mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-PTO-2864mimmun-2864Research ArticleОБЗОРЫREVIEWSПотенциальные мишени гепарина при прогрессировании и метастазировании злокачественных новообразованийPotential targets of heparin during progression and metastasis of malignant neoplasmshttps://orcid.org/0000-0003-3437-0926МалащенкоВ. В.MalashchenkoV. V.

Малащенко Владимир Владимирович – к.б.н., научный сотрудник Центра иммунологии и клеточных биотехнологий.

Калининград

Vladimir V. Malashchenko - PhD (Biology), Research Associate, Center for Immunology and Cellular Biotechnology, Science and Technology Park “Fabrica”, Immanuel Kant Baltic Federal University.

Kaliningrad

vmalashchenko@kantiana.ruhttps://orcid.org/0000-0003-3465-8452ХлусовИ. А.KhlusovI. A.

Хлусов Игорь Альбертович – д.м.н., cтарший научный сотрудник Центра иммунологии и клеточных биотехнологий, НТП «Фабрика», ФГАОУ ВО «БФУ им. И. Канта»; профессор кафедры морфологии и общей патологии ФГБОУ ВО «СибГМУ» МЗ РФ.

Калининград; Томск

Igor A. Khlusov - PhD, MD (Medicine), Senior Research Associate, Center for Immunology and Cellular Biotechnology, Science and Technology Park “Fabrica”, Immanuel Kant Baltic Federal University; Professor, Department of Morphology and General Pathology, Siberian State Medical University.

Kaliningrad; Tomsk

khlusov63@mail.ruhttps://orcid.org/0000-0001-6146-3330ЮроваК. А.YurovaK. A.

Юрова Кристина Алексеевна – к.м.н., научный сотрудник Центра иммунологии и клеточных биотехнологий.

Калининград

Kristina A. Yurova - PhD (Medicine), Research Associate, Center for Immunology and Cellular Biotechnology, Science and Technology Park “Fabrica”, Immanuel Kant Baltic Federal University.

Kaliningrad

kristina_kofanova@mail.ruhttps://orcid.org/0000-0002-5525-3529ХазиахматоваО. Г.KhaziakhmatovaO. G.

Хазиахматова Ольга Геннадьевна – к.б.н., научный сотрудник Центра иммунологии и клеточных биотехнологий.

Калининград

Olga G. Khaziakhmatova - PhD (Biology), Research Associate, Center for Immunology and Cellular Biotechnology, Science and Technology Park “Fabrica”, Immanuel Kant Baltic Federal University.

Kaliningrad

olga_khaziakhmatova@mail.ruhttps://orcid.org/0000-0001-7468-4861ТодосенкоН. М.TodosenkoN. M.

Тодосенко Наталья Михайловна – к.б.н., cтарший научный сотрудник Центра иммунологии и клеточных биотехнологий.

Калининград

Natalia M. Todosenko - PhD (Biology), Senior Research Associate, Center for Immunology and Cellular Biotechnology, Science and Technology Park “Fabrica”, Immanuel Kant Baltic Federal University.

Kaliningrad

tod_89@mail.ruhttps://orcid.org/0000-0001-5231-6910ЛитвиноваЛ. С.LitvinovaL. S.

Литвинова Лариса Сергеевна – д.м.н., директор Центра иммунологии и клеточных биотехнологий НТП «Фабрика», ФГАОУ ВО «БФУ им. И. Канта»; научный сотрудник ФГБОУ ВО «СибГМУ» МЗ РФ.

236001, Калининград, уд. Гайдара, 6

Тел.: 8 (4012) 59-55-95 (доп. 6634)

Larisa S. Litvinova - PhD, MD (Medicine), Director, Center for Immunology and Cellular Biotechnology, Science and Technology Park “Fabrica”, Immanuel Kant Baltic Federal University; Research Associate, Siberian State Medical University.

6 Gaidar St Kaliningrad 236001

Phone: +7 (4012) 59-55-95 (acc. 6634)

larisalitvinova@yandex.ruНаучно-технологический парк «Фабрика», ФГАОУ ВО «Балтийский федеральный университет имени Иммануила Канта»РоссияScience and Technology Park “Fabrica”, Immanuel Kant Baltic Federal UniversityRussian FederationНаучно-технологический парк «Фабрика», ФГАОУ ВО «Балтийский федеральный университет имени Иммануила Канта»; ФГБОУ ВО «Сибирский государственный медицинский университет» Министерства здравоохранения РФРоссияScience and Technology Park “Fabrica”, Immanuel Kant Baltic Federal University; Siberian State Medical UniversityRussian Federation202413092023262237252Copyright © Малащенко В.В., Хлусов И.А., Юрова К.А., Хазиахматова О.Г., Тодосенко Н.М., Литвинова Л.С., 20242024Малащенко В.В., Хлусов И.А., Юрова К.А., Хазиахматова О.Г., Тодосенко Н.М., Литвинова Л.С.Malashchenko V.V., Khlusov I.A., Yurova K.A., Khaziakhmatova O.G., Todosenko N.M., Litvinova L.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/2864

