Age-related characteristics of the content and activity of certain components of the blood fibrinolytic system in cases of uterine cancer

Uterine cancer (UC) is the third most common cancer in women in Russia. Knowledge of age-specific features of the fibrinolytic system in patients with UC can be useful in terms of improving its pathogenetic therapy. Aim of the study was to investigate the peculiarities of the content and activity of some components of the fibrinolytic system in the blood of UC patients of different age groups. Material and methods. 30 healthy women (donors) and 56 patients with uterine cancer T1a-2N0M0, adenocarcinoma G1–G3 were divided into subgroups according to age: reproductive, perimenopause and menopause. ELISA of urokinase (u-PA), its receptor (u-PAR) and its inhibitor (PAI-1), tissue-type plasminogen activator (t-PA) content were performed in blood collected before treatment. Results. In reproductive UC patients, inhibitor u-PA (PAI-1) activity increased 14-fold (hereinafter the difference is statistically significant, p < 0.05) and content increased 2.9-fold, while receptor u-PA (u-PAR) level decreased 1.7-fold compared to reproductive donors. Perimenopausal UC patients showed a 3.3-fold increase in PAI-1 content and a 6.3-fold increase in PAI-1 activity compared to perimenopausal donors, t-PA concentration decreased 1.3-fold relative to donors and was 1.9-fold lower than in reproductive UC patients. In menopausal patients with UC, the activity and content of PAI-1 enhanced 5.5-fold and 4.5-fold, respectively, compared to donors. Additionally, they were 2.1-fold and 1.2-fold lower than in reproductive UC patients. The activity of u-PA increased 2.6-fold, reaching the values of reproductive UC patients. The activity of t-PA was 1.3-fold higher than in donors, but did not differ from the activity in other RTM patients, while the level of t-PA occupied an intermediate position between the corresponding indices in young UC patients (it was 1.4-fold lower) and perimenopausal UC patients (it was 1.4-fold higher). Conclusions. The development of UC is accompanied by an imbalance of components of the fibrinolytic system in the blood, depending on the age of women, with a minimum spectrum of changes in the indicators in reproductive patients and maximum - in menopause patients, which indicates the pathognomonicity of these factors in PTM and requires an individual approach to the management of such patients.

1. Mimoune N., Azzouz M.Yа., Benadjel U., Khelef D., Kaidi R. Uterine cancer at a glance. Journal of Siberian Medical Sciences. 2021;(3):116–136. [In Russian]. doi: 10.31549/2542-1174-2021-3-116-136

2. Yucel Celik O., Unsal M., Kilic F., Unsal P., Aytekin O., Cakir C., Kimyon Comert G., Turkmen O., Turan T. Defining prognostic factors in older patients with endometrial cancer. Ir. J. Med. Sci. 2022;191(3):1123–1131. doi: 10.1007/s11845-021-02663-7

3. Morkhov K.Yu., Kreinina Yu.M., Pokataev I.A., Nechushkina V.M. Interdisciplinary approach to the management of patients with uterine cancer progression. Opukholi zhenskoy reproduktivnoy sistemy = Women Reproductive System Tumors. 2022;18(1):87– 96. [In Russian]. doi: 10.17650/1994-4098-2022-18-1-87-96

4. Malignant neoplasms in Russia in 2020 (morbidity and mortality). Ed. А.В. Kaprin, V.V. Starinsky, A.O. Shakhzadovа. Moscow: MNIOI, 2022. 252 р [In Russian].

5. Miller K.D., Nogueira L., Devasia T., Mariotto A.B., Yabroff K.R., Jemal A., Kramer J., Siegel R.L. Cancer treatment and survivorship statistics, 2022. CA Cancer J. Clin. 2022;72(5):409–436. doi: 10.3322/caac.21731

6. Somasegar S., Bashi A., Lang S.M., Liao C.I., Johnson C., Darcy K.M., Tian C., Kapp D.S., Chan J.K. Trends in uterine cancer mortality in the United States: a 50-year population-based analysis. Obstet. Gynecol. 2023;142(4):978–986. doi: 10.1097/AOG.0000000000005321

7. Luzarraga-Aznar A., Teixeira N., Luna-Guibourg R., Español P., Soler-Moreno C., Rovira R. Surgical treatment in older patients with endometrial cancer: A retrospective study. Surg. Oncol. 2022;44:101852. doi: 10.1016/j.suronc.2022.101852

8. Moiseenko T.I., Nepomnyashchaya E.M., Shishkina O.G., Vovkochina M.A. Morphological features of endometrial cancer in patients of different ages. Nauchnye vedomosti Belgorodskogo gosudarstvennogo universiteta. Seriya: Meditsina. Farmatsiya = Scientific Statements of Belgorod State University. Series: Medicine. Pharmacy. 2012;(10):36–39. [In Russian].

