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DOI 10.34014/2227-1848-2019-4-50-62

BLOOD SERUM CYTOKINE STATUS IN OVARIAN CANCER PATIENTS WITH DIFFERENT LEVELS OF CIRCULATING TUMOR CELLS

S.O. Gening¹, T.V. Abakumova¹, I.I. Antoneeva¹, D.U. Gafurbaeva², R.R. Miftakhova², D.R. Dolgova¹, A.B. Peskov¹

1Ulyanovsk State University, Ulyanovsk, Russia;

2Kazan Federal University, Kazan, Russia

 

Circulating tumor cells (CTCs) are essential for hematogenous metastasis. In 2003, it was found out that such cells were present in the blood of patients diagnosed with ovarian cancer (OC). It is known that inflammation plays an important role in tumor progression. There are CSCs with a large number of components in the blood, e.g. cytokines that can modulate the metastatic potential of a tumor cell.

The aim of the study is to assess the blood serum cytokine status in ovarian cancer patients with different levels of circulating tumor cells.

Materials and Methods. Untreated primary patients (n=24) with histologically or cytologically verified ovarian cancer, stage II–IV according to FIGO classification, were the trial subjects. Flow cytometry was used to detect the number of circulating tumor cells in the blood from the patients; the authors also determined IL-6, IL-17A, IL-1β, TGF-α, IL-4, VEGF, TNF-α, HGF, IL-18, IL-10, IL-8 levels. The results were processed using the Statistica Windows software package.

Results. The authors determined that TNF-α, HGF, IL-10, IL-18 cytokine level in the blood serum from OC patients significantly increased, and IL-8 level decreased with CTC increase.

Conclusion. The obtained results suggest a correlation of CTC level with TNF-α, HGF, IL-10, IL-18, IL-8 cytokine serum level in patients diagnosed with advanced ovarian cancer. At the same time, a sharp and significant increase in TNF-α level accompanied with CTC increase may indicate a change in the phenotypes of TNF-producing cells in OC.

Keywords: ovarian cancer, cytokines, circulating tumor cells.

Conflict of interest. The authors declare no conflict of interest.

 

References

  1. Judson P.L., Geller M.A., Bliss R.L., Boente M.P., Downs L.S., Argenta P.A. Preoperative detection of peripherally circulating cancer cells and its prognostic significance in ovarian cancer. Gynecologic oncology. 2003; 91 (2): 389–394.

  2. Pearl M.L., Zhao Q., Yang J., Dong H., Tulley S., Zhang Q. Prognostic analysis of invasive circulating tumor cells (iCTCs) in epithelial ovarian cancer. Gynecologic oncology. 2014; 134 (3): 581–590.

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

  4. Aceto N., Bardia A., Miyamoto D.T. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014; 158 (5): 1110–1122.

  5. Klein C.A. Framework models of tumor dormancy from patient-derived observations. Current Opinion in Genetics & Development. 2011; 21 (1): 42–49.

  6. Bonnomet A., Syne L., Brysse A. 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.

  7. Kim M.Y., Oskarsson T., Acharyya S., Nguyen D.X., Zhang X.H., Norton L., Massagué J. Tumor self-seeding by circulating cancer cells. Cell. 2009; 139 (7): 1315–1326.

  8. Škovierová H., Okajčeková T., Strnádel J., Vidomanová E., Halašová E. Molecular regulation of epithelial-to-mesenchymal transition in tumorigenesis (Review). Int. J. Mol. Med. 2018; 41 (3): 1187–1200.

  9. Moffitt L., Karimnia N., Stephens A., Bilandzic M. Therapeutic Targeting of Collective Invasion in Ovarian Cancer. Int. J. Mol. Sci. 2019; 20 (6): 1466.

  10. Hudson L.G., Zeineldin R., Stack M.S. Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression. Clin. Exp. Metastasis. 2008; 25 (6): 643–655.

  11. Blassl C., Kuhlmann J.D., Webers A., Wimberger P., Fehm T., Neubauer H. Gene expression profiling of single circulating tumor cells in ovarian cancer – Establishment of a multi-marker gene panel. Mol. Oncol. 2016; 10 (7): 1030–1042.

  12. Strauss R., Li Z.Y., Liu Y. Analysis of epithelial and mesenchymal markers in ovarian cancer reveals phenotypic heterogeneity and plasticity [published correction appears in PLoS One. 2011; 6 (2)]. PLoS One. 2011; 6 (1): e16186.

  13. Trinchieri G. Cancer and inflammation: an old intuition with rapidly evolving new concepts. Ann. Rev. Immunol. 2012; 30: 677–706.

