БИОХИМИЯ, 2019, том 84, вып. 7, с. 972–984

УДК 616-006.04-091.811-033.2; 611.018.5; 577.2

Интравазация опухолевых клеток — важнейшее звено метастазирования

Обзор

© 2019 М.В. Завьялова 1,2, Е.В. Денисов 1, Л.А. Таширева 1*, О.Е. Савельева 1, Е.В. Кайгородова 1,2, Н.В. Крахмаль 1,2, В.М. Перельмутер 1

1 Научно-исследовательский институт онкологии, Томский национальный исследовательский медицинский центр РАН, 634009 Томск, Россия; электронная почта: tashireva@oncology.tomsk.ru

2 Сибирский государственный медицинский университет Минздрава России, 634050 Томск, Россия

Поступила в редакцию 20.02.2019
После доработки 10.04.2019
Принята к публикации 10.04.2019

DOI: 10.1134/S0320972519070078

КЛЮЧЕВЫЕ СЛОВА: интравазация, инвазия, гематогенное метастазирование, карциномы, TMEM, экструзия.

Аннотация

В настоящем обзоре обсуждаются современные представления о механизмах интравазации опухолевых клеток в кровеносные и лимфатические сосуды. Интравазация — ключевой этап в метастазировании злокачественных новообразований, в ходе которого опухолевые клетки, проходя через стенку сосудов, попадают в циркуляцию, становясь циркулирующими опухолевыми клетками и потенциальными метастатическими «семенами». Понимание молекулярных механизмов, лежащих в основе интравазации, является критически важным для разработки терапевтических стратегий предотвращения метастатической болезни. В качестве прототипов интравазации опухолевых клеток рассматривается выход зрелых тимоцитов в циркуляцию и дендритных клеток в регионарные лимфатические узлы. В условиях патологии прототипом данного процесса служит реверсная трансэндотелиальная миграция лейкоцитов в кровь из очагов воспаления с участием лиганд-рецепторного взаимодействия сфингозин-1-фосфата и его рецепторов. Отдельно обсуждаются механизмы интравазации, как связанные с инвазией, так и не зависящие от нее. Отмечается место опухолевой мезенхимальной и амебовидной инвазии в интравазации, а также роль в этом процессе неоангиогенеза и ремоделирования сосудов. Особое внимание уделено участию макрофагов в интравазации через паракринную передачу сигналов CSF1–EGF (колониестимулирующий фактор 1 — эпидермальный фактор роста) и механизм, опосредованный TMEM (Tumor MicroEnvironment of Metastasis — метастатическое микроокружение опухоли). Дополнительно рассматривается несколько механизмов интравазации: интравазация благодаря окружению кластеров клеток опухоли эндотелием, вследствие чего они попадают в сосудистое русло; кооперативная интравазация, при которой опухолевая клетка, не обладающая инвазивными свойствами, попадает в кровоток вслед за инвазивной клеткой опухоли; интравазация, связанная с васкулогенной мимикрией, которая проявляется в формировании каналов, выстланных клетками опухоли, подобно эндотелию. В обзоре обращается внимание на возможность существования иных, не обсуждаемых в литературе, механизмов интравазации опухолевых клеток. В заключение подчеркивается важность разработки адресных терапевтических стратегий, препятствующих интравазации.

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Финансирование

Работа выполнена при поддержке Российского научного фонда (грант № 19-75-30016).

Конфликт интересов

Авторы заявляют об отсутствии конфликта интересов.

Соблюдение этических норм

Настоящая статья не содержит описания выполненных авторами исследований с участием людей или использованием животных в качестве объектов.

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