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Expression of Insulin-Like Growth Factor-II and Its Receptor in Pediatric and Adult Adrenocortical Tumors

Unidade de Endocrinologia do Desenvolvimento (M.Q.A., M.C.B.V.F., M.G.S., M.Y.N., M.H.S.C., A.M.L., A.A.L.J., B.B.M., A.C.L.), Laboratório de Hormônios e Genética Molecular/LIM42 da Disciplina de Endocrinologia do Hospital das Clínicas da Faculdade de Medicina, and Laboratório de Estrutura e Função Celular (C.F.P.L., C.C.M., G.E.M.), Departamento de Anatomia, Instituto de Ciências Biomédicas, Universidade de São Paulo, 05403-900 São Paulo, Brazil

Address all correspondence and requests for reprints to: Madson Queiroz Almeida, M.D., Unidade de Endocrinologia do Desenvolvimento e Laboratorio de Hormonios e Genetica Molecular LIM-42, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Eneas de Carvalho Aguiar, 155, 20 andar Bloco 6, 05403-900 Sao Paulo, SP, Brasil. E-mail: madsonalmeida{at}gmail.com; anacl{at}usp.br.

Background: Adrenocortical tumors are heterogeneous neoplasms with incompletely understood pathogenesis. IGF-II overexpression has been consistently demonstrated in adult adrenocortical carcinomas.

Objectives: The objective of the study was to analyze expression of IGF-II and its receptor (IGF-IR) in pediatric and adult adrenocortical tumors and the effects of a selective IGF-IR kinase inhibitor (NVP-AEW541) on adrenocortical tumor cells.

Patients: Fifty-seven adrenocortical tumors (37 adenomas and 20 carcinomas) from 23 children and 34 adults were studied.

Methods: Gene expression was determined by quantitative real-time PCR. Cell proliferation and apoptosis were analyzed in NCI H295 cells and a new cell line established from a pediatric adrenocortical adenoma.

Results: IGF-II transcripts were overexpressed in both pediatric adrenocortical carcinomas and adenomas. Otherwise, IGF-II was mainly overexpressed in adult adrenocortical carcinomas (270.5 ± 130.2 vs. 16.1 ± 13.3; P = 0.0001). IGF-IR expression was significantly higher in pediatric adrenocortical carcinomas than adenomas (9.1 ± 3.1 vs. 2.6 ± 0.3; P = 0.0001), whereas its expression was similar in adult adrenocortical carcinomas and adenomas. IGF-IR expression was a predictor of metastases in pediatric adrenocortical tumors in univariate analysis (hazard ratio 1.84; 95% confidence interval 1.28–2.66; P = 0.01). Furthermore, NVP-AEW541 blocked cell proliferation in a dose- and time-dependent manner in both cell lines through a significant increase of apoptosis.

Conclusion: IGF-IR overexpression was a biomarker of pediatric adrenocortical carcinomas. Additionally, a selective IGF-IR kinase inhibitor had antitumor effects in adult and pediatric adrenocortical tumor cell lines, suggesting that IGF-IR inhibitors represent a promising therapy for human adrenocortical carcinoma.