  14. Klymenko Y., Nephew K.P. Epigenetic Crosstalk between the Tumor Microenvironment and Ovarian Cancer Cells: A Therapeutic Road Less Traveled. Cancers (Basel). 2018; 10 (9): 295.

  15. Li Y.C., Zou J.M., Luo C., Shu Y., Luo J., Qin J., Wang Y., Li D., Wang S.S., Chi G., Guo F., Zhang G.M., Feng Z.H. Circulating tumor cells promote the metastatic colonization of disseminated carcinoma cells by inducing systemic inflammation. Oncotarget. 2017; 8 (17): 28418–28430.

  16. Ning Y., Cui Y., Li X., Cao X., Chen A., Xu C., Cao J., Luo X. Co-culture of ovarian cancer stem-like cells with macrophages induced SKOV3 cells stemness via IL-8/STAT3 signaling. Biomed. Pharmacother. 2018; 103: 262–271.

  17. Yung M.M., Tang H.W., Cai P.C. GRO-α and IL-8 enhance ovarian cancer metastatic potential via the CXCR2-mediated TAK1/NFκB signaling cascade. Theranostics. 2018; 8 (5): 1270–1285.

  18. House C.D., Jordan E., Hernandez L. NFκB Promotes Ovarian Tumorigenesis via Classical Pathways That Support Proliferative Cancer Cells and Alternative Pathways That Support ALDH+ Cancer Stem-like Cells. Cancer Res. 2017; 77 (24): 6927–6940.

  19. Zhai J., Shen J., Xie G., Wu J., He M., Gao L., Zhang Y., Yao X., Shen L. Cancer-associated fibroblasts-derived IL-8 mediates resistance to cisplatin in human gastric cancer. Cancer Lett. 2019; 454: 37–43.

  20. Wang Y., Li L., Guo X., Jin X., Sun W., Zhang X., Xu R.C. Interleukin-6 signaling regulates anchorage-independent growth, proliferation, adhesion and invasion in human ovarian cancer cells. Cytokine. 2012; 59 (2): 228–36.

  21. Stronach E.A., Cunnea P., Turner C. The role of interleukin-8 (IL-8) and IL-8 receptors in platinum response in high grade serous ovarian carcinoma. Oncotarget. 2015; 6 (31): 31593–31603.

  22. Sanguinete M.M.M., Oliveira P.H., Martins-Filho A., Micheli D.C., Tavares-Murta B.M., Murta E.F.C., Nomelini R.S. Serum IL-6 and IL-8 Correlate with Prognostic Factors in Ovarian Cancer. Immunol. Invest. 2017; 46 (7): 677–688.

  23. Huh S.J., Liang S., Sharma A., Dong C., Robertson G.P. Transiently entrapped circulating tumor cells interact with neutrophils to facilitate lung metastasis development. Cancer Res. 2010; 70 (14): 6071–6082.

  24. Lohmann A.E., Dowling R.J.O., Ennis M., Amir E., Elser C., Brezden-Masley C., Vandenberg T., Lee E., Fazaee K., Stambolic V., Goodwin P.J., Chang M.C. Association of Metabolic, Inflammatory, and Tumor Markers With Circulating Tumor Cells in Metastatic Breast Cancer. JNCI Cancer Spectr. 2018; 2 (2): pky028.

  25. König A., Vilsmaier T., Rack B., Friese K., Janni W., Jeschke U., Andergassen U., Trapp E., Jückstock J., Jäger B., Alunni-Fabbroni M., Friedl T., Weissenbacher T., Success Study Group. Determination of Interleukin-4, -5, -6, -8 and -13 in Serum of Patients with Breast Cancer Before Treatment and its Correlation to Circulating Tumor Cells. Anticancer Res. 2016; 36 (6): 3123–3130.

  26. Kwon Y., Godwin A.K. Regulation of HGF and c-MET Interaction in Normal Ovary and Ovarian Cancer. Reprod. Sci. 2017; 24 (4): 494–501.

  27. Dorayappan K.D.P., Gardner M.L., Hisey C.L., Zingarelli R.A., Smith B.Q., Lightfoot M.D.S., Gogna R., Flannery M.M., Hays J., Hansford D.J., Freitas M.A., Yu L., Cohn D.E., Selvendiran K. A microfluidic chip enables isolation of exosomes and establishment of their protein profiles and associated signaling pathways in ovarian cancer. Cancer Res. 2019; 79 (13): 3503–3513.

