Expression of insulin-like growth factor-II and its receptor in pediatric and adult adrenocortical tumors.
BACKGROUND
Adrenocortical tumors are heterogeneous neoplasms with incompletely understood pathogenesis. IGF-II overexpression has been consistently demonstrated in adult adrenocortical carcinomas.


OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
Almeida
Madson Q
MQ
Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM-42 da Disciplina de Endocrinologia do Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, SP, Brasil. madsonalmeida@gmail.com
Fragoso
Maria Candida Barisson Villares
MC
Lotfi
Claudimara Ferini Pacicco
CF
Santos
Mariza Gerdulo
MG
Nishi
Mirian Yumie
MY
Costa
Marcia Helena Soares
MH
Lerario
Antonio Marcondes
AM
Maciel
Carolina Canton
CC
Mattos
Gabriele Ebling
GE
Jorge
Alexander Augusto Lima
AA
Mendonca
Berenice B
BB
Latronico
Ana Claudia
AC
D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017527:Receptor, IGF Type 2 / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D017527:Receptor, IGF Type 2; D007335:Insulin-Like Growth Factor II