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Анализ прогрессии мелкоклеточной карциномы легких на мышах с помощью секвенирования генома

Pages: 1, 2, 3, 4, 5, 6, 7
slavak4609, 07.04.2014 13:54
картинка: Small.gifКонсервативность процессов и путей, способствующих и препятствующих развитию опухоли в клетках человека и мышей, делает мышей, модифицированных с помощью генной инженерии, очень эффективной моделью исследования рака человека. На такой модели с использованием сравнительного секвенирования геномов прослежена последовательность молекулярных событий при формировании опухолей мелкоклеточной карциномы легких и предложена модель ее развития.

Мелкоклеточная карцинома легких (small cell lung carcinoma – SCLC) – высоколетальное заболевание, составляющее у курильщиков примерно четверть всех раков легких. Мишеней, которые можно использовать для химиотерапии SCLC, известно пока мало. К моменту обнаружения опухоли её клетки успевают накопить множество мутаций, среди которых есть как драйверы, определяющие прогрессию SCLC, так и множество нейтральных мутаций-”пассажиров”. Главной задачей проводимых в последнее время широкомасштабных работ по секвенированию раковых геномов является идентификация драйверов. Но эти работы иногда дают противоречивые результаты. Одной из существенных причин этого является отсутствие адекватной модели для проверки эффекта мутаций in vivo.

При SCLC часто наблюдаются инактивирующие мутации в генах TP53 и RB1. Поэтому для экспериментов были использованы мыши, у которых были делетированы соответствуюшие мышиные ортологи Tp53 и Rb1. У этих мышей достоверно воспроизводилась клиническая картина SCLC взрослого человека, включая длительный латентный период (12-14 месяцев) и часто развивающиеся метастазы.

Был создан банк мышиных тканей из первичных опухолей на различных стадиях прогрессии и метастазов. Проведено секвенирование экзомов 27 опухолей и метастазов и секвенирование полных геномов 14 опухолей. Для сравнения проводилось секвенирование ДНК из заведомо нормальной ткани из образцов хвостов. Выявлено множество повторяющихся хромосомных перестроек, включая дупликации и потери хромосом. Ряд перестроек был аналочичен таковым, наблюдающихся в человеческих ортологах при SCLC. Предварительные данные по точечным мутациям показывают специфичность их набора, и этот набор отличается от набора точечных мутаций у KrasG12D/p53-null мышей – модели аденокарциномы легких.

Из точечных мутаций в SCLC мышей чаще других наблюдались мутации гена Pten, а также в других генах сигнального пути Pten. Часто наблюдалась и утрата хромосомы 19, в которой локализован Pten. Дефекты PTEN идентифицированы и в SCLC человека. Иммуногистохимическое исследование показало дефицит продукта Pten в опухолях по сравнению с нейроэндокринными тельцами, из которых опухоли развиваются. В то же время активизировались компоненты сигнального пути PI3K/AKT, который стимулируется в ответ на инактивацию пути Pten. Следовательно, нарушение пути Pten должно способствовать прогрессии опухоли. Это было прямо подтверждено на мышах, у которых кроме Tp53 и Rb1 был делетирован Pten. У них сильно сокращался латентный период развития опухолей и, как следствие, ускорялась гибель.

Изучение наборов мутаций в различных участках опухолей, в метастазах, формировавшихся в лимфатических узлах и в печени, позволило проследить клональную эволюцию индивидуальных клеток-предшественников и постепенное накопление соматических мутаций.

Проведенное исследование представляет собой наиболее полное описание молекулярных событий, происходящих в соматических клетках при развитии злокачественной опухоли. В отсутствие мутагенеза, вызванного табачным дымом или другими канцерогенами, обнаружено значительно меньше мутаций, чем присутствует в опухолях SCLC пациентов-курильщиков. Это позволило в занчительной мере отсечь «мутационный шум», достоверно установить последовательность молекулярных нарушений, предложить модель формирования и прогрессии SCLC. Консервативность способствующих и препятствующих развитию опухоли процессов и путей в клетках человека делает мышей, модифицированных с помощью методов генной инженерии, очень эффективной моделью исследования рака человека с использованием сравнительного секвенирования геномов.
авторский текст

Источник: McFadden DG, Papagiannakopoulos T, Taylor-Weiner A, Stewart C, Carter SL, Cibulskis K, Bhutkar A, McKenna A, Dooley A, Vernon A, Sougnez C, Malstrom S, Heimann M, Park J, Chen F, Farago AF, Dayton T, Shefler E, Gabriel S, Getz G, Jacks T. Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing. // Cell. 2014; V. 156: P. 1298-1311.

Подпись к рисунку: Модель онкогенеза при мелкоклеточной карциноме легких.
A.I.Mukhankin, 20.05.2014 09:05
Исследование ради самого исследования...

Как показывает опыт работы "молекулярных биологов", исследовать опухолевые клетки можно до бесконечности для публикации в "Cell", "Nature", "Science", для повышения рейтинга цитируемости, для привлечения грантов и т.д. (нужное подчеркнуть).
При этом впустую тратятся колоссальные средства, поскольку на решение проблемы онкологических заболеваний исследователям молекул по большому счёту наплевать.
В представленной работе отсутствует онкологическая проблематика, как и знания о природе опухолей: она, как и подавляющее большинство подобных работ по исследованию молекулярных структур в опухолевой клетке, антинаучна и потому совершенно бесполезна для онкологии.
petr, 29.05.2014 23:50
Хорошая статья, чего цепляетесь?
Или можете написать лучше? Так дерзните.
pollard45p, 28.09.2019 17:32
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