  28. Spirina L.V., Kondakova I.V., Klisho E.V., Kakurina G.V., Shishkin D.A. Metalloproteinazy kak regulyatory neoangiogeneza v zlokachestvennykh novoobrazovaniyakh [Metalloproteinases as neoangiogenesis regulators in malignant neoplasms]. Sibirskiy onkologicheskiy zhurnal. 2007; 1: 67–71 (in Russian).

  29. Yasuda K., Nakanishi K., Tsutsui H. Interleukin-18 in Health and Disease. Int. J. Mol. Sci. 2019;

    20 (3): 649.

  30. Carbotti G., Barisione G., Orengo A.M., Brizzolara A., Airoldi I., Bagnoli M., Pinciroli P., Mezzanzanica D., Centurioni M.G., Fabbi M., Ferrini S. The IL-18 antagonist IL-18-binding protein is produced in the human ovarian cancer microenvironment. Clin. Cancer Res. 2013; 19 (17): 4611–4620.

  31. Orengo A.M., Fabbi M., Miglietta L., Andreani C., Bruzzone M., Puppo A., Cristoforoni P., Centurioni M.G., Gualco M., Salvi S., Boccardo S., Truini M., Piazza T., Canevari S., Mezzanzanica D., Ferrini S. Interleukin (IL)-18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor. Int. J. Cancer. 2011; 129 (5): 1116–1125.

  32. Ioana Braicu E., Mustea A., Toliat M.R., Pirvulescu C., Könsgen D., Sun P., Nürnberg P., Lichtenegger W., Sehouli J. Polymorphism of IL-1alpha, IL-1beta and IL-10 in patients with advanced ovarian cancer: results of a prospective study with 147 patients. Gynecol. Oncol. 2007; 104 (3): 680–685.

  33. Takaishi K., Komohara Y., Tashiro H., Ohtake H., Nakagawa T., Katabuchi H., Takeya M. Involvement of M2-polarized macrophages in the ascites from advanced epithelial ovarian carcinoma in tumor progression via Stat3 activation. Cancer Sci. 2010; 101 (10): 2128–2136.

  34. Szczerba B.M., Castro-Giner F., Vetter M., Krol I., Gkountela S., Landin J., Scheidmann M.C., Donato C., Scherrer R., Singer J., Beisel C., Kurzeder C., Heinzelmann-Schwarz V., Rochlitz C., Weber W.P., Beerenwinkel N., Aceto N. Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature. 2019; 566 (7745): 553–557.

  35. Lau T.S., Chan L.K., Wong E.C., Hui C.W., Sneddon K., Cheung T.H., Yim S.F., Lee J.H., Yeung C.S., Chung T.K., Kwong J. A loop of cancer-stroma-cancer interaction promotes peritoneal metastasis of ovarian cancer via TNFα-TGFα-EGFR. Oncogene. 2017; 36 (25): 3576–3587.

  36. Szlosarek P.W., Grimshaw M.J., Kulbe H., Wilson J.L., Wilbanks G.D., Burke F., Balkwill F.R. Expression and regulation of tumor necrosis factor alpha in normal and malignant ovarian epithelium. Mol. Cancer Ther. 2006; 5: 382–390.

  37. Piura B., Medina L., Rabinovich A., Dyomin V., Levy R.S., Huleihel M. Distinct expression and localization of TNF system in ovarian carcinoma tissues: possible involvement of TNF-alpha in morphological changes of ovarian cancerous cells. Anticancer Res. 2014; 34: 745–752.

  38. Kulbe H., Thompson R., Wilson J.L. The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells. Cancer Res. 2007; 67 (2): 585–592.

  39. Geng Y., Chandrasekaran S., Hsu J.W., Gidwani M., Hughes A.D., King M.R. Phenotypic switch in blood: effects of pro-inflammatory cytokines on breast cancer cell aggregation and adhesion. PLoS One. 2013; 8 (1): e54959.

  40. Reymond N., d’Água B.B., Ridley A.J. Crossing the endothelial barrier during metastasis. Nature Reviews Cancer. 2013; 13 (12): 858–870.

  41. Evani S.J., Prabhu R.G., Gnanaruban V., Finol E.A., Ramasubramanian A.K. Monocytes mediate metastatic breast tumor cell adhesion to endothelium under flow. FASEB J. 2013; 27 (8): 3017–3029.

