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El Centro Nacional de Investigaciones Oncológicas (CNIO) fue creado en 1998 por el Instituto de Salud Carlos III, si bien fue fundado por el Ministerio de Sanidad y Consumo, el CNIO se integra desde finales del 2011 en el Ministerio de Economía y Competitividad (PDF 81 KB). El CNIO está gestionado por una fundación, creada simultáneamente con el Centro, cuya denominación es la de Fundación Centro Nacional de Investigaciones Oncológicas Carlos III. La Fundación tiene el carácter de fundación de titularidad estatal y está regida por un Patronato. Al Centro le corresponde desarrollar la actividad científica y está dirigido por un Director y asesorado por un Comité Científico Asesor. https://www.cnio.es

Un gen que aumenta el riesgo de cáncer de páncreas controla la inflamación en el tejido normal

Fuente: CNIO | Publicado: 19-02-2018
Investigadores del CNIO descubren que las células sanas del páncreas mantienen inhibida la inflamación a menos que sea necesaria.
El hallazgo ayuda a entender el origen de los tumores y sugiere nuevas estrategias para mejorar la prevención del cáncer de páncreas.
El trabajo se publicó en Nature.
Derechos: Imagen histológica de tejido pancreático inflamado (pancreatitis). La inflamación crónica aumenta el riesgo de desarrollar cáncer de páncreas. CNIO.
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La inflamación es una respuesta de defensa del organismo ante agresiones, pero cuando persiste puede ser perjudicial e incluso predisponer al cáncer. Por eso es crucial entender bien la relación entre inflamación y cáncer. Un grupo de investigadores del Centro Nacional de Investigaciones Oncológicas (CNIO) ha descubierto ahora un vínculo inesperado entre ambos procesos: en el páncreas, uno de los genes que aumenta el riesgo de desarrollar cáncer de páncreas se ocupa también de controlar la inflamación en el tejido normal. Este hallazgo implica “un importante cambio conceptual”, explica Paco Real, jefe del Grupo de Carcinogénesis Epitelial del CNIO, que además de ayudar a entender el origen de los tumores sugiere nuevas estrategias para mejorar la prevención del cáncer de páncreas. 


El trabajo se publicó el 14 de febrero en la revista Nature, que además lo comenta en su sección de News & Views.



El cambio de paradigma que implica este resultado tiene que ver con el concepto mismo de inflamación. En general la inflamación se considera una respuesta defensiva que la célula organiza partiendo de cero cuando hay una agresión externa, pero los investigadores la ven ahora como “un mecanismo de defensa que la célula mantiene inactivado, inhibido, a menos que le haga falta”, afirma Real. Lo que demuestra el nuevo resultado es que en el tejido sano la célula cuenta con mecanismos específicos de control que suprimen la inflamación.


Con este cambio conceptual como punto de partida, el grupo del CNIO ha descubierto además que, al menos en el páncreas, los mecanismos moleculares implicados en las funciones normales del tejido sano, como la diferenciación celular, son también los que suprimen la inflamación. Es decir, mantener la inflamación bajo llave es lo habitual, y se lleva a cabo mediante mecanismos moleculares implicados en el funcionamiento normal de la célula.


Estos resultados ayudan a entender otros trabajos previos de los mismos investigadores, en que utilizando modelos de ratón habían observado que cuando se elimina el mecanismo que suprime la inflamación en las células pancreáticas, el tejido se vuelve más propenso a desarrollar un cáncer inducido por mutaciones en el gen KRAS –un gen clave en los tumores de páncreas–.



“Vemos que cuando las células no se diferencian correctamente se produce un estado de pre-inflamación, y sabemos que en ese contexto las células son más sensibles a mutaciones en KRAS; es como si las células se colocaran en una parrilla de salida para la inflamación y el cáncer”, explica Real. El mecanismo que controla la inflamación es un gen llamado NR5A2. Los investigadores han estudiado a fondo su función en ratones y después han comprobado que los resultados son extrapolables a humanos.


Como explica Real, “en ratones, cuando hay niveles normales de NR5A2 se suprimen los fenómenos inflamatorios, mientras que cuando los niveles de NR5A2 bajan, entonces se activan programas inflamatorios y aumenta el riesgo de desarrollar cáncer de páncreas; en humanos, los individuos que tienen niveles bajos de este mismo gen en el páncreas muestran un estado de pre-inflamación muy parecido al que detectamos en ratones”. 


No es casual que el interruptor de la inflamación sea NR5A2, dado que en humanos se han identificado ya variantes de este gen que aumentan el riesgo de cáncer de páncreas. Son variantes frecuentes en la población; portarlas no basta para generar cáncer de páncreas, pero ahora se sabe que disparan las etapas iniciales de la inflamación y aumentan el riesgo si concurren además otras circunstancias, como mutaciones en KRAS


Esto encaja muy bien con lo que se observa en la clínica: el cáncer de páncreas con frecuencia ocurre en pacientes con predisposición genética, mutaciones en el gen KRAS y con pancreatitis –una inflamación del páncreas–.



Ante los investigadores se abren ahora dos nuevas vías de avance: Una es determinar si la existencia de un vínculo genético entre inflamación y cáncer se da también en otros órganos, además del páncreas; la otra es tratar de aplicar el nuevo conocimiento a la prevención del cáncer de páncreas, que es hoy día uno de los cánceres de peor pronóstico en parte debido a su diagnóstico tardío.


Los investigadores creen que detectar los estadios iniciales de la inflamación permitiría disponer de útiles señales de alerta. Pero para eso necesitan poder detectar esas señales en un simple análisis de sangre: “No se puede biopsiar el páncreas como otros tejidos más fácilmente accesibles; vamos a tratar de detectar el estado preinflamatorio en sangre, primero en ratones y luego en humanos”, dice Real.


Paco Real es, además de jefe de grupo en el CNIO, jefe de grupo del CIBER de Cáncer (CIBERONC). En el trabajo han participado también el Grupo de Genes, Desarrollo y Enfermedad, el Grupo de Epidemiología Genética y Molecular y la Unidad de Microscopía Confocal del CNIO.


Este trabajo ha sido financiado por el Ministerio de Economía, Industria y Competitividad, el Instituto de Salud Carlos III, el Séptimo Programa Marco de la Unión Europea, Worldwide Cancer Research (WCR), el Fondo de Investigaciones Sanitarias (FIS), EUPancreas COST Action, el Intramural Research Program de los Institutos Nacionales de Salud de EEUU (NIH), el Instituto Nacional del Cáncer de EEUU, la Fundación Europea de la Ciencia (ESF), la Fundación Juegaterapia y la Asociación Española Contra el Cáncer (AECC).


Artículo de referencia: Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas. Isidoro Cobo, Paola Martinelli, Marta Flández, Latifa Bakiri, Mingfeng Zhang, Enrique Carrillo-de-Santa-Pau, Jinping Jia, Víctor J. Sánchez-Arévalo Lobo, Diego Megías, Irene Felipe, Natalia del Pozo, Irene Millán, Liv Thommesen, Torunn Bruland, Sara Olson, Jill Smith, Kristina Schoonjans, William R. Bamlet, Gloria M Petersen, Núria Malats, Laufey T Amundadottir, Erwin F. Wagner, Francisco X Real (Nature 2018). DOI: 10.1038/nature25751
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