Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press82310.17650/2313-805X-2025-12-4-8-23REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИReview ArticleRearrangement of signaling pathways and adaptation of tumor cells to hypoxiaРеаранжировка сигнальных путей и адаптация опухолевых клеток к гипоксииhttps://orcid.org/0000-0002-6015-6619AndreevaO. E.АндрееваО. Е.
Russian Federation
krasilnikovm1@ya.ruhttps://orcid.org/0000-0002-1299-9080MikhaevichE. I.МихаевичЕ. И.
Russian Federation
krasilnikovm1@ya.ruhttps://orcid.org/0000-0002-5902-7633Krasil’nikovM. A.КрасильниковМ. А.
Russian Federation
krasilnikovm1@ya.ruN.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России1412202512482330102025Copyright ©; 2025, Andreeva O.E., Mikhaevich E.I., Krasil’nikov M.A.Copyright ©; 2025, Андреева О.Е., Михаевич Е.И., Красильников М.А.2025Andreeva O.E., Mikhaevich E.I., Krasil’nikov M.A.Андреева О.Е., Михаевич Е.И., Красильников М.А.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/823

Malignant tumors developing in the conditions of chronic hypoxia, unlike normal tissues, quickly acquire resistance to decreased oxygen level. Hypoxia-resistant cells in malignant disease obtain various features promoting their survival: they alter metabolism to aerobic glycolysis, activate angiogenesis-stimulating programs, and rearrange signaling cascades to adapt to hypoxia. At the same time, tumor cells become resistant to chemotherapy and radiation therapy and effectively colonize metastatic niches.

This review analyzes signaling pathways which activate in the conditions of chronic hypoxia and underlie tumor adaptation to insufficient oxygen. Apart from the main pathway associated with activation of hypoxia-inducible factor 1α (HIF-1α), such cascades as STAT3, Snail cascade associated with epithelial-mesenchymal transition, NRF2 factor responsible for adaptation to reactive oxygen species, and stemness factors OCT4, SOX2 and NANOG are also considered. Effective killing of tumor cells requires simultaneous inhibition of several parts of signaling pathways because disruption of just one will lead to switching of signaling proteins to bypass the blocked one. The article lists various inhibitors of signaling pathways patricipating in tumor cell adaptation to chronic hypoxia and describes their mechanisms of action and targets. Development of successful strategies for treatment of hypoxia-resistant tumors requires identification of an effective combination of the above-mentioned and other inhibitors of the key signaling cascades participating in adaptation to hypoxia.

Злокачественные опухоли, развивающиеся в условиях хронической гипоксии, в отличие от клеток нормальных тканей, быстро приобретают устойчивость к пониженному содержанию кислорода. Известно, что устойчивые к гипоксии клетки в рамках злокачественной прогрессии приобретают различные свойства, способствующие их выживаемости: они изменяют метаболизм на аэробный гликолиз, активируют программы, обусловливающие ангиогенез, и перестраивают сигнальные каскады в рамках адаптации к гипоксии. При этом такие опухолевые клетки становятся устойчивыми к химио- и радиотерапии, а также эффективно колонизируют метастатические ниши.

Данный обзор посвящен анализу сигнальных путей, которые активируются в условиях хронической гипоксии и отвечают за адаптацию опухолей к недостатку кислорода. Помимо основного пути, связанного с активацией гипоксией индуцируемого фактора 1α (HIF-1α), рассмотрены и такие каскады, как STAT3, связанный с эпителиально-мезенхимальным переходом каскад Snail, отвечающий за адаптацию к активным формам кислорода фактор NRF2, а также факторы стволовости OCT4, SOX2 и NANOG. Известно, что для эффективного воздействия на опухолевые клетки необходимо одновременное ингибирование нескольких участников сигнальных путей, поскольку воздействие лишь на один из них приведет к переключению сигнальных белков в обход заблокированного. В статье перечислены различные ингибиторы сигнальных путей, которые участвуют в адаптации опухолевых клеток к хронической гипоксии, и рассмотрены механизмы их действия на мишени. Для разработки успешных стратегий лечения устойчивых к гипоксии опухолей необходим поиск эффективной комбинации упомянутых и других ингибиторов ключевых сигнальных каскадов, участвующих в адаптации к гипоксии.

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