  42. Trabert B., Pinto L., Hartge P., Kemp T., Black A., Sherman M.E., Brinton LA., Pfeiffer R.M., Shiels M.S., Chaturvedi A.K., Hildesheim A., Wentzensen N. Pre-diagnostic serum levels of inflammation markers and risk of ovarian cancer in the prostate, lung, colorectal and ovarian cancer (PLCO) screening trial. Gynecol. Oncol. 2014; 135 (2): 297–304.

  43. Elizabeth M. Poole, I-Min Lee, Paul M. Ridker, Julie E. Buring, Susan E. Hankinson, Shelley S. Tworoger. A Prospective Study of Circulating C-Reactive Protein, Interleukin-6, and Tumor Necrosis Factor α Receptor 2 Levels and Risk of Ovarian Cancer. Am. J. Epidemiol. 2013; 178 (8): 1256–1264.

  44. Treffers L.W., Hiemstra I.H., Kuijpers T.W., van den Berg T.K., Matlung H.L. Neutrophils in cancer. Immunol. Rev. 2016; 273 (1): 312–328.

  45. Fidler I.J., Poste G. The "seed and soil" hypothesis revisited. Lancet Oncol. 2008; 9 (8): 808.

  46. Vinogradova T.V., Chernov I.P., Monastyrskaya G.S., Kondrat'eva L.G., Sverdlov E.D. Rakovye stvolovye kletki: plastichnost' protiv terapii [Cancerous stem cells: plasticity versus therapy]. Acta Naturae (russkoyazychnaya versiya). 2015; 4 (27): 52–63 (in Russian).

  47. Liu Q., Zhang H., Jiang X., Qian C., Liu Z., Luo D. Factors involved in cancer metastasis: a better understanding to "seed and soil" hypothesis. Mol. Cancer. 2017; 16 (1): 176.

  48. Xu Z., Jiang Y., Steed H., Davidge S., Fu Y. TGFβ and EGF synergistically induce a more invasive phenotype of epithelial ovarian cancer cells. Biochem. Biophys. Res. Commun. 2010; 401 (3): 376–381.

  49. Yeung T.L., Leung C.S., Wong K.K. TGF-β modulates ovarian cancer invasion by upregulating CAF-derived versican in the tumor microenvironment. Cancer Res. 2013; 73 (16): 5016–5028.

  50. Lo C.W., Chen M.W., Hsiao M., Wang S., Chen C.A., Hsiao S.M., Chang J.S., Lai T.C., Rose-John S., Kuo M.L., Wei L.H. IL-6 trans-signaling in formation and progression of malignant ascites in ovarian cancer. Cancer Res. 2011; 71 (2): 424–434.

Received 28 June 2019; Accepted 05 November 2019.

 

Information about the authors

Gening Snezhanna Olegovna, Teaching Assistant, Chair of Physiology and Pathophysiology, Post-Graduate Student, Chair of Oncology and Radiology, Ulyanovsk State University. 432017, Russia, Ulyanovsk, L. Tolstoy St., 42; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: http://orcid.org/0000-0001-6970-6659

Gafurbaeva Dina Urkhanovna, Junior Researcher, Scientific Research Laboratory OpenLab “Genetic and Cellular Technologies”, Kazan Federal University. 420008, Russia, Kazan, Parizhskoy Kommuny St., 9; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: http://orcid.org/0000-0002-3305-1942

Miftakhova Regina Rivkatovna, Ph.D, Senior Researcher, Scientific Research Laboratory OpenLab “Genetic and Cellular Technologies”, Kazan Federal University. 420008, Russia, Kazan, Parizhskoy Kommuny St., 9; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. ORCID ID: http://orcid.org/0000-0002-6686-1968

Peskov Andrey Borisovich, Doctor of Sciences (Medicine), Professor, Dean, Department of Postgraduate Medical and Pharmaceutical Education, Ulyanovsk State University. 432017, Russia, Ulyanovsk, L. Tolstoy St., 42; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: http://orcid.org/0000-0001-7323-9934

 

For citation:

Gening S.O., Abakumova T.V., Antoneeva I.I., Gafurbaeva D.U., Miftakhova R.R., Dolgova D.R., Peskov A.B. Tsitokinovyy status syvorotki krovi bol'nykh rakom yaichnikov s razlichnym urovnem tsirkuliruyushchikh opukholevykh kletok [Blood serum cytokine status in ovarian cancer patients with different levels of circulating tumor cells]. Ulyanovsk Medico-Biological Journal. 2019; 4: 50–62. DOI: 10.34014/2227-1848-2019-4-50-62

 

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УДК 616-006.66:616-08-039.34

