Excodra Barcelonra
IMIM

IMIM

El IMIM (Instituto Hospital del Mar de Investigaciones Médicas), ubicado en el Parque de Investigación Biomédica de Barcelona (PRBB), está conformado en un 82% por grupos de investigación liderados por profesionales del Parque de Salud MAR, en buena parte vinculados a la Universidad Autónoma de Barcelona y la Universidad Pompeu Fabra, así como por personal adscrito proveniente del Centro de Investigación en Epidemiología Ambiental (CREAL), Centro de Regulación Genómica (CRG), Departamento de Ciencias Experimentales y de la Salud de la Universidad Pompeu Fabra (DCEXS-UPF), Centro de Medicina Regenerativa de Barcelona (CMRB) y del Parque de Investigación Biomédica de Barcelona (PRBB). El 16 de diciembre de 2013, el Comité de Acreditación del Instituto de Salud Carlos III (ISCIII) aprobó la acreditación del IMIM como Instituto de Investigación Sanitaria, la cual fue ratificada por la Secretaría de Estado de Investigación, Desarrollo e Innovación por la Orden de 17 de febrero de 2014. c/ Doctor Aiguader, 88. 08003. Barcelona. http://www.imim.es

Entrevista con el Dr. Antonio García de Herreros

Fuente: Excodra | Publicado: 17-11-2016
Más recientemente, y en algunos tumores concretos, las terapias que están teniendo más éxito se basan en incrementar la respuesta inmune contra las células tumorales. En general, los tumores se escapan de la respuesta inmune e incluso la pervierten, reclutando sólo las células de este sistema que pueden aprovechar para su crecimiento. La evasión del sistema inmune la realizan expresando una serie de proteínas que previenen la acción de los linfocitos. Las terapias más actuales (inmunoterapia) se basan en suministrar anticuerpos contra estas proteínas, de manera que el freno proporcionado por las células tumorales queda eliminado y los tumores generan una respuesta inmune mucho mayor que eventualmente puede llegar a destruirlas.
Derechos: Antonio García de Herreros
22 comentarios

Antonio, muy genéricamente, ¿qué es el cáncer?

El cáncer es una enfermedad en la que se altera el programa correcto de una célula, que implica su crecimiento y diferenciación; esto es, la adquisición de unas propiedades específicas necesarias para su función (por ejemplo, en una célula del estómago ser capaz de secretar enzimas digestivas o en una intestinal, absorber los nutrientes). La alteración de estas propiedades supone que estas células proliferen aumentando su número de manera incontrolada, modifiquen su entorno para adaptarlo a sus necesidades y en muchos casos, sean capaces de establecer colonias en otras partes distantes del organismo (metastatizar).  

Yendo hacia vuestro grupo de investigación, en el que en concreto lleváis 25 años trabajando en el IMIM, que no es poco... ¿cómo han sido todos estos años y cómo habéis ido creciendo?



El IMIM es un instituto creado hace ya más de 60 años e inaugurado por Alexander Fleming en su visita a Barcelona en el año 48. Fue renovado a principios de los 90, lo que supuso entre otras cosas mi incorporación y la creación de mi grupo.


La verdad es que hemos sido muy afortunados en aprovechar dos grandes momentos positivos para la Ciencia en España; uno inicial durante los años 90, causado por la consolidación de los programas estatales de investigación y por la Agencia Nacional de Evaluación y Perspectiva (ANEP) que hizo posible que, tras una evaluación seria, los grupos de investigación recibiesen una financiación digna de una manera continuada. Otras instituciones privadas, por ejemplo la Asociación Española Contra el Cáncer también han incrementado en gran medida los recursos dedicados a la investigación. El segundo gran impulso a la investigación de nuestro grupo fue consecuencia del gran auge de la investigación biomédica en Barcelona originado por las medidas del en aquel momento Conseller Andreu Mas-Colell, al crear el instituto ICREA (un CSIC virtual catalán) y centros de investigación de élite como el Centro de Recerca Genòmica, con una estructura y reglas totalmente diferentes de los existentes hasta el momento. Estos dos hechos hicieron progresar extraordinariamente la calidad de la ciencia hecha en Barcelona y permitieron reclutar numerosos científicos extranjeros. Desgraciadamente la crisis y la disminución de recursos también nos ha afectado, unido a la revolución del “big data” que ha encarecido mucho la investigación que nos gustaría realizar.  

Por acercarnos a lo más actual ¿qué tipo de proteína es la E-cadherina y cuál es su papel en el desarrollo de tumores?

La E-cadherina es una proteína transmembrana, que tiene dominios tanto dentro de la membrana plasmática como en el interior y en el exterior de la célula. Se encuentra solamente en células epiteliales y es necesaria para que las células epiteliales se unan entre sí, algo totalmente necesario para que formen un epitelio funcional. La E-cadherina está presente en los tumores que se generan por las células epiteliales (los más comunes, por ejemplo de colon, de mama o de pulmón) y su expresión se asocia a un mejor pronóstico; es decir, cuanta más E-cadherina haya más fácil es que el tumor no forme metástasis.



