Progression to adrenocortical tumorigenesis in mice and humans through insulin-like growth factor 2 and β-catenin.
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.
Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, USA.
Joanne H
JH
Heaton
Michelle A
MA
Wood
Alex C
AC
Kim
Lorena O
LO
Lima
Ferdous M
FM
Barlaskar
Madson Q
MQ
Almeida
Maria C B V
MC
Fragoso
Rork
R
Kuick
Antonio M
AM
Lerario
Derek P
DP
Simon
Ibere C
IC
Soares
Elisabeth
E
Starnes
Dafydd G
DG
Thomas
Ana C
AC
Latronico
Thomas J
TJ
Giordano
Gary D
GD
Hammer
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000305:Adrenal Cortex Hormones / Q000378:metabolism; D000306:Adrenal Cortex Neoplasms / Q000235:genetics / Q000473:pathology*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D019175:DNA Methylation / Q000235:genetics; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D018392:Genomic Imprinting; D006801:Humans; D006965:Hyperplasia; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D055550:Protein Stability; D021381:Protein Transport; D015854:Up-Regulation / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism*
D025601:Adenomatous Polyposis Coli Protein; D000305:Adrenal Cortex Hormones; D014408:Biomarkers, Tumor; D051821:Lymphoid Enhancer-Binding Factor 1; D051176:beta Catenin; D007335:Insulin-Like Growth Factor II