Удалось выяснить, почему рак может уснуть и проснуться через много лет

Рис. 1. Основные события и механизмы отбора и поддержания раковых клеток в латентном («спящем») состоянии. Большинство отделившихся от опухоли клеток, попадая в кровоток, разрушается под действием защитных механизмов, прежде всего вследствие атаки естественными киллерами (NK cells). Но клоны со свойственной стволовым клеткам усиленной экспрессией факторов транскрипции SOX2/SOX9 могут уклониться от действия иммунной системы и поселиться в различных органах. Если под влиянием факторов микроокружения такие латентные («спящие») раковые клетки (latency competent cancer cells, LCC-клетки) начинают реплицироваться, то естественные киллеры предотвращают размножение их потомства, и сохраняются только латентные раковые клетки. Вследствие усиленной экспрессии в LCC-клетках гена DDK1 в них подавлена активность сигнального пути WNT, активирующего пролиферацию. Кроме того, в LCC-клетках подавлена экспрессия лигандов, необходимых для узнавания их киллерами, и они уклоняются от элиминации естественными киллерами. Через какое-то время латентные раковые клетки могут «проснуться», начать реплицироваться и образовать метастазы. Рисунок из обсуждаемой статьи в Cell

Через несколько месяцев или лет после успешного удаления раковой опухоли, даже на ранних стадиях ее роста, могут развиться удаленные метастазы. Это серьезная проблема в лечении онкологических заболеваний. Недавно ученым удалось сделать шаг к ее решению: найдены клоны клеток рака легких и молочной железы человека, которые при инъекции подопытным мышам образуют опухоли очень нескоро — через несколько месяцев. Показано, что эти клетки «впадают в спячку» — переходят в латентное состояние — вследствие подавления индуктора пролиферации сигнального пути WNT. Также определены механизмы, позволяющие латентным клеткам уклоняться от иммунного ответа и активироваться при определенных условиях, чтобы дать начало новым опухолям.

Рак не перестает удивлять исследователей и врачей своим коварством. Казалось бы, опухоль у пациента аккуратно и своевременно удалена, метастазов в лимфатических узлах не найдено. Но через довольно длительное время, порой через несколько лет, у пациентов, у которых опухоль удаляли даже на ранних стадиях ее развития, возникают удаленные метастазы. В случае аденокарциномы легких это происходит у половины пациентов. Аналогичные события наблюдаются после поначалу успешной терапии рака молочной железы с помощью антител.

Источником этих осложнений являются свободные или диссеминирующие опухолевые клетки (disseminated tumor cells, DTCs). Некоторые из них обладают свойствами так называемых латентных раковых клеток (latency competent cancer cells, LCC cells). До того как был поставлен диагноз и удалена опухоль, из нее успевает отпочковаться множество свободных опухолевых клеток. Большинство их погибает в кровотоке или в органах, куда они были занесены. Но некоторые могут выжить и существовать в латентном состоянии в различных органах и тканях. Такие латентные метастазы представляют собой большую нерешенную проблему в клинической онкологии. Об их природе и механизмах, которые позволяют им оставаться в «спящем» состоянии, уклоняясь от действия систем иммунитета и сохраняя при этом способность инициировать опухоли и превращаться в агрессивные метастазы, известно еще очень мало. Причиной этого, в частности, было отсутствие адекватных животных моделей, воспроизводящих ключевые свойства, механизмы формирования, существования и активации спящих метастазов.

Группа американских ученых разработала экспериментальные мышиные модели для исследования латентных метастазов. С помощью методов генетической инженерии они ввели в культивируемые клетки ранней аденокарциномы легкого H2087 или рака молочной железы человека HСС1954 гены

Источник: elementy.ru

785 КОММЕНТАРИИ

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