The role of the insulin-like growth factor system in adrenocortical tumourigenesis.

Abstract

The insulin-like growth factor (IGF) system plays a central role in the mechanism of transformation and tumourigenesis. Elevated levels of IGF-II and IGF-I have been found in adrenocortical carcinomas. We examined binding characteristics and concentrations of both IGF-receptors in normal adult human adrenocortical glands, and compared them with the IGF-I receptor binding in adrenocortical rumours of various origins. The human IGF-I receptor was overexpressed in the mouse adrenocortical tumour cell line Y1, and growth studied in response to IGF stimulation. The influence of IGF-II on adrenal morphology and function was assessed in transgenic mice that postnatally overexpress IGF-II. While the abundance of the IGF-I receptor in adrenocortical hyperplasias and adenomas was similar to normal tissue, a strong overexpression of the intact IGF-I receptor was found in three out of four adrenocortical carcinomas. Y1 cells overexpressing the human IGF-I receptor respond to IGF-I with an increase in thymidine incorporation by 140%. Furthermore, the antiproliferative effect of ACTH is blunted. In transgenic mice postnatally overexpressing IGF-II, adrenal weight is increased, mainly due to a 50% increase in the number of zona fasciculata cells. Plasma corticosterone levels in these mice are twofold higher than in controls, in contrast to similar plasma ACTH levels, thus indicating a direct effect of IGF-II on adrenal cell hyperplasia and function. There is substantial evidence that the IGF-system is involved in adrenal growth and tumourigenesis. High local levels of IGF-II in combination with elevated IGF-I receptor concentrations would represent a significant growth advantage of the adrenocortical carcinoma cell and could contribute to a highly malignant phenotype. IGF-II overexpression alone seems not to be sufficient for malignant transformation.