Deregulation of the IGF axis in cancer: epidemiological evidence and potential therapeutic interventions.

The IGF system performs a fundamental role in the regulation of cellular proliferation, differentiation and apoptosis. These diverse biological actions are mediated primarily by IGF association with the type I IGF receptor (IGF-IR), which is in turn regulated by a group of high-affinity IGF-binding proteins (IGFBP-1 to -6). All of the IGFBPs can have growth-inhibitory effects by competitively binding IGFs and preventing their association with the IGF-IR. IGFBP-3 is the most abundant binding protein in the circulation and controls the actions of the IGFs by regulating their distribution and bioavailability to target tissues. Disruptions in the balance of IGF system components leading to excessive proliferation and survival signals have been implicated in the development of different tumor types. Epidemiological evidence indicates that increased levels of IGF-I, reduced levels of IGFBP-3 or an increased ratio of IGF-I to IGFBP-3 in the circulation are associated with an increased risk for the development of several common cancers, including those of the breast, prostate, lung and colon. The results of preclinical studies indicate that a diversity of interventions which antagonize IGF-IR signaling or augment IGFBP-3 function inhibit tumor cell growth in models of human cancers. A more comprehensive understanding of the interplay between cellular targets of the IGF system and antineoplastic agents will facilitate the development of novel strategies for the prevention and treatment of cancer.