vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJGB-22-03vavilov-3251Research ArticleМОЛЕКУЛЯРНАЯ И КЛЕТОЧНАЯ БИОЛОГИЯMOLECULAR AND CELL BIOLOGYОпухоль-ассоциированные фибробласты и их роль в опухолевой прогреcсииCancer-associated fibroblasts and their role in tumor progressionhttps://orcid.org/0000-0001-7107-4187ЕрмаковМ. С.ErmakovM. S.

Новосибирск

Novosibirsk

https://orcid.org/0000-0001-9367-807XНуштаеваА. А.NushtaevaA. A.

Новосибирск

Novosibirsk

РихтерВ. А.RichterV. A.

Новосибирск

Novosibirsk

https://orcid.org/0000-0001-7788-2249КовальО. А.KovalO. A.

Новосибирск

Novosibirsk

o_koval@ngs.ruИнститут химической биологии и фундаментальной медицины Сибирского отделения Российской академии наукРоссияInstitute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of SciencesRussian FederationИнститут химической биологии и фундаментальной медицины Сибирского отделения Российской академии наук; Новосибирский национальный исследовательский государственный университетРоссияInstitute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Sciences; Novosibirsk State UniversityRussian Federation2022280220222611421Copyright © Ермаков М.С., Нуштаева А.А., Рихтер В.А., Коваль О.А., 20222022Ермаков М.С., Нуштаева А.А., Рихтер В.А., Коваль О.А.Ermakov M.S., Nushtaeva A.A., Richter V.A., Koval O.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/3251

Стромальные элементы опухоли могут стимулировать прогрессию опухолевого роста и метастазирование. В структуру опухолевой стромы входят соединительнотканные элементы, сосуды, нервы и внеклеточный матрикс. Одним из клеточных элементов стромы опухоли являются опухоль-ассоциированные фибробласты (ОАФ), происхождение и функции которых активно изучают на протяжении последних тридцати лет. ОАФ продуцируют основной каркасный белок внеклеточного матрикса – коллаген, избыток которого в строме опухоли стимулирует фиброз, повышает жесткость опухолевой ткани и нарушает передачу сигналов пролиферации и дифференцировки. ОАФ контролируют ангиогенез в опухоли, подвижность опухолевых клеток, иммуногенные свойства опухоли и развитие резистентности к химиопрепаратам и иммунотерапии. В результате метаболической адаптации быстрорастущей опухолевой ткани к нехватке питательных веществ и кислорода, при конверсии основного типа производства энергии в клетках с окислительного фосфорилирования на анаэробный гликолиз инициируются молекулярные изменения, в том числе индукция определенных транскрипционных факторов, которые обусловливают активацию ОАФ. Молекулярный фенотип активированных ОАФ имеет сходство с фибробластами, активированными в процессе воспаления. В активированных ОАФ происходит de novo синтез альфа-актина гладкой мускулатуры (α-SMA), продукция различных протеаз и фибронектина. Поскольку ОАФ обнаружены во всех типах карцином, эти клетки могут быть мишенями для разработки новых подходов противоопухолевой терапии. Часть ОАФ происходит из резидентных фибробластов пораженного опухолью органа, другие берут свое начало из опухолевых эпителиоцитов, претерпевая эпителиально-мезенхимальный переход. На сегодняшний день обнаружено большое количество молекулярных и метаболических индукторов эпителиально-мезенхимального перехода, к которым относят трансформирующий фактор роста бета (TGF-β), гипоксию и воспаление. В данном обзоре систематизированы современные представления о молекулярных маркерах ОАФ, их функциональных особенностях, этапах эпителиально-мезенхимального перехода и обсуждается возможность использования ОАФ в качестве мишеней для противоопухолевой терапии.

The stromal elements of a malignant tumor can promote cancer progression and metastasis. The structure of the tumor stroma includes connective tissue elements, blood vessels, nerves, and extracellular matrix (ECM). Some of the cellular elements of the tumor stroma are cancer-associated fibroblasts (CAFs). The origin and function of CAFs have been actively studied over the past thirty years. CAFs produce collagen, the main scaffold protein of the extracellular matrix. Collagen in the tumor stroma stimulates fibrosis, enhances the rigidity of tumor tissue, and disrupts the transmission of proliferation and differentiation signaling pathways. CAFs control tumor angiogenesis, cell motility, tumor immunogenic properties, and the development of resistance to chemo- and immunotherapy. As a result of metabolic adaptation of rapidly growing tumor tissue to the nutrients and oxygen deprivation, the main type of energy production in cells changes from oxidative phosphorylation to anaerobic glycolysis. These changes lead to sequential molecular alterations, including the induction of specified transcriptional factors that result in the CAFs activation. The molecular phenotype of activated CAFs is similar to fibroblasts activated during inflammation. In activated CAFs, alpha-smooth muscle actin (α-SMA) is synthetized de novo and various proteases and fibronectin are produced. Since CAFs are found in all types of carcinomas, these cells are potential targets for the development of new approaches for anticancer therapy. Some CAFs originate from resident fibroblasts of the organs invaded by the tumor, while others originate from epithelial tumor cells, which are undergoing an epithelial-mesenchymal transition (EMT). To date, many molecular and metabolic inducers of the EMT have been discovered including the transforming growth factor-beta (TGF-β), hypoxia, and inflammation. This review classifies modern concepts of molecular markers of CAFs, their functional features, and discusses the stages of epithelial-mesenchymal transition, and the potential of CAFs as a target for antitumor therapy.

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