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Am J Pathol ; 181(3): 1017-33, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22800756

RESUMO

Dysregulation of the WNT and insulin-like growth factor 2 (IGF2) signaling pathways has been implicated in sporadic and syndromic forms of adrenocortical carcinoma (ACC). Abnormal ß-catenin staining and CTNNB1 mutations are reported to be common in both adrenocortical adenoma and ACC, whereas elevated IGF2 expression is associated primarily with ACC. To better understand the contribution of these pathways in the tumorigenesis of ACC, we examined clinicopathological and molecular data and used mouse models. Evaluation of adrenal tumors from 118 adult patients demonstrated an increase in CTNNB1 mutations and abnormal ß-catenin accumulation in both adrenocortical adenoma and ACC. In ACC, these features were adversely associated with survival. Mice with stabilized ß-catenin exhibited a temporal progression of increased adrenocortical hyperplasia, with subsequent microscopic and macroscopic adenoma formation. Elevated Igf2 expression alone did not cause hyperplasia. With the combination of stabilized ß-catenin and elevated Igf2 expression, adrenal glands were larger, displayed earlier onset of hyperplasia, and developed more frequent macroscopic adenomas (as well as one carcinoma). Our results are consistent with a model in which dysregulation of one pathway may result in adrenal hyperplasia, but accumulation of a second or multiple alterations is necessary for tumorigenesis.


Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Transformação Celular Neoplásica/patologia , Progressão da Doença , Fator de Crescimento Insulin-Like II/metabolismo , beta Catenina/metabolismo , Proteína da Polipose Adenomatosa do Colo/metabolismo , Corticosteroides/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Animais , Biomarcadores Tumorais/metabolismo , Transformação Celular Neoplásica/genética , Metilação de DNA/genética , Regulação Neoplásica da Expressão Gênica , Impressão Genômica , Humanos , Hiperplasia , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Camundongos , Camundongos Knockout , Análise Multivariada , Mutação/genética , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estabilidade Proteica , Transporte Proteico , Regulação para Cima/genética
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