lenz H.-J., Magliocco A. M., Maru D. [et al.]. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). Journal of Clinical Oncology, 2017, vol. 35, no. 4, pp. 285-294. htpps://doi.org/10.1200/JCO.20.01994Cancer stem cells, a fuzzy evolving concept: a cell population or a cell property? / А. Antoniou [et al.] // Cell Cycle. -2013. - Vol. 12, N 24. - P. 3743-3748. https://doi.org/10.4161/cc.27305Antoniou A., Hebrant A., Dom G., Dumont J., Maenhaunt C. Cancer stem cells, a fuzzy evolving concept: a cell population or a cell property? Cell Cycle, 2013, vol. 12, no. 24, pp. 3743-3748. htpps://doi.org/10.4161/cc.27305Understanding the cancer stem cell / S. Bomken [et al.] // Br. J. Cancer. - 2010. - Vol. 103, N 4. - P. 439-445. https://doi.org/10.1038/sj.bjc.6605821Bomken S., Fiser K., Heidenreich O., Vormoor J. Understanding the cancer stem cell. British Journal of Cancer, 2010, vol. 103, no. 4, pp. 439-445. https://doi.org/10.1038/sj.bjc.6605821Bonnet, D. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell / D. Bonnet, J. E. Dick // Nat. Med. - 1997. - Vol. 3, N 7. - P. 730-737. https://doi.org/10.1038/nm0797-730Bonnet D., Dick J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine, 1997, vol. 3, no. 7, pp. 730-737. htpps://doi.org/10.1038/nm.0797-730Eun, K. Cancer stem cell heterogeneity: origin and new perspectives on CSC targeting / K. Eun, S. W. Ham, H. Kim // BMB Rep. - 2017. - Vol. 50, N 3. - P. 117-125. https://doi.org/10.5483/bmbrep.2017.50.3.222Eun K., Ham S. W., Kim H. Cancer stem cell heterogeneity: origin and new perspectives on CSC targeting. BMB Reports, 2017, vol. 50, no. 3, pp. 117-125. htpps://doi.org/10.5483/bmbrep.2017.50.3.222Lang, F. Stem Cell Hierarchy and Clonal Evolution in Acute Lymphoblastic Leukemia / F. Lang, B. Wojcik, M. A. Rieger // Stem Cells Int. - 2015. - Vol. 2015. - P. 1-13. https://doi.org/10.1155/2015/137164Lang F., Wojcik B., Rieger M. A. Stem cell hierarchy and clonal evolution in acute lymphoblastic leukemia. Stem Cells International, 2015, vol. 2015, pp. 1-13. htpps://doi.org/10.1155/2015/137164Visvader, J. E. Cancer stem cells: current status and evolving complexities / J. E. Visvader, G. J. Lindeman // Cell Stem Cell. - 2012. - Vol. 10, N 6. - P. 717-728. https://doi.org/10.1016/j.stem.2012.05.007Visvader J. E., Lindeman G. J. Cancer stem cells: current status and evolving complexities. Cell Stem Cell, 2012, vol. 10, no. 6, pp. 717-728. htpps://doi.org/10.1016/j.stem.2012.05.007Mani S. A. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 2008, vol. 133, pp. 704-715. htpps://doi.org/10.1016/j.cell.2008.03.027Mani S. A. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 2008, vol. 133, pp. 704-715. htpps://doi.org/10.1016/j.cell.2008.03.027Hollier, B. G. The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapies / B. G. Hollier, K. Evans, S. A. Mani // J. Mammary Gland Biol. Neoplasia. - 2009. - Vol. 14, N 1. - P. 29-43. https://doi.org/10.1007/s10911-009-9110-3Hollier B. G., Evans K., Mani S. A. The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapies. Journal of Mammary Gland Biology and Neoplasia, 2009, vol. 14, no. 1, pp. 29-43. htpps://doi.org/10.1007/s10911-009-9110-3Молекулярные маркеры раковых стволовых клеток, верифицированные in vivo / Я. С. Ким [и др.] // Биомед. химия. - 2016. - Т. 62, № 3. - C. 228-238.Kim Ya. S., Kaidina A. M., Chang Yu. Kh., Yarygin K. N., Lupatov A. Yu. Molecular markers of cancer stem cells verified in