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p53 y Pten control neuronal y la renovación y diferenciación de células madre/progenitoras de glioma
Hongwu Zheng1, Haoqiang Ying, Haiyan Yan
1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature
|October 25, 2008
Resumen
La doble inactivación de p53 y Pten en ratones crea un modelo de tumor cerebral que se asemeja al glioblastoma primario humano. Este estudio revela que Myc.
Área de la Ciencia:
- Neuro-oncología y neuro-oncología.
- Biología del cáncer Biología del cáncer.
- Genética molecular La genética molecular.
Sus antecedentes:
- El glioblastoma (GBM) es un tumor cerebral letal con subtipos primarios y secundarios.
- La MGB primaria a menudo tiene mutaciones en EGFR, PTEN y CDKN2A.
- La GBM secundaria surge de tumores de bajo grado con eventos de PDGF y TP53.
Objetivo del estudio:
- Investigar el papel de la inactivación de p53 y Pten en el desarrollo del glioblastoma.
- Para explorar los mecanismos moleculares subyacentes a la patogénesis de GBM.
- Identificar posibles objetivos terapéuticos para la MGB primaria.
Principales métodos:
- Se creó un modelo de ratón con deleción específica del SNC de p53 y Pten.
- Se analizaron las mutaciones TP53 y PTEN en la MGB primaria humana.
- Realizó perfiles transcriptómicos y análisis de promotores in silico.
- Ha realizado estudios funcionales sobre las células madre neurales (CNS) y las neurosferas tumorales (TNS) murinas.
Principales resultados:
- El modelo de ratón exhibió un fenotipo de glioma maligno de alto grado similar al GBM primario humano.
- La MGB primaria humana mostró frecuentes mutaciones inactivadoras en TP53 y PTEN.
- La doble inactivación de p53/Pten promovió un estado indiferenciado con un alto potencial de renovación en las NSC.
- Se observaron un aumento de los niveles y la actividad de la proteína Myc, lo que contribuye a una disminución de la diferenciación y una mayor auto-renovación.
- Myc mantuvo el potencial tumorigénico de las SNT p53.../-) Pten.../-) TNS.
Conclusiones:
- La co-deleción de p53 y Pten en el SNC genera un modelo relevante para la MGB primaria.
- Las mutaciones TP53 y PTEN son eventos clave en la patogénesis primaria de GBM.
- Myc es un mediador crítico de las funciones cooperativas de p53 y Pten en la regulación de la diferenciación y la autorrenovación de las células madre en GBM.
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