transmedТрансляционная медицинаTranslational Medicine2311-44952410-5155Almazov National Medical Research Centre, Saint Petersburg, Russia10.18705/2311-4495-2018-5-2-38-46transmed-375Research ArticleОНКОЛОГИЧЕСКИЕ ЗАБОЛЕВАНИЯCANCERДИНАМИКА ТКАНЕВОЙ СИСТЕМЫ РЕГУЛЯТОРОВ ПЛАЗМИНОГЕНА ПРИ МЕЛАНОМЕ КОЖИ НА ФОНЕ ХРОНИЧЕСКОЙ БОЛИ У САМОК МЫШЕЙDYNAMICS OF THE TISSUE SYSTEM OF PLASMINOGEN REGULATORS IN CUTANEOUS MELANOMA WITH CHRONIC PAIN IN FEMALE MICEКитО. И.KitO. I.

Кит Олег Иванович - член-корр. РАН, доктор медицинских наук, профессор, заслуженный врач РФ, генеральный директор.

Ростов-на-Дону

Oleg I. Kit - corresponding member of RAS, Dr.Sci., professor, honored doctor of the Russian Federation, general director.

Rostov-on-Don

ФранциянцЕ. М.FrantsiyantsE. M.

Франциянц Елена Михайловна – доктор биологических наук, профессор, зам. генерального директора РНИОИ по науке, рук. «Лаборатории изучения патогенеза злокачественных опухолей».

Ростов-на-Дону

Elena M. Frantsiyants - Dr.Sci., professor, deputy general director for science, head of laboratory of Malignant Tumor Pathogenesis Study.

Rostov-on-Don

КотиеваМ. М.KotievaI. M.

Котиева Инга Мавликиевна - кандидат медицинских наук, старший научный сотрудник.

Ростов-на-Дону

Inga M. Kotieva - PhD, senior researcher.

Rostov-on-Don

КаплиеваИ. В.KaplievaI. V.

Каплиева Ирина Викторовна - кандидат медицинских наук, старший научный сотрудник.

Ростов-на-Дону

Irina V. Kaplieva - PhD, senior researcher.

Rostov-on-Don

ТрепитакиЛ. К.TrepitakiL. K.

Трепитаки Лидия Константиновна - научный сотрудник.

Ростов-на-Дону

Lidia K. Trepitaki – researcher.

Rostov-on-Don

БандовкинаВ. А.BandovkinaV. A.

Бандовкина Валерия Ахтямовна – кандидат биологических наук, старший научный сотрудник.

Ростов-на-Дону

Valeria A. Bandovkina - PhD, senior researcher.

Rostov-on-Don

https://orcid.org/0000-0002-3907-0976КозловаЛ. С.KozlovaL. S.

Козлова Лариса Степановна – кандидат биологических наук, старший научный сотрудник.

14-я линия, д.63, Ростов-на-Дону, 344037, SPIN-код РИНЦ 5299-5451

Larisa S. Kozlova - PhD, Associate Professor, senior researcher.

Rostov-on-Don

super.gormon@yandex.ruПогореловаЮ. А.PogorelovaYu. A.

Погорелова Юлия Александровна - кандидат биологических наук, старший научный сотрудник.

Ростов-на-Дону

Yulia A. Pogorelova - PhD, senior researcher.

Rostov-on-Don

РозенкоЛ. Я.RozenkoL. Ya.

Розенко Людмила Яковлевна - доктор медицинских наук, профессор, главный научный сотрудник.

Ростов-на-Дону

Lyudmila Ya. Rozenko - Dr.Sci., professor, chief researcher.

Rostov-on-Don

ЧеряринаН. Д.CheryarinaN. D.

Черярина Наталья Дмитриевна - врач-лаборант.

Natalia D. Cheryarina - laboratory doctor.

Rostov-on-Don

Федеральное государственное бюджетное учреждение «Ростовский научно-исследовательский онкологический институт» Министерства здравоохранения Российской ФедерацииРоссияRostov Research Institute of OncologyRussian Federation201817062018523846Copyright © Кит О.И., Франциянц Е.М., Котиева М.М., Каплиева И.В., Трепитаки Л.К., Бандовкина В.А., Козлова Л.С., Погорелова Ю.А., Розенко Л.Я., Черярина Н.Д., 20182018Кит О.И., Франциянц Е.М., Котиева М.М., Каплиева И.В., Трепитаки Л.К., Бандовкина В.А., Козлова Л.С., Погорелова Ю.А., Розенко Л.Я., Черярина Н.Д.Kit O.I., Frantsiyants E.M., Kotieva I.M., Kaplieva I.V., Trepitaki L.K., Bandovkina V.A., Kozlova L.S., Pogorelova Y.A., Rozenko L.Y., Cheryarina N.D.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://transmed.almazovcentre.ru/jour/article/view/375

Хроническая боль – патологический процесс, изменяющий метаболизм всего организма.