DOI 10.34014/2227-1848-2019-4-50-62

ЦИТОКИНОВЫЙ СТАТУС СЫВОРОТКИ КРОВИ БОЛЬНЫХ РАКОМ ЯИЧНИКОВ С РАЗЛИЧНЫМ УРОВНЕМ ЦИРКУЛИРУЮЩИХ ОПУХОЛЕВЫХ КЛЕТОК

С.О. Генинг¹, Т.В. Абакумова¹, И.И. Антонеева¹, Д.У. Гафурбаева², Р.Р. Мифтахова², Д.Р. Долгова¹, А.Б. Песков¹

1ФГБОУ ВО «Ульяновский государственный университет», г. Ульяновск, Россия;

2ФГАОУ ВО «Казанский (Приволжский) федеральный университет», г. Казань, Россия

 

Циркулирующие опухолевые клетки (ЦОК) представляют собой основу гематогенного метастазирования. В 2003 г. было продемонстрировано их существование в крови больных раком яичников (РЯ). Известно, что воспаление играет важную роль в прогрессировании опухолей. В крови ЦОК встречаются с большим количеством компонентов, в т.ч. с цитокинами, которые способны модулировать метастатический потенциал опухолевой клетки.

Целью данного исследования была оценка цитокинового статуса сыворотки крови больных раком яичников с различным уровнем циркулирующих опухолевых клеток.

Материалы и методы. Объектом исследования явились первичные больные с верифицированным (гистологически либо цитологически) раком яичников II–IV степеней по FIGO (n=24) до лечения. В крови пациенток определяли число циркулирующих опухолевых клеток методом проточной цитофлюориметрии и уровни IL-6, IL-17A, IL-1β, TGF-α, IL-4, VEGF, TNF-α, HGF, IL-18, IL-10, IL-8. Обработку результатов проводили с использованием пакета программ Statistica Windows.

Результаты. Было установлено, что уровень цитокинов TNF-α, HGF, IL-10, IL-18 в сыворотке крови больных РЯ статистически значимо повышался, а уровень IL-8 снижался с увеличением количества ЦОК.

Выводы. Полученные результаты позволяют предполагать корреляцию уровня ЦОК с сывороточным уровнем цитокинов TNF-α, HGF, IL-10, IL-18, IL-8 у больных распространенным РЯ. При этом резкое и значимое возрастание уровня TNF-α при увеличении числа ЦОК может свидетельствовать о смене фенотипов TNF-продуцирующих клеток при РЯ.

Ключевые слова: рак яичников, цитокины, циркулирующие опухолевые клетки.

Конфликт интересов. Авторы заявляют об отсутствии конфликта интересов.

 

Литература

  1. Judson P.L., Geller M.A., Bliss R.L., Boente M.P., Downs L.S., Argenta P.A. Preoperative detection of peripherally circulating cancer cells and its prognostic significance in ovarian cancer. Gynecologic oncology. 2003; 91 (2): 389–394.

  2. Pearl M.L., Zhao Q., Yang J., Dong H., Tulley S., Zhang Q. Prognostic analysis of invasive circulating tumor cells (iCTCs) in epithelial ovarian cancer. Gynecologic oncology. 2014; 134 (3): 581–590.

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

  4. Aceto N., Bardia A., Miyamoto D.T. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014; 158 (5): 1110–1122.

  5. Klein C.A. Framework models of tumor dormancy from patient-derived observations. Current Opinion in Genetics & Development. 2011; 21 (1): 42–49.

  6. Bonnomet A., Syne L., Brysse A. 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.

  7. Kim M.Y., Oskarsson T., Acharyya S., Nguyen D.X., Zhang X.H., Norton L., Massagué J. Tumor self-seeding by circulating cancer cells. Cell. 2009; 139 (7): 1315–1326.

  8. Škovierová H., Okajčeková T., Strnádel J., Vidomanová E., Halašová E. Molecular regulation of epithelial-to-mesenchymal transition in tumorigenesis (Review). Int. J. Mol. Med. 2018; 41 (3): 1187–1200.

  9. Moffitt L., Karimnia N., Stephens A., Bilandzic M. Therapeutic Targeting of Collective Invasion in Ovarian Cancer. Int. J. Mol. Sci. 2019; 20 (6): 1466.

  10. Hudson L.G., Zeineldin R., Stack M.S. Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression. Clin. Exp. Metastasis. 2008; 25 (6): 643–655.

  11. Blassl C., Kuhlmann J.D., Webers A., Wimberger P., Fehm T., Neubauer H. Gene expression profiling of single circulating tumor cells in ovarian cancer – Establishment of a multi-marker gene panel. Mol. Oncol. 2016; 10 (7): 1030–1042.