9. Gavrish Yu.E., Berlev I.V., Artemieva A.S. Uterine cancer in older women: what are its distinguishing characteristics? Opukholi zhenskoy reproduktivnoy sistemy = Women Reproductive System Tumors. 2017;13(2): 56–60. [In Russian]. doi: 10.17650/1994-4098-2017-13-2-56-60

10. Koensgen D., Stope M.B., Tuerbachova I., Bruennert D., Kohlmann T., Braicu I., Sehouli J., Denkert C., Darb-Esfahani S., Stickeler E., Sofroni D., Dahl E., Mustea A. Expression, intracellular localization, and prognostic value of plasminogen activator inhibitor 1 and PAI-1 RNA-binding protein 1 in primary and recurrent ovarian cancer: A study of the Tumor Bank Ovarian Cancer Network. Gynecol. Obstet. Invest. 2018;83(5):508–514. doi: 10.1159/000479027

11. Nantajit D., Chailapakul P., Bawornpatarapakorn S., Chamchod S., Laebua K. Prognostic significance of uPA and uPAR expression in patients with cervical cancer undergoing radiotherapy. Oncol. Lett. 2021;21(5):423. doi: 10.3892/ol.2021.12684

12. Madunić J. The urokinase plasminogen activator system in human cancers: An overview of its prognostic and predictive role. Thromb Haemost. 2018;118(12):2020–2036. doi: 10.1055/s-0038-1675399

13. Liu Q., Li W., Yang S., Liu Z. High expression of uPA related to p38MAPK in esophageal cancer indicates poor prognosis. Onco Targets Ther. 2018;11:8427–8434. doi: 10.2147/OTT.S181701

14. Fang L., Xu Q., Qian J., Zhou J.Y. Aberrant factors of fibrinolysis and coagulation in pancreatic cancer. Onco Targets Ther. 2021;14:53–65. doi: 10.2147/OTT.S281251

15. Frantsiyants E.M., Komarova E.F., Vereskunova M.I., Cheryarina N.D. Condition of tissue fibrinolytic system in case of tumors of women’s reproductive system. Uspekhi sovremennogo yestestvoznaniya = Advances in Current Natural Sciences. 2014;4:46–48. [In Russian].

16. Li S., Wei X., He J., Tian X., Yuan S., Sun L. Plasminogen activator inhibitor-1 in cancer research. Biomed. Pharmacother. 2018;105:83–94. doi: 10.1016/j.biopha.2018.05.119

17. Kubala M.H., Punj V., Placencio-Hickok V.R., Fang H., Fernandez G.E., Sposto R., deClerck Y.A. Plasminogen activator inhibitor-1 promotes the recruitment and polarization of macrophages in cancer. Cell Rep. 2018;25(8):2177–2191.e7. doi: 10.1016/j.celrep.2018.10.082

18. Furuya H., Sasaki Y., Chen R., Peres R., Hokutan K., Murakami K., Kim N., Chan O.T.M., Pagano I., Dyrskjøt L., … Rosser C.J. PAI-1 is a potential transcriptional silencer that supports bladder cancer cell activity. Sci. Rep. 2022;12(1):12186. doi: 10.1038/s41598-022-16518-3

19. Wang J., Peng Y., Guo H., Li C. PAI-1 polymorphisms have significant associations with cancer risk, especially feminine cancer. Technol. Cancer Res. Treat. 2021;20:15330338211037813. doi: 10.1177/15330338211037813

20. Kaplieva I.V., Zakharchenko V.R., Frantsiyants E.M., Verenikina E.V., Guskova N.K., Pogorelova Y.A., Trepitaki L.K., Myagkova T.Y., Rozenko L.Y. Age-related characteristics of the blood fibrinolytic system in women with uterine fibroid. Sovremennye problemy nauki i obrazovaniya = Modern Problems of Science and Education. 2024;(3):1. [In Russian]. doi: 10.17513/spno.33364

21. Kwaan H.C., Lindholm P.F. Fibrin and fibrinolysis in cancer. Semin. Thromb. Hemost. 2019;45(4):413– 422. doi: 10.1055/s-0039-1688495