The IGF axis and hepatocarcinogenesis

Abstract

Deregulation of the insulin-like growth factor (IGF) axis, including the autocrine production of IGFs, IGF binding proteins (IGFBPs), IGFBP proteases, and the expression of the IGF receptors, has been identified in the development of hepatocellular carcinoma (HCC). Characteristic alterations detected in HCC and hepatoma cell lines comprise the increased expression of IGF-II and the IGF-I receptor (IGF-IR), which have emerged as crucial events in malignant transformation and the growth of tumours. Alterations of IGFBP production and the proteolytic degradation of IGFBPs resulting in an excess of bioactive IGFs, as well as the defective function of the IGF degrading IGF-II/mannose 6-phosphate receptor (IGF-II/M6PR), may further potentiate the mitogenic effects of IGFs in the development of HCC.

Figure 1

Expression of insulin-like growth factor I (IGF-I), IGF-II, IGF binding protein 1 (IGFBP-1), IGFBP-4, the IGF-I receptor (IGF-IR), and IGF-II/M6PR (mannose 6-phosphate receptor) in rat liver after low number pancreatic islet transplantation into the livers of streptozotocin induced diabetic rats. Schematic illustration demonstrating representative results from immunohistochemical analysis and in situ hybridisation of antisense mRNA to normal liver (normal; N), to glycogen storing foci (GSF; circular area within the square), and hepatocellular carcinoma (HCC) developing after pancreatic islet transplantation. The intensity of gene expression is directly proportional to the darkness of the section. The circular area (hatched) within the circle is a schematic representation of a transplanted pancreatic islet within the GSF.