  12. Strauss R., Li Z.Y., Liu Y. Analysis of epithelial and mesenchymal markers in ovarian cancer reveals phenotypic heterogeneity and plasticity [published correction appears in PLoS One. 2011; 6 (2)]. PLoS One. 2011; 6 (1): e16186.

  13. Trinchieri G. Cancer and inflammation: an old intuition with rapidly evolving new concepts. Ann. Rev. Immunol. 2012; 30: 677–706.

  14. Klymenko Y., Nephew K.P. Epigenetic Crosstalk between the Tumor Microenvironment and Ovarian Cancer Cells: A Therapeutic Road Less Traveled. Cancers (Basel). 2018; 10 (9): 295.

  15. Li Y.C., Zou J.M., Luo C., Shu Y., Luo J., Qin J., Wang Y., Li D., Wang S.S., Chi G., Guo F., Zhang G.M., Feng Z.H. Circulating tumor cells promote the metastatic colonization of disseminated carcinoma cells by inducing systemic inflammation. Oncotarget. 2017; 8 (17): 28418–28430.

  16. Ning Y., Cui Y., Li X., Cao X., Chen A., Xu C., Cao J., Luo X. Co-culture of ovarian cancer stem-like cells with macrophages induced SKOV3 cells stemness via IL-8/STAT3 signaling. Biomed. Pharmacother. 2018; 103: 262–271.

  17. Yung M.M., Tang H.W., Cai P.C. GRO-α and IL-8 enhance ovarian cancer metastatic potential via the CXCR2-mediated TAK1/NFκB signaling cascade. Theranostics. 2018; 8 (5): 1270–1285.

  18. House C.D., Jordan E., Hernandez L. NFκB Promotes Ovarian Tumorigenesis via Classical Pathways That Support Proliferative Cancer Cells and Alternative Pathways That Support ALDH+ Cancer Stem-like Cells. Cancer Res. 2017; 77 (24): 6927–6940.

  19. Zhai J., Shen J., Xie G., Wu J., He M., Gao L., Zhang Y., Yao X., Shen L. Cancer-associated fibroblasts-derived IL-8 mediates resistance to cisplatin in human gastric cancer. Cancer Lett. 2019; 454: 37–43.

  20. Wang Y., Li L., Guo X., Jin X., Sun W., Zhang X., Xu R.C. Interleukin-6 signaling regulates anchorage-independent growth, proliferation, adhesion and invasion in human ovarian cancer cells. Cytokine. 2012; 59 (2): 228–36.

  21. Stronach E.A., Cunnea P., Turner C. The role of interleukin-8 (IL-8) and IL-8 receptors in platinum response in high grade serous ovarian carcinoma. Oncotarget. 2015; 6 (31): 31593–31603.

  22. Sanguinete M.M.M., Oliveira P.H., Martins-Filho A., Micheli D.C., Tavares-Murta B.M., Murta E.F.C., Nomelini R.S. Serum IL-6 and IL-8 Correlate with Prognostic Factors in Ovarian Cancer. Immunol. Invest. 2017; 46 (7): 677–688.

  23. Huh S.J., Liang S., Sharma A., Dong C., Robertson G.P. Transiently entrapped circulating tumor cells interact with neutrophils to facilitate lung metastasis development. Cancer Res. 2010; 70 (14): 6071–6082.

  24. Lohmann A.E., Dowling R.J.O., Ennis M., Amir E., Elser C., Brezden-Masley C., Vandenberg T., Lee E., Fazaee K., Stambolic V., Goodwin P.J., Chang M.C. Association of Metabolic, Inflammatory, and Tumor Markers With Circulating Tumor Cells in Metastatic Breast Cancer. JNCI Cancer Spectr. 2018; 2 (2): pky028.

  25. König A., Vilsmaier T., Rack B., Friese K., Janni W., Jeschke U., Andergassen U., Trapp E., Jückstock J., Jäger B., Alunni-Fabbroni M., Friedl T., Weissenbacher T., Success Study Group. Determination of Interleukin-4, -5, -6, -8 and -13 in Serum of Patients with Breast Cancer Before Treatment and its Correlation to Circulating Tumor Cells. Anticancer Res. 2016; 36 (6): 3123–3130.

  26. Kwon Y., Godwin A.K. Regulation of HGF and c-MET Interaction in Normal Ovary and Ovarian Cancer. Reprod. Sci. 2017; 24 (4): 494–501.

