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La necroptosis de células endoteliales inducida por células tumorales a través del receptor de muerte 6 promueve la
Nature
|August 4, 2016
Resumen
Las células tumorales provocan la muerte celular programada (necroptosis) en las células endoteliales, promoviendo la metástasis del cáncer. La inhibición de esta vía a través de RIPK1 o DR6 ofrece una terapia potencial contra la metástasis.
Área de la Ciencia:
- En el campo de la oncología
- Biología celular
- La medicina molecular
Sus antecedentes:
- La metástasis, la propagación de las células cancerosas, es la principal causa de mortalidad por cáncer.
- La extravasación de las células tumorales, un paso crítico en la metástasis, implica cruzar la barrera endotelial.
- Los mecanismos moleculares que regulan la interacción de las células tumorales con las células endoteliales durante la extravasación no se comprenden completamente.
Objetivo del estudio:
- Elucidar los mecanismos moleculares por los cuales las células tumorales se extravasan a través de la barrera endotelial.
- Investigar el papel de la muerte celular programada (necroptosis) en las células endoteliales durante la metástasis tumoral.
- Identificar posibles objetivos terapéuticos para inhibir la metástasis del cáncer.
Principales métodos:
- Se investigó la interacción entre las células tumorales y las células endoteliales in vitro e in vivo.
- Utilizó el inhibidor de la serina/treonina-proteína quinasa 1 (RIPK1) que interactúa con los receptores y la manipulación genética de RIPK3 y caspasa-8 en las células endoteliales.
- Se examinaron las funciones de la proteína precursora amiloide (APP) y el receptor de muerte 6 (DR6) en la mediación de la extravasación de las células tumorales.
Principales resultados:
- Las células tumorales inducen la necroptosis en las células endoteliales, facilitando la extravasación y la metástasis.
- La inhibición de RIPK1 o RIPK3 redujo la necroptosis endotelial inducida por las células tumorales, la extravasación y la metástasis.
- La inhibición de la caspasa o la pérdida de la caspasa-8 promovieron estos procesos metastásicos.
- La APP expresada por las células tumorales y la DR6 expresada por las células endoteliales se identificaron como mediadores clave de esta extravasación inducida por la necroptosis.
Conclusiones:
- La necroptosis endotelial inducida por células tumorales es un nuevo mecanismo que promueve la extravasación y la metástasis de las células cancerosas.
- Dirigirse a las vías de señalización necroptótica mediadas por DR6 endotelial presenta una estrategia prometedora para las terapias anti-metastásicas.
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