DYNAMICS OF THE TISSUE SYSTEM OF PLASMINOGEN REGULATORS IN CUTANEOUS MELANOMA WITH CHRONIC PAIN IN FEMALE MICE

Background. Chronic pain is a pathologic process changing the whole body metabolism.

Objective: determination of plasminogen regulators in tissues of cutaneous melanoma and in the skin tissues not associated with the tumor in female mice in the dynamics of the growth of experimental melanoma with chronic neurogenic pain.

Design and methods. в16/F10 melanoma with chronic pain was reproduced in female С57вL/6 mice. Plasmin-alpha2-antiplasmin complex (PAP), urokinase (pro-uPA and uPA) and tissue (pro-tPA and tPA) plasminogen activators, the uPA (uPAR) receptor and serpin-1 (PAI-1) were determined by ELISA using standard test systems. Results were analyzed using the Statistica 10 program.

Results. Chronic neurogenic pain was accompanied by significant changes in the fibrinolysis components in the skin of female С57вL/6 mice. After the в16/ F10 melanoma transplantation (1-3 weeks), skin and tumor tissues showed higher levels of рар and the uPAR receptor (p<0.05), decreased levels of pro-uPA and uPA, pro-tPA and tPA, and PAI-1 (p<0.05), compared to the comparison group (standard melanoma model).

Conclusion. Analysis of the state of the tissue fibrinolysis in the skin and tumors of female С57вL/6 mice demonstrated that during the tumor formation with chronic neurogenic pain, plasmin, tPA, uPA, uPAR and PAI-1 play a leading role in the rapid growth and increased malignancy of melanoma. The study of the proposed model will make it possible to clarify many questions of carcinogenesis and the generalization of the malignant process. Studying the model can clarify many issues of the carcinogenesis and progression of the malignant process.

1. Kumar A, Kaur H, Singh A. Neuropathic Pain models caused by damage to central or peripheral nervous system. Pharmacol Rep. 2018; 70(2): 206-216.

2. Yamanaka H, Obata K, Fukuoka T., et al. Tissue plasminogen activator in primary afferents induces dorsal horn excitability and pain response after peripheral nerve injury. Eur J Neurosci. 2004; 19: 93-102.

3. Yamanaka H, Obata K, Fukuoka T., et al. Induction of plasminogen activator inhibitor-1 and -2 in dorsal root ganglion neurons after peripheral nerve injury. Neuroscience. 2005; 132:183-191.

4. Kozai T, Yamanaka H, Dai Y., et al. Tissue type plasminogen activator induced in rat dorsal horn astrocytes contributes to mechanical hypersensitivity following dorsal root injury. Glia. 2007; 55: 595-603.

5. Berta T, Liu YC, Xu ZZ, Ji RR. Tissue plasminogen activator contributes to morphine tolerance and induces mechanical allodynia via astrocytic IL-1β and ERK signaling in the spinal cord of mice. Neuroscience. 2013;247:376385.

6. Chlebowski RT, Col N. Bisphosphonates and breast cancer prevention. Anticancer Agents Med. Chem. 2012; 12(2): 144-150.

7. Yamanaka H, Kobayashi K, Okubo M., et al. Annexin A2 in primary afferents contributes to neuropathic pain associated with tissue type plasminogen activator. Neuroscience. 2016; 314: 189-199. 8. Nishioka N, Matsuoka T, Yashiro M., et al. Plasminogen activator inhibitor 1 RNAi suppresses gastric cancer metastasis in vivo. Cancer Sci. 2012; 103(2): 228-232.

8. Valiente M, Obenauf AC, Jin X., et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell. 2014; 156(5): 1002-1016.

9. Sato M, Kawana K, Adachi K., et al. Decreased expression of the plasminogen activator inhibitor type 1 is involved in degradation of extracellular matrix surrounding cervical cancer stem cells. Int J Oncol. 2016; 48(2): 829835.

10. Kit OI, Frantsiyants EM, Kotieva IM., et al. Some mechanisms of increasing malignancy of B16/ F10 melanoma in female mice with chronic pain. Russian Journal of Pain. 2017; 53 (2): 14-20. In Russian

11. Kit OI, Frantsiyants EM, Kotieva IM et al. The effect of chronic pain on the dynamics of some growth factors in the intact and pathologically altered skin of female mice with в16/ F10 melanoma. Russian Journal of Pain. 20172; (3-4): 37-44. In Russian

12. Dingemanе KP. B-16 melanoma metastasis in mouse liver and lung. Inv. Metast. 1985; (5): 50-60.

13. Ji RR, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain. 2013;154 Suppl 1:S10-28.

14. Wu F, Catano M, Echeverry R, et al. Urokinase-type plasminogen activator promotes dendritic spine recovery and improves neurological outcome following ischemic stroke. J Neurosci. 2014;34(43):14219-14232.

15. Mahmood N, Mihalcioiu C, Rabbani SA. Multifaceted Role of the Urokinase-Type Plasminogen Activator (uPA) and Its Receptor (uPAR): Diagnostic, Prognostic, and Therapeutic Applications. Front Oncol. 2018;8:24.

16. Merino P, Diaz A, Jeanneret V, et al. Urokinase-type Plasminogen Activator (uPA) Binding to the uPA Receptor (uPAR) Promotes Axonal Regeneration in the Central Nervous System. J Biol Chem. 2017;292(7):2741-2753.

17. Mazzieri R, Pietrogrande G, Gerasi L, et al. Urokinase Receptor Promotes Skin Tumor Formation by Preventing Epithelial Cell Activation of Notch1. Cancer Res. 2015; 75(22):4895-4909. 19. Gonias SL, Hu J. Urokinase receptor and resistance to targeted anticancer agents. Front Pharmacol. 2015; (6): 154.

18. Pavón MA, Arroyo-Solera I, Céspedes MV, et al. uPA/uPAR and SERPINE1 in head and neck cancer: role in tumor resistance, metastasis, prognosis and therapy. Oncotarget. 2016;7(35):57351-57366.

19. Chen JS, Chang LC, Wu CZ, et al. Significance of the urokinase-type plasminogen activator and its receptor in the progression of focal segmental glomerulosclerosis in clinical and mouse models. J Biomed Sci. 2016; 23: 24.

20. Schuliga M. The inflammatory actions of coagulant and fibrinolytic proteases in disease. Mediators Inflamm. 2015; 2015: 437695.

21. Santibanez JF, Obradović H, Kukolj T, Krstić J. Transforming growth factor-β, matrix metalloproteinases, and urokinase-type plasminogen activator interaction in the cancer epithelial to mesenchymal transition. Dev Dyn. 2018; 247(3): 382-395.

22. Santibanez JF. Transforming growth factor-Beta and urokinase-type plasminogen activator: dangerous partners in tumorigenesis-implications in skin cancer. ISRN Dermatol. 2013; 2013: 597927.