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

• Published in: The journal of clinical endocrinology and metabolism 2008-09, Vol.93 (9), p.3524-3531
• Main Authors: Almeida, Madson Q., Fragoso, Maria Candida Barisson Villares, Lotfi, Claudimara Ferini Pacicco, Santos, Mariza Gerdulo, Nishi, Mirian Yumie, Costa, Marcia Helena Soares, Lerario, Antonio Marcondes, Maciel, Carolina Canton, Mattos, Gabriele Ebling, Jorge, Alexander Augusto Lima, Mendonca, Berenice B., Latronico, Ana Claudia
• Format: Article
• Language: English
• Subjects: Adenoma - genetics; Adenoma - pathology; Adolescent; Adrenal Cortex Neoplasms - genetics; Adrenal Cortex Neoplasms - pathology; Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Adult; Aged; Biological and medical sciences; Carcinoma - genetics; Carcinoma - pathology; Child; Child, Preschool; Endocrinopathies; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic; Humans; Infant; Insulin-Like Growth Factor II - genetics; Insulin-Like Growth Factor II - metabolism; Male; Malignant tumors; Medical sciences; Middle Aged; Neoplasm Metastasis; Receptor, IGF Type 2 - genetics; Receptor, IGF Type 2 - metabolism; Tumor Cells, Cultured; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2008-0065

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.