  27. Dorayappan K.D.P., Gardner M.L., Hisey C.L., Zingarelli R.A., Smith B.Q., Lightfoot M.D.S., Gogna R., Flannery M.M., Hays J., Hansford D.J., Freitas M.A., Yu L., Cohn D.E., Selvendiran K. A microfluidic chip enables isolation of exosomes and establishment of their protein profiles and associated signaling pathways in ovarian cancer. Cancer Res. 2019; 79 (13): 3503–3513.

  28. Спирина Л.В., Кондакова И.В., Клишо Е.В., Какурина Г.В., Шишкин Д.А. Металлопротеиназы как регуляторы неоангиогенеза в злокачественных новообразованиях. Сибирский онкологический журнал. 2007; 1: 67–71.

  29. Yasuda K., Nakanishi K., Tsutsui H. Interleukin-18 in Health and Disease. Int. J. Mol. Sci. 2019; 20 (3): 649.

  30. Carbotti G., Barisione G., Orengo A.M., Brizzolara A., Airoldi I., Bagnoli M., Pinciroli P., Mezzanzanica D., Centurioni M.G., Fabbi M., Ferrini S. The IL-18 antagonist IL-18-binding protein is produced in the human ovarian cancer microenvironment. Clin. Cancer Res. 2013; 19 (17): 4611–4620.

  31. Orengo A.M., Fabbi M., Miglietta L., Andreani C., Bruzzone M., Puppo A., Cristoforoni P., Centurioni M.G., Gualco M., Salvi S., Boccardo S., Truini M., Piazza T., Canevari S., Mezzanzanica D., Ferrini S. Interleukin (IL)-18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor. Int. J. Cancer. 2011; 129 (5): 1116–1125.

  32. Ioana Braicu E., Mustea A., Toliat M.R., Pirvulescu C., Könsgen D., Sun P., Nürnberg P., Lichtenegger W., Sehouli J. Polymorphism of IL-1alpha, IL-1beta and IL-10 in patients with advanced ovarian cancer: results of a prospective study with 147 patients. Gynecol. Oncol. 2007; 104 (3): 680–685.

  33. Takaishi K., Komohara Y., Tashiro H., Ohtake H., Nakagawa T., Katabuchi H., Takeya M. Involvement of M2-polarized macrophages in the ascites from advanced epithelial ovarian carcinoma in tumor progression via Stat3 activation. Cancer Sci. 2010; 101 (10): 2128–2136.

  34. Szczerba B.M., Castro-Giner F., Vetter M., Krol I., Gkountela S., Landin J., Scheidmann M.C., Donato C., Scherrer R., Singer J., Beisel C., Kurzeder C., Heinzelmann-Schwarz V., Rochlitz C., Weber W.P., Beerenwinkel N., Aceto N. Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature. 2019; 566 (7745): 553–557.

  35. Lau T.S., Chan L.K., Wong E.C., Hui C.W., Sneddon K., Cheung T.H., Yim S.F., Lee J.H., Yeung C.S., Chung T.K., Kwong J. A loop of cancer-stroma-cancer interaction promotes peritoneal metastasis of ovarian cancer via TNFα-TGFα-EGFR. Oncogene. 2017; 36 (25): 3576–3587.

  36. Szlosarek P.W., Grimshaw M.J., Kulbe H., Wilson J.L., Wilbanks G.D., Burke F., Balkwill F.R. Expression and regulation of tumor necrosis factor alpha in normal and malignant ovarian epithelium. Mol. Cancer Ther. 2006; 5: 382–390.

  37. Piura B., Medina L., Rabinovich A., Dyomin V., Levy R.S., Huleihel M. Distinct expression and localization of TNF system in ovarian carcinoma tissues: possible involvement of TNF-alpha in morphological changes of ovarian cancerous cells. Anticancer Res. 2014; 34: 745–752.

  38. Kulbe H., Thompson R., Wilson J.L. The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells. Cancer Res. 2007; 67 (2): 585–592.

  39. Geng Y., Chandrasekaran S., Hsu J.W., Gidwani M., Hughes A.D., King M.R. Phenotypic switch in blood: effects of pro-inflammatory cytokines on breast cancer cell aggregation and adhesion. PLoS One. 2013; 8 (1): e54959.

  40. Reymond N., d’Água B.B., Ridley A.J. Crossing the endothelial barrier during metastasis. Nature Reviews Cancer. 2013; 13 (12): 858–870.

  41. Evani S.J., Prabhu R.G., Gnanaruban V., Finol E.A., Ramasubramanian A.K. Monocytes mediate metastatic breast tumor cell adhesion to endothelium under flow. FASEB J. 2013; 27 (8): 3017–3029.

