Progression to Adrenocortical Tumorigenesis in Mice and Humans through Insulin-Like Growth Factor 2 and β-Catenin

• Published in: The American journal of pathology Vol. 181; no. 3; pp. 1017 - 1033
• Main Authors: Heaton, Joanne H, Wood, Michelle A, Kim, Alex C, Lima, Lorena O, Barlaskar, Ferdous M, Almeida, Madson Q, Fragoso, Maria C.B.V, Kuick, Rork, Lerario, Antonio M, Simon, Derek P, Soares, Ibere C, Starnes, Elisabeth, Thomas, Dafydd G, Latronico, Ana C, Giordano, Thomas J, Hammer, Gary D
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.09.2012; American Society for Investigative Pathology
• Subjects: Adenomatous Polyposis Coli Protein - metabolism; Adrenal Cortex Hormones - secretion; Adrenal Cortex Neoplasms - genetics; Adrenal Cortex Neoplasms - pathology; Animals; beta Catenin - metabolism; Biological and medical sciences; Biomarkers, Tumor - metabolism; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Disease Progression; DNA Methylation - genetics; Gene Expression Regulation, Neoplastic; Genomic Imprinting; Humans; Hyperplasia; Insulin-Like Growth Factor II - metabolism; Investigative techniques, diagnostic techniques (general aspects); Lymphoid Enhancer-Binding Factor 1 - metabolism; Medical sciences; Mice; Mice, Knockout; Multivariate Analysis; Mutation - genetics; Neoplasm Grading; Neoplasm Staging; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Prognosis; Proportional Hazards Models; Protein Stability; Protein Transport; Regular; Up-Regulation - genetics; Human; Vertebrata; Anatomic pathology; Mammalia; Mouse; Animal; Rodentia; β Catenin; Adrenal cortex; Tumorigenicity; Carcinogenesis; Insulin like growth factor 2
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2012.05.026

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.