Progression to adrenocortical tumorigenesis in mice and humans through insulin-like growth factor 2 and β-catenin
Open accessAbstract
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.
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High-grade ACCs are enriched for mutations of TP53 and/or CTNNB1, and these mutations tend to be mutually exclusive.
“High-grade ACCs are enriched for mutations of TP53 (14, 140–142) and/or CTNNB1 (143–149), and these mutations tend to be mutually exclusive (reviewed in Ref. 150).”
From Adrenocortical carcinoma (2014) · cites this paper as [143]
When Apc-knockout mice were crossed with adrenal-specific Igf2 overexpression mice, early-onset adrenal nodular hyperplasia evolving to large tumors later in life was observed, suggesting synergistic effects on adrenocortical tumorigenesis.
“However, when the Apc-knockout mice were crossed with adrenal-specific Igf2 overexpression mice, early-onset adrenal nodular hyperplasia evolving to large tumors later in life (including an invasive cortical tumor similar to an ACC) was observed, suggesting that both pathways may have synergistic effects on adrenocortical tumorigenesis (143).”
From Adrenocortical carcinoma (2014) · cites this paper as [143]
No adrenal phenotype is observed in the adrenal-specific Igf2 overexpression mouse model.
“On the other hand, no adrenal phenotype is observed in the adrenal-specific Igf2 overexpression mouse model.”
From Adrenocortical carcinoma (2014) · cites this paper as [143]
Mice with constitutive activation of Wnt signaling via adrenal-specific Apc knockout develop adrenal hyperplasia and adenomas by 30 weeks of life.
“Mice with constitutive activation of the Wnt signaling pathway obtained by adrenal-specific Apc knockout develop adrenal hyperplasia and adenomas by 30 weeks of life.”
From Adrenocortical carcinoma (2014) · cites this paper as [143]
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References 82 · Cited by 173
- Authors
- Heaton, J. H., Wood, M. A., Kim, A. C., Lima, L. O., Barlaskar, F. M., Almeida, M. Q., Fragoso, M. C. B. V., Kuick, R., Lerario, A. M., Simon, D. P., Soares, I. C., Starnes, E., Thomas, D. G., Latronico, A. C., Giordano, T. J., & Hammer, G. D.
- Affiliations
- University of Michigan (US)
- Universidade de São Paulo (BR)
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 181
- Issue
- 3
- Pages
- 1017-1033
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC3432433
- OpenAlex
- W2162921257
- Cited by
- 173
- References
- 82
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 4 · 2023: 10 · 2022: 9 · 2021: 12 · 2020: 15 · 2019: 9 · 2018: 13 · 2017: 15 · 2016: 11 · 2015: 22 · 2014: 18 · 2013: 15 · 2012: 2
- FWCI
- 18.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Scientific Electronic Library Online (São Paulo Research Foundation, Latin American and Caribbean Center on Health Sciences Information, Conselho Nacional de Desenvolvimento Científico e Tecnológico) (publishedVersion)
- Funders
- University of Pennsylvania
- Universidade de São Paulo
- National Cancer Institute (R01CA134606, CA134606, T32CA009676)
- National Institute of General Medical Sciences (T32GM007315)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK062027, T32-DK07245, T32DK007245, R01DK062027)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007505)
- Topics
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- adrenocortical carcinoma, adrenal adenoma, insulin-like growth factor II, β-catenin, CTNNB1 mutation, Wnt signaling, adrenocortical hyperplasia, carcinogenesis, mouse model, survival, adrenal tumors
- MeSH terms
- Adrenal Cortex Hormones, Adrenal Cortex Neoplasms, Animals, Cell Transformation, Neoplastic, Humans, Hyperplasia, Insulin-Like Growth Factor II, Mutation, Neoplasm Staging, Prognosis, Biomarkers, Tumor, Up-Regulation, Gene Expression Regulation, Neoplastic, Multivariate Analysis, Proportional Hazards Models, Mice, Knockout, Genomic Imprinting, Disease Progression, DNA Methylation, Protein Transport, Adenomatous Polyposis Coli Protein, beta Catenin, Mice, Lymphoid Enhancer-Binding Factor 1, Protein Stability, Neoplasm Grading
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