Esto se debe al hecho de que los tumores más indiferenciados, es decir, que han perdido las características propias de las células epiteliales y también la expresión de la E-cadherina, son más invasivos y forman más metástasis que los que mantienen las características de las células originales.  



Cadherinas, cateninas y proteínas Snail ¿cómo interaccionan y, hasta qué punto son clave para frenar el cáncer?

Las cadherinas y concretamente, la E-cadherina, se unen por su parte intracelular a unas proteínas denominadas colectivamente cateninas. Entre estas, la b-catenina es la que ha recibido más atención porque cuando se libera de la E-cadherina viaja al núcleo y participa en la expresión de genes que facilitan tanto el crecimiento del tumor como en darle capacidad invasiva. Por tanto, en tumores, la cantidad de b-catenina presente en el núcleo está incrementada, bien porque se libera mejor de la E-cadherina o bien porque las proteínas que impiden su paso al núcleo no funcionan. Entre estas proteínas, una de ellas APC, está mutada en prácticamente todos los tumores de colon. La proteína Snail impide que la E-cadherina se sintetice, facilitando así el crecimiento y la invasión de los tumores, cooperando con la b-catenina. De ahí su importancia en la lucha contra el cáncer.   

Por hacer un breve recorrido sobre los tratamientos, ¿cómo se comenzó a tratar el cáncer, cómo evolucionaron y qué nuevos tratamientos y fármacos están surgiendo y con cuáles estáis trabajando en vuestro laboratorio?

Los tratamientos iniciales del cáncer, algunos de los cuales todavía se utilizan, se basaron en sustancias que afectan la capacidad de crecimiento de cualquier tipo celular. Se pensaron considerando que en un paciente con cáncer la mayoría de las células que se dividen son las tumorales y por tanto serían las más sensibles a los fármacos. Aunque en algunos casos funcionan bien (la mayoría de los tumores de testículo, por ejemplo), en general son muy tóxicos y tienen muchos efectos secundarios. Posteriormente se diseñaron tratamientos más específicos, basados en características concretas de las células tumorales, como por ejemplo el hecho de que algunos tumores posean niveles elevados del receptor de un factor extracelular. Estos tratamientos tratan de bloquear la acción de este factor y por tanto inhibir de una manera selectiva el crecimiento del tumor y no de células sanas del organismo.



Más recientemente, y en algunos tumores concretos, las terapias que están teniendo más éxito se basan en incrementar la respuesta inmune contra las células tumorales. En general, los tumores se escapan de la respuesta inmune e incluso la pervierten, reclutando sólo las células de este sistema que pueden aprovechar para su crecimiento. La evasión del sistema inmune la realizan expresando una serie de proteínas que previenen la acción de los linfocitos. Las terapias más actuales (inmunoterapia) se basan en suministrar anticuerpos contra estas proteínas, de manera que el freno proporcionado por las células tumorales queda eliminado y los tumores generan una respuesta inmune mucho mayor que eventualmente puede llegar a destruirlas. De momento estos tratamientos están teniendo éxito en algunos tumores muy específicos: tumores de riñón y melanomas.


En el laboratorio proponemos estrategias alternativas basadas no tanto en atacar directamente a las células tumorales sino a las células que las rodean, denominadas colectivamente estroma. El estroma proporciona a las células tumorales un ambiente propicio para que crezcan y sean capaces de invadir los tejidos circundantes. Nosotros pensamos que atacando estas células del entorno, que el tumor ha reorganizado para que le sean útiles, podremos restringir el crecimiento del tumor y hacerlo más sensible a la acción de otros fármacos.  

Hay algo que siempre me ha llamado mucho la atención, y es cómo del núcleo de lo que es el cáncer, es decir, la proliferación incontrolada de células, como comentábamos al inicio, de este mal, digamos, nos llevó a desarrollar las líneas celulares in vitro, que son herramienta básica para casi cualquier investigación biomédica… ¿nos podrías comentar un poco qué son y cómo extrapolamos lo que en ellas se descubre y cómo se aplica después a los pacientes lo descubierto? Para dar una visión vertical de las investigaciones.



Las líneas tumorales son una herramienta básica para la investigación oncológica, muy útil pero con ciertas limitaciones. La primera, la línea HeLa fue establecida a mediados del siglo pasado a partir de un tumor de cérvix y desde entonces se han obtenido y caracterizado muchas más. Para obtenerlas se cultivan fragmentos de un tumor obtenido de un paciente en una placa de Petri especial con nutrientes y factores de crecimiento; en muchos casos se observa la proliferación de células tumorales que presentan características semejantes a las del tumor original.


