Progression to Adrenocortical Tumorigenesis in Mice and Humans through Insulin-Like Growth Factor 2 and β-Catenin
| Autor: | Dafydd G. Thomas, Iberê C. Soares, Joanne H. Heaton, Gary D. Hammer, Derek P. Simon, Alex C. Kim, Antonio M. Lerario, Maria Candida Barisson Villares Fragoso, Ana Claudia Latronico, Lorena de Oliveira Lima, Thomas J. Giordano, Michelle A. Wood, Madson Q. Almeida, Rork Kuick, Ferdous M. Barlaskar, Elisabeth Starnes |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
medicine.medical_specialty
Adenoma endocrine system diseases Lymphoid Enhancer-Binding Factor 1 Adenomatous Polyposis Coli Protein Biology medicine.disease_cause Adrenocortical adenoma Pathology and Forensic Medicine Genomic Imprinting Mice Adrenal Cortex Hormones Insulin-Like Growth Factor II Internal medicine medicine Biomarkers Tumor Adrenocortical carcinoma Animals Humans beta Catenin Neoplasm Staging Proportional Hazards Models Mice Knockout Hyperplasia Protein Stability Wnt signaling pathway Regular Article DNA Methylation medicine.disease Prognosis Adrenal Cortex Neoplasms Up-Regulation Gene Expression Regulation Neoplastic Protein Transport stomatognathic diseases Endocrinology Cell Transformation Neoplastic Catenin Insulin-like growth factor 2 Multivariate Analysis Mutation Cancer research biology.protein Disease Progression Neoplasm Grading Carcinogenesis |
| Zdroj: | The American Journal of Pathology. 181(3):1017-1033 |
| ISSN: | 0002-9440 |
| DOI: | 10.1016/j.ajpath.2012.05.026 |
| Popis: | 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 β-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 β-catenin accumulation in both adrenocortical adenoma and ACC. In ACC, these features were adversely associated with survival. Mice with stabilized β-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 β-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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|