vivo. Biomeditsinskaya khimiya [Biomedical chemistry], 2016, vol. 62, no. 3, pp. 228-238 (in Russian).Therapeutic strategies targeting cancer stem cells and their microenvironment / H. R. Sun [et al.] // Front. Oncol. -2019. - Vol. 9, N 9. - P. 1104. https://doi.org/10.3389/fonc.2019.01104Sun H., Wang S., Yan S., Zhang Yu., Nelson P., Jia H., Qin L., Dong Q. Therapeutic strategies targeting cancer stem cells and their microenvironment. Frontiers in Oncology, 2019, vol. 9, no. 9, p. 1104. htpps://doi.org/10.3389/fonc.2019.01104Fillmore, C. M. Human breast cancer cell lines contain stem-like cells that selfrenew, give rise to phenotypically diverse progeny and survive chemotherapy / C. M. Fillmore, C. Kuperwasser // Breast Cancer Res. - 2008. - Vol. 10, N 2. -Art. R25. https://doi.org/10.1186/bcr1982Fillmore C. M., Kuperwasser C. Human breast cancer cell lines contain stem-like cells that selfrenew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Research, 2008, vol. 10, no. 2, art. R25. htpps://doi.org/10.1186/bcr1982ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome / C. Ginestier [et al.] // Cell Stem Cell. - 2007. - Vol. 1, N 5. - P. 555-567. https://doi.org/10.1016/j.stem.2007.08.014Ginestier C., Hur M., Charafe-Jauffret E., Birnbaum D., Wicha M., Dontu G. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell, 2007, vol. 1, no. 5, pp. 555567. htpps://doi.org/10.1016/j.stem.2007.08.014Begicevic, R. R. ABC transporters in cancer stem cells: beyond chemoresistance / R. R Begicevic, M. Falasca // Int. J. Mol. Sci. - 2017. - Vol. 18. - P. 2362. https://doi.org/10.3390/ijms18112362Begicevic R. R., Falasca M. ABC transporters in cancer stem cells: beyond chemoresistance. International Journal of Molecular Sciences, 2017, vol. 18, p. 2362. htpps://doi.org/10.3390/ijms18112362Hanahan D. Hallmarks of cancer: the next generation / D. Hanahan, R. A. Weinberg // Cell. - 2011. - Vol. 144, N 5. -P. 646-674. https://doi.org/10.1016/j.cell.2011.02.013Hanahan D., Weinberg R. A. Hallmarks of cancer: the next generation. Cell, 2011, vol. 144, no. 5, pp. 646-674. htpps://doi.org/10.1016/j.cell.2011.02.013Książkiewicz, M. Epithelial-mesenchymal transition: a hallmark in metastasis formation linking circulating tumor cells and cancer stem cells / M. Książkiewicz, A. Markiewicz, A. J. Zaczek // Pathobiology. - 2012. - Vol. 79, N 4. -P. 195-208. https://doi.org/10.1159/000337106Ksiqzkiewicz M., Markiewicz A., Zaczek A. J. Epithelial-mesenchymal transition: a hallmark in metastasis formation linking circulating tumor cells and cancer stem cells. Pathobiology, 2012, vol. 79, no. 4, pp. 195-208. htpps://doi.org/10.1159/000337106Epithelial-to-mesenchymal transitions and circulating tumor cells / A. Bonnomet [et al.] // J. Mammary Gland Biol. Neoplasia. - 2010. - Vol. 15, N 2. - P. 261-273. https://doi.org/10.1007/s10911-010-9174-0Bonnomet A., Brysse A., Tachsidis A., Waltham M., Thompson E., Polette M., Gilles C. Epithelial-to-mesenchymal transitions and circulating tumor cells. Journal of Mammary Gland Biology and Neoplasia, 2010, vol. 15, no. 2, pp. 261-273. htpps://doi.org/10.1007/s10911-010-9174-0Kalluri, R. EMT: when epithelial cells decide to become mesenchymal-like cells / R. Kalluri // J. Clin. Invest. - 2009. -Vol. 119, N 6. - P. 1417-1419. https://doi.org/10.1172/jci39675Kalluri R. EMT: when epithelial cells decide to become mesenchymal-like cells. Journal of Clinical Investigation, 2009, vol. 119, no. 