  42. Trabert B., Pinto L., Hartge P., Kemp T., Black A., Sherman M.E., Brinton LA., Pfeiffer R.M., Shiels M.S., Chaturvedi A.K., Hildesheim A., Wentzensen N. Pre-diagnostic serum levels of inflammation markers and risk of ovarian cancer in the prostate, lung, colorectal and ovarian cancer (PLCO) screening trial. Gynecol. Oncol. 2014; 135 (2): 297–304.

  43. Elizabeth M. Poole, I-Min Lee, Paul M. Ridker, Julie E. Buring, Susan E. Hankinson, Shelley S. Tworoger. A Prospective Study of Circulating C-Reactive Protein, Interleukin-6, and Tumor Necrosis Factor α Receptor 2 Levels and Risk of Ovarian Cancer. Am. J. Epidemiol. 2013; 178 (8): 1256–1264.

  44. Treffers L.W., Hiemstra I.H., Kuijpers T.W., van den Berg T.K., Matlung H.L. Neutrophils in cancer. Immunol. Rev. 2016; 273 (1): 312–328.

  45. Fidler I.J., Poste G. The "seed and soil" hypothesis revisited. Lancet Oncol. 2008; 9 (8): 808.

  46. Виноградова Т.В., Чернов И.П., Монастырская Г.С., Кондратьева Л.Г., Свердлов Е.Д. Раковые стволовые клетки: пластичность против терапии. Acta Naturae (русскоязычная версия). 2015; 4 (27): 52–63.

  47. Liu Q., Zhang H., Jiang X., Qian C., Liu Z., Luo D. Factors involved in cancer metastasis: a better understanding to "seed and soil" hypothesis. Mol. Cancer. 2017; 16 (1): 176.

  48. Xu Z., Jiang Y., Steed H., Davidge S., Fu Y. TGFβ and EGF synergistically induce a more invasive phenotype of epithelial ovarian cancer cells. Biochem. Biophys. Res. Commun. 2010; 401 (3): 376–381.

  49. Yeung T.L., Leung C.S., Wong K.K. TGF-β modulates ovarian cancer invasion by upregulating CAF-derived versican in the tumor microenvironment. Cancer Res. 2013; 73 (16): 5016–5028.

  50. Lo C.W., Chen M.W., Hsiao M., Wang S., Chen C.A., Hsiao S.M., Chang J.S., Lai T.C., Rose-John S., Kuo M.L., Wei L.H. IL-6 trans-signaling in formation and progression of malignant ascites in ovarian cancer. Cancer Res. 2011; 71 (2): 424–434.

Поступила в редакцию 28.06.2019; принята 05.11.2019.

 

Авторский коллектив

Генинг Снежанна Олеговна – ассистент кафедры физиологии и патофизиологии, аспирант кафедры онкологии и лучевой диагностики, ФГБОУ ВО «Ульяновский государственный университет». 432017, Россия, г. Ульяновск, ул. Л. Толстого, 42; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: http://orcid.org/0000-0001-6970-6659

Гафурбаева Дина Урхановна – младший научный сотрудник, НИЛ OpenLab «Генные и клеточные технологии» ФГАОУ ВО «Казанский (Приволжский) федеральный университет». 420008, Россия, г. Казань, ул. Парижской Коммуны, 9; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: http://orcid.org/0000-0002-3305-1942

Мифтахова Регина Ривкатовна – Ph.D., старший научный сотрудник, НИЛ OpenLab «Генные и клеточные технологии», ФГАОУ ВО «Казанский (Приволжский) федеральный университет». 420008, Россия, г. Казань, ул. Парижской Коммуны, 9; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. ORCID ID: http://orcid.org/0000-0002-6686-1968

Песков Андрей Борисович – доктор медицинских наук, профессор, декан факультета постдипломного медицинского и фармацевтического образования, ФГБОУ ВО «Ульяновский государственный университет». 432017, Россия, г. Ульяновск, ул. Л. Толстого, 42; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: http://orcid.org/0000-0001-7323-9934

 

Образец цитирования

Генинг С.О., Абакумова Т.В., Антонеева И.И., Гафурбаева Д.У., Мифтахова Р.Р., Долгова Д.Р., Песков А.Б. Цитокиновый статус сыворотки крови больных раком яичников с различным уровнем циркулирующих опухолевых клеток. Ульяновский медико-биологический журнал. 2019; 4: 50–62. DOI: 10.34014/2227-1848-2019-4-50-62