Онкологические заболевания занимают одну из лидирующих позиций в структуре смертности населения. Комплексный подход в онкотерапии, помимо прямого воздействия на злокачественные опухоли, направлен на снижение рисков их рецидивов и метастазирования, а также снижение тяжести побочных эффектов противоопухолевой химио- и радиотерапии заболевания. При онкологических заболеваниях повышается вязкость крови, что сопровождается гиперкоагуляционным синдромом. Для преодоления его последствий активно используются прямые и непрямые антикоагулянты, в частности гепарин и его производные. Биологические функции и структурные особенности гепарина делают его потенциальной универсальной платформой в разработке препаратов для широкого применения, в том числе в онкологии. Появление технологии фракционирования гепаринов и получения низкомолекулярных форм и их производных позволило сосредоточиться не только на антикоагуляционных эффектах, но и получать фракции с целевой фармакологической активностью. Применение антикоагулянтов в некоторых случаях позволило выявить их противоопухолевый эффект, что послужило основанием для более детального исследования фармакотерапевтических эффектов этой группы препаратов. В настоящее время получены данные о множественных путях взаимодействия гепарина и опухолевых клеток. В процессе развития первичной опухоли и при формировании вторичных метастазов в отдаленных органах есть ряд общих черт, обусловленных использованием одних и тех же молекулярно-клеточных механизмов. В качестве мишеней для гепарина здесь могут выступать молекулы, отвечающие за межклеточные взаимодействия как между опухолевыми клетками, так и между клетками опухоли и опухоль ассоциированными иммунокомпетентными клетками, преимущественно лимфоцитами и макрофагами, что способствует уходу опухоли от иммунного надзора. Другой важной мишенью являются цитокины, стимулирующие опухолевый ангиогенез. Производные гепарина способны подавлять активность опухолей и нарушать процессы метастазирования на различных этапах, ингибируя активность гепараназы, P-/L-селектина, ангиогенез, модулируя хемокиновую ось CXCL12-CXCR4, регулируя активность ОАМ.

Данный краткий обзор рассматривает реальные контуры понимания и использования потенциальных антиметастатических свойств гепарина и его производных при злокачественных новообразованиях костной ткани, поскольку препараты на основе гепарина применяются в качестве антикоагулянтов при эндопротезировании крупных суставов и дефектов кости у больных остеосаркомой.

In the modern world, oncological diseases occupy the leading positions in the structure of mortality. An integrated approach to oncotherapy is not only aimed at immediate affection of malignant tumors, but also directed at reducing the risk of tumor recurrence and metastasis, as well as alleviating side effects of chemotherapy and radiotherapy of the disease. In oncologic disorders, blood viscosity increases, thus being associated with hypercoagulation syndrome. To prevent its consequences, the direct and indirect anticoagulants, especially heparin and its derivatives, are actively used. Biological functions and structural features of heparin make it a potential universal platform of a drug development for broad application, including oncology. With the advent of heparin fractionation technology and preparation of low-molecular weight forms and their derivatives, it has become possible to focus not only on anticoagulant activity but also to obtain fractions with targeted pharmacological activity. Usage of the anticoagulants has shown their antitumor activity in some cases, thus providing a basis for a more detailed study of pharmacotherapeutic effects of this group of drugs. Currently, some data suggest various pathways of interaction between heparin and tumor cells. There are multiple common features in development of a primary tumor and formation of secondary distant metastases, which may be attributed to similar molecular cellular mechanisms. The molecules mediating intercellular interactions, both between the tumor cells and between malignant cells and tumor-associated immune cells (e.g., lymphocytes and macrophages) may serve as targets for heparin thus helping the tumor to evade immune surveillance. The cytokines that stimulate tumor angiogenesis represent another important therapeutic target. Heparin derivatives are able to suppress tumor activity and prevent metastatic processes at various stages by inhibiting heparanase, P-/L-selectin, and angiogenesis activity, modulating the CXCL12-CXCR4 chemokine axis, and regulating OAM activity.

This brief review addresses the current understanding and application of the potentially antimetastatic properties of heparin and its derivatives in malignant bone tumors since the heparin-based drugs are used as anticoagulants in arthroplasty of large joints and bone defects in patients with osteosarcoma.

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