Цель

Цель: определение регуляторов плазминогена в ткани меланомы кожи и участков кожи, не связанных с опухолью, мышей-самок в динамике роста экспериментальной меланомы, воспроизведенной на фоне хронической нейрогенной боли.

Материалы и методы

Материалы и методы. Меланома в16/F10 воспроизведена на фоне модели хронической нейрогенной боли на самках мышей С57ВL/6. Определяли содержание плазмина, связанного с α-2-антиплазмином (рар), урокиназного (pro-uPA и uPA) и тканевого (pro-tPA и tPA) активаторов плазминогена, рецептор uPA (uPAR), серпин-1 (PAI-1) методами ИФА на стандартных тест-системах. Статистика: программа Statistica 10.

Результаты

Результаты. При хронизации нейрогенного болевого синдрома установлены значимые изменения компонентов фибринолиза в коже самок мышей С57ВL/6. После перевивки меланомы в16/F10 (1-3 недели), в коже и опухоли найдены: достоверно более высокое содержание РАР, рецептора uPAR (р<0,05), достоверно пониженное содержание pro-uPA и uPA, pro-tPA и tPA, PAI-1 (р<0,05), относительно данных группы сравнения (стандартная модель меланомы).

Заключение

Заключение. Результаты определения состояния тканевого фибринолиза в коже и опухоли самок мышей С57ВL/6 свидетельствуют о том, что, при формировании опухоли на фоне хронической нейрогенной боли, плазмин, tPA, uPA, uPAR и PAI-1 играют ведущую роль в быстром росте и повышении злокачественности меланомы. Изучение предлагаемой модели позволит прояснить многие вопросы канцерогенеза и генерализации злокачественного процесса.

Background

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

Objective

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

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

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

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.

больмеланома кожиметастазированиеактиваторы плазминогенаPAI-1paincutaneous melanomametastasisplasminogen activatorsPAI-1ReferencesKumar A, Kaur H, Singh A. Neuropathic Pain models caused by damage to central or peripheral nervous system. Pharmacol Rep. 2018; 70(2): 206-216.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.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.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.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.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.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.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.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.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.Chlebowski RT, Col N. Bisphosphonates and breast cancer prevention. Anticancer Agents Med. Chem. 2012; 12(2): 144-150.Chlebowski RT, Col N. Bisphosphonates and breast cancer prevention. Anticancer Agents Med. Chem. 2012; 12(2): 144-150.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.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.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.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.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.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.Кит О.И., Франциянц Е.М., Котиева И.М. и др. некоторые механизмы повышения злокачественности меланомы. Российский журнал боли. 2017; 53 (2): 14-20.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 RussianКит О.И., Франциянц Е.М., Котиева И.М. и др. Влияние хронической боли на динамику некоторых ростовых факторов в интактной и патологически измененной коже самок мышей с меланомой в16/F10. Российский журнал боли. 2017; (3-4): 37-44].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 RussianDingemanе KP. B-16 melanoma metastasis in mouse liver and lung. Inv. Metast. 1985; (5): 50-60.Dingemanе KP. B-16 melanoma metastasis in mouse liver and lung. Inv. Metast. 1985; (5): 50-60.Ji RR, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain. 2013;154 Suppl 1:S10-28.Ji RR, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain. 2013;154 Suppl 1:S10-28.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.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.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.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.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.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.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.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.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.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.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.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.Schuliga M. The inflammatory actions of coagulant and fibrinolytic proteases in disease. Mediators Inflamm. 2015; 2015: 437695.Schuliga M. The inflammatory actions of coagulant and fibrinolytic proteases in disease. Mediators Inflamm. 2015; 2015: 437695.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.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.Santibanez JF. Transforming growth factor-Beta and urokinase-type plasminogen activator: dangerous partners in tumorigenesis-implications in skin cancer. ISRN Dermatol. 2013; 2013: 597927.Santibanez JF. Transforming growth factor-Beta and urokinase-type plasminogen activator: dangerous partners in tumorigenesis-implications in skin cancer. ISRN Dermatol. 2013; 2013: 597927.

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