6, pp. 1417-1419. htpps://doi.org/10.1172/jci39675Kalluri, R. The basics of epithelial-mesenchymal transition / R. Kalluri, R. A. Weinberg // J. Clin. Invest. - 2009. -Vol. 119, N 6. - P. 1420-1428. https://doi.org/10.1172/jci39104Kalluri R., Weinberg R. A. The basics of epithelial-mesenchymal transition. Journal of Clinical Investigation, 2009, vol. 119, no. 6, pp. 1420-1428. htpps://doi.org/10.1172/jci39104Chaffer, C. L. Mesenchymal to epithelial transition in development and disease / C. L. Chaffer, E. W. Thompson, E. D. Williams // Cells Tissues Organs. - 2007. - Vol. 185, N 1-3. - P. 7-19. https://doi.org/10.1159/000101298Chaffer C. L., Thompson E. W., Williams E. D. Mesenchymal to epithelial transition in development and disease. Cells Tissues Organs, 2007, vol. 185, no. 1-3, pp. 7-19. htpps://doi.org/10.1159/000101298Chao, Y. L. Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition / Y. L. Chao, C. R. Shepard, A. Wells // Mol. Cancer. - 2010. - Vol. 9, N 1. - Art. 179. https://doi.org/10.1186/1476-4598-9-179Chao Y. L., Shepard C. R., Wells A. Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Molecular Cancer, 2010, vol. 9, art. 179. htpps://doi.org/10.1186/1476-4598-9-179Klymkowsky, M. W. Epithelialmesenchymal transition: a cancer researcher's conceptual friend and foe / M. W. Klymkowsky, P. Savagner // Am. J. Pathol. - 2009. - Vol. 174, N 5. - P. 1588-1593. https://doi.org/10.2353/ajpath.2009.080545Klymkowsky M. W., Savagner P. Epithelialmesenchymal transition: a cancer researcher's conceptual friend and foe. American Journal of Pathology, 2009, vol. 174, no. 5, pp. 1588-1593. htpps://doi.org/10.2353/ajpath.2009.080545Tsuji, T. Epithelial-mesenchymal transition and cell cooperativity in metastasis / T. Tsuji, S. Ibaragi, G. F. Hu // Cancer Res. - 2009. - Vol. 69, N 18. - P. 7135-7139. https://doi.org/10.1158/0008-5472.can-09-1618Tsuji T., Ibaragi S., Hu G. F. Epithelial-mesenchymal transition and cell cooperativity in metastasis. Cancer Research, 2009, vol. 69, no. 18, pp. 7135-7139. htpps://doi.org/10.1158/0008-5472.can-09-1618Hall, C. Circulating tumor cells in breast cancer patients / C. Hall, L. Valad, A. Lucci // Crit. Rev. Oncog. - 2016. -Vol. 21, N 1-2. - P. 125-139. https://doi.org/10.1615/critrevoncog.2016016120Hall C., Valad L., Lucci A. Circulating tumor cells in breast cancer patients. Critical Rewievs in Oncogenesis, 2016, vol. 21, no. 1-2, pp. 125-139. htpps://doi.org/10.1615/critrevoncog.2016016120Циркулирующие опухолевые клетки (ЦОК) при раке молочной железы: прогностическая значимость и методы выделения / Д. А. Зубцов [и др.] // Тр. МФТИ. - 2012. - Т. 4, № 3. - С. 18-26.Zubtsov D. A., Zubtsova Zh. I., Lavrov A. V., Legchenko E. V., Aladinskii V. A., Poteryakhina A. V., Gol'dshtein D. V. Circulating tumor cells (CTCs) in breast cancer: prognostic significance and methods for isolation. Trudy MFTI. Trudy Moskovskogo fiziko-tekhnicheskogo instituta (natsional'nogo issledovatel'skogo universiteta) [Proceedings of MIPT. Proceedings of the Moscow Institute of Physics and Technology (National Research University)], 2012, vol. 4, no. 3, pp. 18-26 (in Russian).Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data / H. I. Scher // Lancet Oncol. - 2009. - Vol. 10, N 3. - P. 233-239. https://doi.org/10.1016/s1470-2045(08)70340-1Scher H. I. Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data. Lancet Oncology, 2009, vol. 10, no. 3, pp. 233-239. htpps://doi.org/10.1016/s1470-2045(08)70340-1Bidard. F. C. Circulating tumor cells in breast cancer / F. C. Bidard, C. Proudhon, J. Y. Pierga // Mol. Oncol. - 2016. -Vol. 10, N 3. - P 418-430. https://doi.org/10.1016Zj.molonc.2016.01.001Bidard F. C., Proudhon C., Pierga J. Y. Circulating tumor cells in breast cancer. Molecular Oncoogy, 2016, vol. 10, no. 3, pp. 418-430. htpps://doi.org/10.1016/j.molonc.2016.01.001Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases / K. J. Luzzi [et al.] // Am. J. Pathol. - 1998. - Vol. 153, N 3. - P. 865-873. https://doi.org/10.1016/s0002-9440(10)65628-3Luzzi K., MacDonald I., Schmidt E., Morris V., Chambers A. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. American Journal of Pathology, 1998, vol. 153, no. 3, pp. 865-873. htpps://doi.org/10.1016/s0002-9440(10)65628-3Increased expression of apoptosis inhibitor protein XIAP contributes to anoikis resistance of circulating human prostate cancer metastasis precursor cells / O. Berezovskaya [et al.] // Cancer Res. - 2005. - Vol. 65, N 6. - P. 2378-2386. https://doi.org/10.1158/0008-5472.can-04-2649Berezovskaya O., Schimmer A. D., Glinskii A. B., Pinilla C., Hoffman R. M., Reed J. C., Glinsky G. V. Increased expression of apoptosis inhibitor protein XIAP contributes to anoikis resistance of circulating human prostate cancer metastasis precursor cells. Cancer Research, 2005, vol. 65, no. 6, pp. 2378-2386. htpps://doi.org/10.1158/0008-5472.can-04-2649Gray, J. W. / Evidence emerges for early metastasis and parallel evolution of primary and metastatic tumors / J. W. Gray // Cancer Cell. - 2003. - Vol. 4, N 1. - P. 4-6. https://doi.org/10.1016/s1535-6108(03)00167-3Gray J. W. Evidence emerges for early metastasis and parallel evolution of primary and metastatic tumors. Cancer Cell, 2003, vol. 4, no. 6, pp. 4-6. htpps://doi.org/10.1016/s1535-6108(03)00167-3Spread of human cancer cells occurs with probabilities indicative of a nongenetic mechanism / J. S. Michaelson [et al.] // Br. J. Cancer. - 2005. - Vol. 93, N 11. - P. 1244-1249. https://doi.org/10.1038/sj.bjc.6602848Michaelson J. S., Cheongsiatmoy J. A., Dewey F., Silverstein M. J., Sgroi D., Smith B., Tanabe K. K. Spread of human cancer cells occurs with probabilities indicative of a nongenetic mechanism. British Journal of Cancer, 2005, vol. 93, no. 11, pp. 1244-1249. htpps://doi.org/10.1038/sj.bjc.6602848Methods for isolating circulating epithelial cells and criteria for their classification as carcinoma cells / T. Fehm [et al.] // Cytotherapy. - 2005. - Vol. 7, N 2. - P. 171-185. https://doi.org/10.1080/14653240510027082Fehm T., Solomayer E. F., Meng S., Tucker T., Lane N., Wang J., Gebauer G. Methods for isolating circulating epithelial cells and criteria for their classification as carcinoma cells. Cytotherapy, 2005, vol. 7, no. 2, pp. 171-185. htpps://doi.org/10.1080/14653240510027082Man, Y. Currently Used markers for CTC isolation - advantages, limitations and impact on cancer prognosis / Y. Man, Q. Wang, W. Kemmner // J. Clin. Exp. Pathol. - 2011. - Vol. 1, N 1. - Art. 102. https://doi.org/10.4172/2161-0681.1000102Man Y., Wang Q., Kemmner W. Currently Used Markers for CTC Isolation - Advantages, Limitations and Impact on Cancer Prognosis. Journal of Clinic and Experimental Pathology, 2011, vol. 1, no. 1, art. 102. https://doi.org/10.4172/2161-0681.1000102Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the CellSearch system / S. Riethdorf [et al.] // Clin. Cancer Res. - 2007. - Vol. 13, N 3. - P. 920-928. https://doi.org/10.1158/1078-0432.ccr-06-1695Riethdorf S., Fritsche H., Muller V., Rau T., Schindlbeck C., Rack B. [et al.]. Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the CellSearch system. Clinical Cancer Research, 2007, vol. 13, no. 3, pp. 920-928. htpps://doi.org/10.1158/1078-0432.ccr-06-1695Circulating tumor cells in solid tumor in metastatic and localized stages / L. M. Maestro [et al.] // Anticancer Res. -2009. - Vol. 29, N 11. - P. 4839-4843.Maestro L., Sastre J., Rafael S., Veganzones S., Vidaurreta M., Martm M. [et al.]. Circulating tumor cells in solid tumor in metastatic and localized stages. Anticancer Research, 2009, vol. 29, no. 11, pp. 4839-4843. htpps://pubmed.ncbi.nlm.nih.gov/20032444/Circulating tumour cells early predict progression-free and overall survival in advanced colorectal cancer patients treated with chemotherapy and targeted agents / J. Tol [et al.] // Ann. Oncol. - 2010. - Vol. 21, N 5. - P. 1006-1012. https://doi.org/10.1093/annonc/mdp463Tol J., Koopman M. C., Miller M. C., Tibbe A., Cats A., Creemers G. J. M., Vos A. H., Nagtegaal I. D., Terstappen L. W. M. M., Punt C. J. A. Circulating tumour cells early predict progression-free and overall survival in advanced colorectal cancer patients treated with chemotherapy and targeted agents. Annals of Oncology, 2010, vol. 21, no. 5, pp. 1006-1012. htpps://doi.org/10.1093/annonc/mdp463Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance / K. R. Fischer [et al.] // Nature. - 2015. - Vol. 527, N 7579. - P. 472-476. htpps://doi.org/10.1038/nature15748Fischer K., Durrans A., Lee S., Sheng J., Li F., Wong S. [et al.]. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature, 2015, vol. 527, no. 7579, pp. 472-476. htpps://doi.org/10.1038/nature15748The initial detection and partial characterization of circulating tumor cells in neuroendocrine prostate cancer / H. Beltran [et al.] // Clin. Cancer Res. - 2016. - Vol. 22, N 6. - P. 1510-1519. https://doi.org/10.1158/1078-0432.ccr-15-0137Beltran H., Jendrisak A., Landers M., Mosquera J., Kossa M., Louw J. [et al.]. The initial detection and partial characterization of circulating tumor cells in neuroendocrine prostate cancer. Clinical Cancer Research, 2016, vol. 22, no. 6, pp. 1510-1519. htpps://doi.org/10.1158/1078-0432.ccr-15-0137Lianidou, E. S. Circulating tumor cells as emerging tumor biomarkers in breast cancer / E. S. Lianidou, A. Markou // Clin. Chem. Lab. Med. - 2011. - Vol. 49, N 10. - P. 1579-1590. https://doi.org/10.1515/cclm.2011.628Lianidou E. S., Markou A. Circulating tumor cells as emerging tumor biomarkers in breast cancer. Clinical Chemistry and Laboratory Medicine, 2011, vol. 49, no. 10, pp. 1579-1590. htpps://doi.org/10.1515/cclm.2011.628Eslami, S. Z. Circulating tumor cells: moving forward into clinical applications / S. Z. Eslami, L. E. Cortes-Hernandez, C. Alix-Panabieres // Precis Cancer Med. March. - 2020. - Vol. 3, N 4. - P 781-791. https://pubmed.ncbi.nlm.nih.gov/31377345/Eslami S. Z., Cortes-Hernandez L. E., Alix-Panabieres C. Circulating tumor cells: moving forward into clinical applications. Precision Cancer Medicine, 2020, vol. 3, no. 4, pp. 781-791. htpps://doi.org/10.1016/j.mam.2019.07.008Antiepithelial cell adhesion molecule antibodies and the detection of circulating normallike breast tumor cells / A. M. Sieuwerts [et al.] // J. Natl. Cancer Inst. - 2009. - Vol. 101, N 1. - P. 