Patología de los tumores neuroblásticos: evaluación pronóstica. Experiencia del centro español de referencia de la SEOP para estudios biopatológicos del neuroblastoma (1992-2005)

Antecedentes: Los tumores neuroblásticos son los tumores sólidos extracraneales más frecuentes en la infancia y se caracterizan por una evolución clínica heterogénea que va desde una progresión rápida a una regresión tumoral espontánea. Existen factores pronósticos conocidos que determinan dicha evolución como son la edad, estadiaje, histopatología, estatus de MYCN, ploidía y diversas ganancias y pérdidas cromosómicas. El objetivo del trabajo es describir nuestra experiencia como laboratorio de referencia español para la determinación de estos parámetros pronósticos. Métodos: Material tumoral de pacientes con neuroblastoma, remitido a nuestro laboratorio desde 1992 hasta 2005, ha sido sometido a estudio histopatológico, molecular para determinar la amplificación de MYCN, histoquímico y morfométrico para estudiar la ploidía y se ha introducido la técnica de CGH para el análisis de ganancias y perdidas cromosómicas. Resultados: El seguimiento clínico durante estos años, ha demostrado la importancia pronóstica de la clasificación histológica Internacional Neuroblastoma Pathology Classification (INPC), la relación de un contenido diploide-tetraploide de ADN con el histopronóstico desfavorable, la proporción del 20% de casos con amplificación de MYCN y su carácter pronostico desfavorable, así como la presencia de ganancias y pérdidas cromosómicas como 11q- que confieren mal pronóstico. Conclusiones: Se confirma la necesidad de determinar parámetros morfológicos y genéticos de valor pronóstico con el fin de estratificar la terapéutica apropiada de elección en los pacientes con neuroblastoma.Background: Neuroblastic tumors are the most frequent extracranial solid tumors in childhood, and are characterized by a heterogeneous clinic behavior, ranging from a rapid progression of disease to a spontaneous regression. Prognostic indicators that condition such behavior, such as age, staging, histopathology, MYCN oncogene status, ploidy, and diverse chromosomal losses and gains, have been demonstrated. The aim of present work is to describe our experience as reference laboratory for the determination of these prognostic factors in neuroblastic tumors. Methods: Tumor material from patients with neuroblastoma, submitted to our laboratory from 1992 to 2005 has been analyzed. Histopathology following Internacional Neuroblastoma Pathology Classification (INPC) classification, PCR and FISH for MYCN status, static cytometry for ploidy and CGH for chromosomal gains and losses, were performed. Results: The clinical follow-up has demonstrated the prognostic value of INPC, the relationship between diploid-tetraploid DNA content and unfavorable histology, the existence of 20% MYCN amplified cases showing an unfavorable prognosis as well as the presence of chromosomal gains and losses especially 11q-, that confer unfavorable prognosis. Conclusions: We confirm the importance of determining morphological and genetic prognostic parameters in neuroblastic tumors in order to stratify the patients to receive the correct therapy accordingly.Navarro Fos, Samuel, [email protected] ; Llombart Bosch, Antonio, [email protected] ; Pellin Perez, Antonio, [email protected] ; Burgues Gasion, Octavio, [email protected]; Ruiz Sauri, Amparo, [email protected]; Piqueras Franco, Marta, [email protected] ; Noguera Salva, Rosa, [email protected]

MicroRNA-33b Suppresses Epithelial-Mesenchymal Transition Repressing the MYC-EZH2 Pathway in HER2+ Breast Carcinoma

Downregulation of miR-33b has been documented in many types of cancers and is being involved in proliferation, migration, and epithelial-mesenchymal transition (EMT). Furthermore, the enhancer of zeste homolog 2-gene (EZH2) is a master regulator of controlling the stem cell differentiation and the cell proliferation processes. We aim to evaluate the implication of miR-33b in the EMT pathway in HER2+ breast cancer (BC) and to analyze the role of EZH2 in this process as well as the interaction between them. miR-33b is downregulated in HER2+ BC cells vs healthy controls, where EZH2 has an opposite expression in vitro and in patients' samples. The upregulation of miR-33b suppressed proliferation, induced apoptosis, reduced invasion, migration and regulated EMT by an increase of E-cadherin and a decrease of ß-catenin and vimentin. The silencing of EZH2 mimicked the impact of miR-33b overexpression. Furthermore, the inhibition of miR-33b induces cell proliferation, invasion, migration, EMT, and EZH2 expression in non-tumorigenic cells. Importantly, the Kaplan-Meier analysis showed a significant association between high miR-33b expression and better overall survival. These results suggest miR-33b as a suppressive miRNA that could inhibit tumor metastasis and invasion in HER2+ BC partly by impeding EMT through the repression of the MYC-EZH2 loop