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Воспаление, индуцированное УФ-облучением, стимулирует ангиотропизм клеток меланомы и образование метастаз

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slavak4609, 07.04.2014 13:24
картинка: uv.pngУФ-облучение сформировавшихся меланом не влияет на развитие опухолей, но стимулирует образование отдаленных метастаз. Ответ на вызванное УФ воспаление катализирует взаимодействие клеток меланомы с клетками эндотелия сосудов, которое приводит к поникновению раковых клеток в кровоток и диссеменации. Блокирование механизмов этого взаимодействия может стать эффективной стратегией для подавления метастазирования.

УФ-облучение является твердо установленным этиологическим фактором развития злокачественной меланомы. Найдены инициирующие опухоли мутации, возникающие в меланоцитах под действием УФ. Но как микроокружение опухолей реагирует на УФ, как это влияет на патогенез меланомы пока изучено недостаточно.

Авторы предположили, что УФ может воздействовать на микроокружение меланомы стимулируя выживание, экспансию и диссеменацию опухоли. Эксперименты проводились на мышах HGF-CDK4(R24C), у которых вследствие усиленной экспрессии фактора роста гепатоцитов HGF нарушена регуляция сигнального пути рецепторной тирозинкиназы и нарушен контроль клеточного цикла вследствие наличия онкогенной мутации CDK4(R24C). Меланомы индуцировали обработкой кожи канцерогеном диметил-бензантраценом. Участки кожи, где образовались опухоли, многократно облучали УФ-дозами, вызывавшими эритему.

Неожиданно оказалось, что повторное УФ-облучение не влияло на развитие меланом кожи, но увеличивало количество метастаз в легких. У 4 из 20 облученных мышей наблюдалась экспансия меланомных клеток в эндотелий кровеносных сосудов кожи. Ранее было известно, что подобное наблюдается у каждого пятого человека больного меланомой и связано с развитием метастаз, с негативным прогнозом.

Показано, что наблюдавшийся эффект связан с мобилизацией и активацией нейтрофилов, инициированных организатором и регулятором транскрипции HMGB1, который секретируется поврежденными кератиноцитами. Воспалительный ответ на УФ стимулировал ангиогенез и способствовал миграции клеток меланомы к клеткам эндотелия. Таким образом, воспалительный ответ на УФ-облучение катализирует взаимодействие клеток меланомы с клетками эндотелия сосудов, которое приводит к поникновению клеток меланомы в кровоток. Этот ангиотропизм представляет собой до сих пор малоизученный механизм метастазирования способствующий диссеменации раковых клеток через кровоток.

Полученные результаты показывают, что воздействие на фенотипическую пластичность клеток меланомы в ответ на воспаление, на механизмы их взаимодействия с клетками эндотелия может стать эффективной стратегией для подавления метастазирования.
авторский текст

Источник: Bald T, Quast T, Landsberg J, Rogava M, Glodde N, Lopez-Ramos D, Kohlmeyer J, Riesenberg S, van den Boorn-Konijnenberg D, Hömig-Hölzel C, Reuten R, Schadow B, Weighardt H, Wenzel D, Helfrich I, Schadendorf D, Bloch W, Bianchi ME, Lugassy C, Barnhill RL, Koch M, Fleischmann BK, Förster I, Kastenmüller W, Kolanus W, Hцlzel M, Gaffal E, Tьting T. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. // Nature. 2014; V. 507: P. 109-113.

Подпись к рисунку: Метастазы меланомы в легких мышей не облучавшихся УФ (вверху) и периодически облучавшихся (внизу).
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