61-66. https://doi.org/10.1093/jnci/djn419Sieuwerts A. M., Kraan J., Bolt J., van der Spoel P., Elstrodt F., Schutte M., Martens J. W. M., Gratama J. W., Sleijfer S., Foekens J. A. Antiepithelial cell adhesion molecule antibodies and the detection of circulating normallike breast tumor cells. Journal of the Nature Cancer Institute, 2009, vol. 101, no. 1, pp. 61-66. htpps://doi.org/10.1093/jnci/djn419Molecular biomarker analyses using circulating tumor cells / E. A. Punnoose [et al.] // PLoS ONE. - 2010. - Vol. 5, N 9. - P. e12517. https://doi.org/10.1371/journal.pone.0012517Punnoose E. A., Atwal S. K., Spoerke J. M., Savage H., Pandita A., Yeh R. [et al.]. Molecular biomarker analyses using circulating tumor cells. PLoS ONE, 2010, vol. 5, no. 9, p. e12517. htpps://doi.org/10.1371/journal.pone.0012517Detection of EpCAM negative and cytokeratin-negative circulating tumor cells in peripheral blood / S. D. Mikolajczyk [et al.] // J. Oncol. - 2011. - Vol. 2011. - P. 252361. https://doi.org/10.1155/2011/252361Mikolajczyk S. D., Millar L. S., Tsinberg P., Coutts S. M., Zomorrodi M., Pham T., Bischoff F. Z., Pircher T. J. Detection of EpCAM negative and cytokeratin-negative circulating tumor cells in peripheral blood. Journal of Oncology, 2011, vol. 2011, pp. 252-361. htpps://doi.org/10.1155/2011/252361EGFR-based immunoisolation as a recovery target for low-EpCAM CTC subpopulation / A. Vila [et al.] // PLoS ONE. -2016. - Vol. 11, N 10. - P. e0163705. https://doi.org/10.1371/journal.pone.0163705Vila A., Abal M., Muinelo-Romay L., Rodriguez-Abreu C., Rivas J., Lopez-Lopez R., Costa C. EGFR-based immunoisolation as a recovery target for Low-EpCAM CTC subpopulation. PLoS ONE, 2016, vol. 11, no. 10, p. e0163705. htpps://doi.org/10.1371/journal.pone.0163705Long term survival following the detection of circulating tumour cells in head and neck squamous cell carcinoma / S. C. Winter [et al.] // BMC Cancer. - 2009. - Vol. 9, N 1. - Art. 424. https://doi.org/10.1186/1471-2407-9-424Winter S. A., Stephenson S. A., Subramaniam S. K., Paleri V., Ha K., Marnane C., Krishnan S., Rees G. Long-term survival following the detection of circulating tumour cells in head and neck squamous cell carcinoma. BMC Cancer, 2009, vol. 9, no. 1, art. 424. htpps://doi.org/10.1186/1471-2407-9-424Cell-free RNA content in peripheral blood as potential biomarkers for detecting circulating tumor cells in non-small cell lung carcinoma / X. M. Yu [et al.] // Int. J. Mol. Sci. - 2016. - Vol. 17, N 11. - P. 1845. https://doi.org/10.3390/ijms17111845Yu X. M., Yi-Chen Wu, Xiang Liu, Xian-Cong Huang, Xiu-Xiu Hou, Jiu-Li Wang, Xiang-Liu Cheng, Wei-Min Mao, Zhi-Qiang Ling. Cell-free RNA content in peripheral blood as potential biomarkers for detecting circulating tumor cells in non-small cell lung carcinoma. International Journal of Molecular Sciences, 2016, vol. 17, no. 11, p. 1845. https://doi.org/10.3390/ijms17111845Correlation of HER2 status between primary tumors and corresponding circulating tumor cells in advanced breast cancer patients / M. Pestrin [et al.] // Breast Cancer Res. Treat. - 2009. - Vol. 118, N 3. - P. 523-530. https://doi.org/10.1007/s10549-009-0461-7Pestrin M., Bessi S., Galardi F., Truglia M., Biggeri A., Biagioni C., Cappadona S., Biganzoli L., Giannini A., Di Leo A. Correlation of HER2 status between primary tumors and corresponding circulating tumor cells in advanced breast cancer patients. Breast Cancer Research and Treatment, 2009, vol. 