Role of the Insulin-like Growth Factor System in Adrenocortical Growth control and Carcinogenesis

Clinically silent adrenocortical adenomas are the most frequent abnormality in the adrenal gland. In contrast, adrenocortical carcinoma is a rare tumor with extremely poor prognosis. The factors responsible for the frequent occurrence of benign adrenocortical tumors on one hand, and the rare malignant transformation on the other, are not known. Several genetic alterations such as loss of imprinting or heterozygosity in the 11p15 gene locus causing strong IGF-II overexpression have been demonstrated to be specific to most adrenocortical carcinomas. In addition to IGF-II overexpression, increased levels of the IGF-I receptor and IGFBP-2 have been found in advanced human adrenocortical carcinomas, suggesting that the IGF system may play an important role in adrenocortical carcinogenesis. IGFs are potent mitogens that regulate growth and apoptosis through interaction with the IGF-I receptor, and IGF-I receptor overexpression promotes ligand-dependent neoplastic transformation in a variety of different cell systems. This is compelling evidence that high IGF-II levels in combination with IGF-I receptor overexpression may represent a significant growth advantage for adrenocortical carcinoma cells, contributing to the highly malignant phenotype of this rare cancer type. IGFBP-2 overexpression has also been shown to promote malignant transformation and resistance to oxidative stress in Y1 mouse adrenocortical tumor cells through unknown IGF-independent mechanisms. However, as transgenic mice with IGF-II overexpression in the adrenal gland do not show any increase in the frequency of adrenal tumors, IGF-II overproduction by itself is probably not sufficient for malignant transformation, and additional factors are required for adrenocortical tumorigenesis.