Estas células crecen de una manera indefinida, y sólo dependen de que se les añada de manera regular los nutrientes y que cuando ocupen toda la placa se las levante, y una parte de ellas se coloque en una nueva placa. A estas células derivadas del tumor que crecen de una manera indefinida se las ha llamado línea tumoral. Se han generado muchas líneas con distintas propiedades (más o menos diferenciadas, con mayor o menor invasión y expresión de E-cadherina) que se pueden hacer crecer en el laboratorio. Estas líneas se pueden manipular fácilmente, para eliminar o sobre-expresar una determinada proteína y así analizar la relevancia de ésta en el crecimiento o invasión celular.
Sin embargo, presentan limitaciones, particularmente debido a que las condiciones en las que se hacen crecer en el laboratorio son distintas a las que existen en un tumor real: ni la disponibilidad de nutrientes es tan alta en los tumores, ni en estos se encuentran las células aisladas sino rodeadas por células del estroma. Por esto, actualmente muchos de los resultados obtenidos en líneas celulares deben ser después verificados en otros sistemas experimentales; por ejemplo en modelos de ratones que expresan oncogenes y desarrollan tumores de forma espontánea.  


De la genética al medioambiente, creo que ya se pueden dar perfiles bastante cercanos de personas con más o menos predisposición a padecer diferentes tipos de cáncer según estilos de vida, sin embargo siento que este lado de la medicina, el de la prevención por perfil genético y hábitos, que parecía muy en boga hace unos años, esté decayendo… o tal vez únicamente a nivel de comunicación social, es sólo una percepción, pero, ¿es así? Y, ¿cuánto se puede hacer desde la prevención por estilo de vida y perfil genético en la lucha contra el cáncer?



No, no creo que la prevención del cáncer sobre la base de hábitos de vida y perfil genético esté decayendo. Tal vez haya habido una “inflación” de informaciones sobre el efecto carcinogénico de diferentes agentes, efecto que probablemente existe pero que debería ser explicado, matizado y ordenado. No es lo mismo, por ejemplo, el efecto del tabaco y el del sedentarismo sobre la probabilidad global de padecer cáncer.


Por otro lado, los perfiles genéticos pueden dar una idea de la predisposición de desarrollar la enfermedad en el futuro; en algunos casos, como en la detección de gen BRCA1, la asociación con el cáncer de mama es bastante directa. Sin embargo, en otros no lo es tanto y la mutación en el gen sólo supone un riesgo algo mayor que el de la población general. Es probable que los estudios de secuenciación completa del DNA de diferentes pacientes identifiquen mutaciones que “cooperen” en el desarrollo de la enfermedad. La asociación de estas mutaciones incrementaría el riesgo global, y señalaría individuos que deben ser seguidos de una manera especial. El abaratamiento de los métodos de secuenciación del DNA y la caracterización del significado de las variantes de secuencia obtenidas (¿producen una proteína con función alterada o no?) permitirán que este tipo de análisis sean muy habituales y útiles.  

Tratando de vislumbrar un poco el futuro… ¿cómo crees que será la medicina de aquí a, digamos, 20 años, teniendo en cuenta toda la avalancha de nuevas tecnologías que están floreciendo? Tanto a nivel de investigador, como de médico, como de paciente.



Además de un gran esfuerzo en la prevención basado en el perfil genético y en desarrollar sistemas de detección muy sensibles que permitan la detección de tumores en fases iniciales, creo que lo que veremos será un gran esfuerzo para conseguir la “cronificación” de la enfermedad; es decir, para que el cáncer sea una enfermedad con la que podamos vivir, como por ejemplo de la misma forma a como vivimos ahora con la diabetes.


En algunos tumores como en el cáncer de pulmón, el tratamiento actual produce una fase inicial de regresión del tumor que disminuye en su tamaño; sin embargo, a partir de un cierto momento el tumor deja de responder y comienza crecer. Este nuevo tumor es resistente a las terapias existentes y eventualmente termina acabando con la vida del paciente. En un futuro, tendremos terapias que permitan controlar estos tumores resistentes según vayan apareciendo. El análisis de los diferentes tumores nos permitirá identificarlos, clasificarlos y utilizar terapias más selectivas que permitan que el tumor inicial no progrese y si aparecen nuevos tumores resistentes volverlos a atacar con la terapia adecuada.

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Antonio García de Herreros

Antonio García de Herreros

Antonio GARCIA DE HERREROS Madueño (Madrid, 1958). Bachelor in Chemistry (Biochemistry), Universidad Complutense de Madrid (1980), PhD in Biochemistry, Universidad Autónoma de Madrid (1985). Postdoctoral training: Memorial Sloan-Kettering Cancer Center, New York, USA (1985-1988), Harvard Medical School, Boston, USA (1988-1990), Hospital Gregorio Marañón, Madrid (1990-1991). Current position: Senior Scientist (Group Leader), Cancer Research Program, Hospital del Mar d’Investigacions Mèdiques; Full Professor, Departament de Ciències Experimentals, Universitat Pompeu Fabra; Barcelona. Current research: Tumor cell cooperation in invasion and metastasis. Author of more than 110 articles in international journals; most cited: Batlle et al, Nat Cell Biol 2000, 2: 84-89, (more than 1200 citations); last three most relevant: Beltran et al, Nucleic Acids Res 2015, 43, 5785-5797; Frias et al, Mol Cell Biol 2016, 36, 923-940; Alba-Castellón et al, Cancer Res, 2016, 76, 6205-6217. Supervisor of 24 PhD theses.

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