118, no. 3, pp. 523-530. htpps://doi.org/10.1007/s10549-009-0461-7Detection of HER2-positive circulating tumor cells using the LiquidBiopsy System in breast cancer / W. Chen [et al.] // Clin. Breast Cancer. - 2019. - Vol. 19, N 1. - P. 239-246. https://doi.org/10.1016/j.clbc.2018.10.009Chen W., Zhang J., Huang L., Chen L., Zhou Y., Tang D., Xie Y., Wang H., Huang C. Detection of HER2-positive circulating tumor cells using the LiquidBiopsy System in breast cancer. Clinical Breast Cancer, 2019, vol. 19, no. 1, pp. 239-246. htpps://doi.org/10.1016/j.clbc.2018.10.009Prognostic significance of MUC-1 in circulating tumor cells in patients with metastatic pancreatic adenocarcinoma / E. Dotan [et al.] // Pancreas. - 2016. - Vol. 45, N 8. - P. 1131-1135. https://doi.org/10.1097/mpa.0000000000000619Dotan E., Alpaugh K., Ruth K., Negin B. P., Denlinger C. S., Hall M. J., Astsaturov I., McAleer, C., Fittipaldi P., Thrash-Bingham C., Meropol N., Cohen S. J. Pancreas, 2016, vol. 45, no. 8, pp. 1131-1135. htpps://doi.org/10.1097/mpa.0000000000000619MUC1-positive circulating tumor cells and MUC1 protein predict chemotherapeutic efficacy in the treatment of metastatic breast cancer / J.-P. Cheng [et al.] // J. Cancer. - 2011. - Vol. 30, N 1. - P. 54-61. https://doi.org/10.5732/cjc.010.10239Cheng J.-P., Yan Y., Wang X.-Y., Lu Y.-L., Lu Y.-L., Jia J., Ren J. MUC1-positive circulating tumor cells and MUC1 protein predict chemotherapeutic efficacy in the treatment of metastatic breast cancer. Cancer Communications, 2011, vol. 30, no. 1, pp. 54-61. htpps://doi.org/10.5732/cjc.010.10239Influence of surgical manipulation and surgical modality on the molecular detection of circulating tumor cells from colorectal cancer / Soo Yeun Park [et al.] // J. Korean Surg. Soc. - 2012. - Vol. 82, N 6. - P. 356-364. https://doi.org/10.4174/jkss.2012.82.6.356Park S. Y., Choi G. S., Park J. S., Kim H. J., Ryuk J. P., Choi W. H. Influence of surgical manipulation and surgical modality on the molecular detection of circulating tumor cells from colorectal cancer. Journal of Korean Surgical Society, 2012, vol. 82, no. 6, pp. 356-364. htpps://doi.org/10.4174/jkss.2012.82.6.356Circulating tumour cells: molecular properties and anti-cancer treatment monitoring / A. Baigenzhin [et al.] // J. Clin. Med. Kazakhstan. - 2013. - Vol. 4, N 30. - P. 9-13.Baigenzhin A., Shaimardanova G., Popova N., Zhussipova B., Ismailova G. Git'culating tumour cells: molecular properties and anti-cancer treatment monitoring. Journal of Clinical Medicine of Kazakhstan, 2013, vol. 4, no. 30, pp. 9-13.Paterlini-Brechot, P. // Circulating tumor cells (CTC) detection: clinical impact and future directions / P. Paterlini-Brechot, N. L. Benali // Cancer Lett. - 2007. - Vol. 253, N 2. - P. 180-204. https://doi.org/10.1016/j.canlet.2006.12.014Paterlini-Brechot P., Benali N. L. Circulating tumor cells (CTC) detection: clinical impact and future directions. Cancer Letters, 2007, vol. 253, no. 2, pp. 180-204. htpps://doi.org/10.1016/j.canlet.2006.12.014Circulating tumor cell count is a prognostic factor in metastatic colorectal cancer patients receiving first-line chemotherapy plus bevacizumab: a Spanish Cooperative Group for the Treatment of Digestive Tumors study / J. Sastre [et al.] // Oncologist. - 2012. - Vol. 17, N 7. - P. 947-955. https://doi.org/10.1634/theoncologist.2012-0048Sastre J., Maestro M. L., Gomez-Espana A., Rivera F., Valladares M., Massuti B. [et al.]