Investigadores del Laboratorio de Desarrollo y Control de Crecimiento del IRB Barcelona identifican los tipos celulares y mecanismos moleculares responsables del crecimiento ilimitado de tumores epiteliales (carcinomas), y demuestran que el crecimiento de estos tumores es independiente del microambiente tumoral.
“En tumores epiteliales causados por inestabilidad cromosómica o pérdida de polaridad celular, la interacción entre dos poblaciones tumorales promueve su crecimiento ilimitado”, explica Marco Milán, profesor de investigación ICREA y líder del laboratorio.
Publicado en la revista Proceedings of the National Academic of Sciences (PNAS) como portada del último número de agosto, el estudio analiza tumores sólidos de origen epitelial en la mosca del vinagre, Drosophila melanogaster. “Hemos inducido tumores de dos formas independientes, generando inestabilidad cromosómica o por pérdida de polaridad celular, validando la relación causal entre estas condiciones, que se observan con frecuencia en carcinomas, y la aparición de tumores”, explica Mariana Muzzopappa, primera autora del estudio e investigadora postdoctoral del Laboratorio de Desarrollo y Control de Crecimiento del IRB Barcelona.
Independiente del microambiente tumoral
Para estudiar el efecto del microambiente tumoral sobre el desarrollo del tumor, los investigadores examinaron su crecimiento en ausencia de poblaciones celulares adyacentes, como el sistema inmune o células mesenquimales —que pueden actuar como nicho proporcionando factores de crecimiento a las células tumorales—. Observaron que en ausencia de estos dos tipos celulares el tumor continuaba creciendo.
Además, demostraron que “los tumores epiteliales dependen de la activación de la vía de señalización de estrés JNK para su crecimiento y que ésta se activa de forma intrínseca al tumor, independientemente del microambiente tumoral”, destaca Marco Milán.
Interacciones entre dos poblaciones tumorales
Los investigadores han identificado dos poblaciones celulares funcionalmente diferentes dentro del tumor, una que prolifera y otra que no, de las que dependen los mecanismos internos de crecimiento. “JNK se activa en un grupo de células que no proliferan, aquellas que tienen mayores niveles de inestabilidad cromosómica o que pierden la polaridad celular. JNK induce la expresión de factores de crecimiento y hace que las células que todavía están en el epitelio sigan proliferando. La proliferación de estas células aumenta los niveles de inestabilidad cromosómica y de pérdida de polaridad epitelial en los tumores. Como consecuencia, aumenta el número de células que expresan factores de crecimiento. Estas interacciones explican el crecimiento ilimitado de estos tumores epiteliales”, describe Mariana Muzzopappa.
El mecanismo de activación de JNK es diferente en función del tumor. “Lo que vemos es que los tumores generados a partir de inestabilidad cromosómica se inducen vía estrés oxidativo de ROS (especies reactivas del oxígeno) que activa JNK. En tumores inducidos por pérdida de la polaridad celular el mecanismo es diferente”, explica Marco Milán.
Los resultados de este trabajo profundizan en la relación causal entre inestabilidad cromosómica, pérdida de polaridad epitelial y tumorigénesis, y abren nuevas vías para la búsqueda de dianas terapéuticas.
Este estudio ha recibido el apoyo del Ministerio de Economía, Industria y Competitividad (MINECO) a través de fondos FEDER “Una manera de hacer Europa” y de la Fundación "la Caixa" a través del programa de becas de doctorado.
Artículo de referencia: Mariana Muzzopappa, Lada Murcia and Marco Milán Feedback amplification loop drives malignant growth in epithelial tissues PNAS (2017): doi: 10.1073/pnas.1701791114
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