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

Background 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. Material and methods We examined binding characteristics and concentrations of both IGF-receptors in normal adult human adrenocortical glands, and com pared them with the IGF-I receptor binding in adrenocortical rumours of var ious origins. The human IGF-I receptor was overexpressed in the mouse adren ocortical tumour cell line Y1, and growth studied in response to IGF stimul ation. The influence of IGF-II on adrenal morphology and function was asses sed in transgenic mice that postnatally overexpress IGF-II. Results While the abundance of the IGF-I receptor in adrenocortical hyperpl asias and adenomas was similar to normal tissue, a strong overexpression of the intact IGF-I receptor was found in three out of four adrenocortical ca rcinomas. Y1 cells overexpressing the human IGF-I receptor respond to IGF-I with an increase in thymidine incorporation by 140%. Furthermore, the anti proliferative effect of ACTH is blunted. In transgenic mice postnatally ove rexpressing IGF-II, adrenal weight is increased, mainly due to a 50% increa se in the number of zona fasciculata cells. Plasma corticosterone levels in these mice are twofold higher than in controls, in contrast to similar pla sma ACTH levels, thus indicating a direct effect of IGF-II on adrenal cell hyperplasia and function. Conclusion There is substantial evidence that the IGF-system is involved in adrenal growth and tumourigenesis. High local levels of IGF-II in combinat ion with elevated IGF-I receptor concentrations would represent a significa nt growth advantage of the adrenocortical carcinoma cell and could contribu te to a highly malignant phenotype. IGF-II overexpression alone seems not t o be sufficient for malignant transformation.