. Circulating tumor cell count is a prognostic factor in metastatic colorectal cancer patients receiving first-line chemotherapy plus bevacizumab: a Spanish Cooperative Group for the Treatment of Digestive Tumors study. Oncologist, 2012, vol. 17, no. 7, pp. 947-955. https://doi.org/10.1634/theoncologist.2012-0048Paoletti, C. Circulating tumor cells / C. Paoletti, D. F. Hayes // Novel Biomarkers in the Continuum of Breast Cancer / ed. V. Stearns. - Cham, 2016. - Vol. 882. - P. 235-258. https://doi.org/10.1007/978-3-319-22909-6_10Paoletti C., Hayes D. F. Circulating tumor cells. Novel Biomarkers in the Continuum of Breast Cancer. Vol. 882. Cham, 2016, pp. 235-258.Gwatkin, R. B. L. Practical flow cytometry, by H. M. Shapiro, Wiley-Liss, New York, 3rd ed., 1994, 542 p. / R. B. L. Gwatkin // Mol. Rep. Dev. - 1995. - Vol. 41, N 4. - P. 540. https://doi.org/10.1002/mrd.1080410419Gwatkin R. B. L. Practical flow cytometry, by H. M. Shapiro, Wiley-Liss, New York, 3rd ed., 1994, 542 p. Molecular Reproduction and Development, 1995, vol. 41, no. 4, p. 530. htpps://doi.org/10.1002/mrd.1080410419Ten-color 15-antibody flow cytometry panel for immunophenotyping of lymphocyte population / A. Rajab [et al.] // Int. J. Lab. Hematol. - 2017. - Vol. 39, suppl. 1. - P. 76-85. https://doi.org/10.1111/ijlh.12678Rajab A., Axler O., Leung J., Wozniak M., Porwit A. Ten-color 15-antibody flow cytometry panel for immunophenotyping of lymphocyte population. International Journal of Laboratory Hematology, 2017, vol. 39, suppl. 1, pp. 76-85. htpps://doi.org/10.1111/ijlh.12678Postoperative metastasis prediction based on portal vein circulating tumor cells detected by flow cytometry in periampullary or pancreatic cancer / L. Tao [et al.] // Cancer Manag. Res. - 2019. - Vol. 11. - P. 7405-7425. https://doi.org/10.2147/cmar.s210332Tao L., Su L., Yuan C., Ma Z., Zhang L., Bo S., Niu Y., Lu S., Xiu D. Postoperative metastasis prediction based on portal vein circulating tumor cells detected by flow cytometry in periampullary or pancreatic cancer. Cancer Management and Research, 2019, vol. 11, pp. 7405-7425. https://doi.org/10.2147/cmar.s210332Isolation and characterization of living circulating tumor cells in patients by immunomagnetic negative enrichment coupled with flow cytometry / Y. Lu [et al.] // Cancer. - 2015. - Vol. 121, N 17. - P. 3036-3045 https://doi.org/10.1002/cncr.2944Lu Y., Liang H., Yu T., Xie J., Chen S., Dong H. [et al.]. Isolation and characterization of living circulating tumor cells in patients by immunomagnetic negative enrichment coupled with flow cytometry. Cancer, 2015, vol. 121, no. 17, pp. 3036-3045 https://doi.org/10.1002/cncr.29444Xu, J. How do we use multicolor flow cytometry to detect minimal residual disease in acute myeloid leukemia? / J. Xu, J. L. Jorgensen, S. A. Wang // Clin. Lab. Med. - 2017. - Vol. 37, N 4. - P. 787-802. https://doi.org/10.1016/j.cll.2017.07.004Xu J., Jorgensen J. L., Wang S. A. How do we use multicolor flow cytometry to detect minimal residual disease in acute myeloid leukemia? Clinics in Laboratory Medicine, 2017, vol. 37, no. 4, pp. 787-802. https://doi.org/10.1016/j.cll.2017.07.004Способ определения циркулирующих опухолевых клеток : пат. BY 23371 / А. Е. Гончаров, О. B. Тимохина. -Опубл. 30.04.2021.Goncharov A. E., Timokhina O. B. Method for determining circulating tumor cells. Patent BY 23371, 2021 (in Russian).

The authors declare that there are no conflicts of interest present.