Role of insulin-like growth factors and their binding proteins in growth control and carcinogenesis

Abstract

Interest in the role of the insulin-like growth factor (IGF) axis in growth control and carcinogenesis has recently been increased by the finding of elevated serum insulin-like growth factor I (IGF-I) levels in association with three of the most prevalent cancers in the United States: prostate cancer, colorectal cancer, and lung cancer. IGFs serve as endocrine, autocrine, and paracrine stimulators of mitogenesis, survival, and cellular transformation. These actions are mediated through the type 1 IGF-receptor (IGF-1R), a tyrosine kinase that resembles the insulin receptor. The availability of free IGF for interaction with the IGF-1R is modulated by the insulin-like growth factor-binding proteins (IGFBPs). IGFBPs, especially IGFBP-3, also have IGF-independent effects on cell growth. IGF-independent growth inhibition by IGFBP-3 is believed to occur through IGFBP-3-specific cell surface association proteins or receptors and involves nuclear translocation. IGFBP-3-mediated apoptosis is controlled by numerous cell cycle regulators in both normal and disease processes. IGFBP activity is also regulated by IGFBP proteases, which affect the relative affinities of IGFBPs, IGFs and IGF-1R. Perturbations in each level of the IGF axis have been implicated in cancer formation and progression in various cell types.

Copyright 2000 Wiley-Liss, Inc.

Figures

Fig. 1

Insulin-like growth factor-binding protein (IGFBP) functions. A: Modulating IGF actions. IGFBP-3, as part of the 150-kDa complex, carries insulin-like growth factors (IGFs) in the circulation and traffics them to the target tissues. At the target cells, IGFBPs can prevent insulin-like growth factor type 1 receptors (IGF-1R) down-regulation by sequestering the IGFs, as shown on the left. When cleaved by IGFBP proteases, the IGFBPs release free IGF to bind to the IGF-1R and stimulate mitogenesis, as shown on the right. B: IGF-independent actions. IGFBP-3, secreted in an autocrine or para-crine manner, can bind to its cell surface receptor and induce apopto-sis in an IGF-independent fashion. IGFBP proteases can cleave the IGFBPs and thereby reduce or completely eliminate this effect.