Targeting insulin-like growth factor axis in hepatocellular carcinoma

Abstract

The insulin-like growth factor (IGF) axis contains ligands, receptors, substrates, and ligand binding proteins. The essential role of IGF axis in hepatocellular carcinoma (HCC) has been illustrated in HCC cell lines and in animal xenograft models. Preclinical evidence provides ample indication that all four components of IGF axis are crucial in the carcinogenic and metastatic potential of HCC. Several strategies targeting this system including monoclonal antibodies against the IGF 1 receptor (IGF-1R) and small molecule inhibitors of the tyrosine kinase function of IGF-1R are under active investigation. This review describes the most up-to-date understanding of this complex axis in HCC, and provides relevant information on clinical trials targeting the IGF axis in HCC with a focus on anti-IGF-1R approach. IGF axis is increasingly recognized as one of the most relevant pathways in HCC and agents targeting this axis can potentially play an important role in the treatment of HCC.

Figure 1

Binding of insulin and IGF ligands to their receptors. Insulin receptor and IGF-1 receptor are both tyrosine kinases. IGF-2R functions as a clearance site for IGF-2. Insulin receptor and IGF-1R are homologous and form hemireceptors. IGF-1 binds to IGF-1R and to IGF-1R/Insulin Receptor hemireceptor; it binds to insulin receptor only at very high concentrations. IGF-2 binds to IGF-1R, IGF-2R and binds to insulin receptor only during early fetal development. Insulin binds to insulin receptor, and it binds to IGF-1R/Insulin Receptor hemireceptor at high concentration. Signal transduction is activated after the activation of IGF-1R, IGF-1R/Insulin Receptor hemireceptor and insulin receptor; however, IGF-2R activation results in no signal downstream. Solid lines represent high affinity binding, dotted lines indicate weak binding.

Figure 2

IGF-IR downstream signal transduction. The activated IGF-IR initiates signalling through two separate connections, the insulin receptor substrate (IRS) and the Shc proteins. Both IRS and Shc proteins can in turn activate both MAP Kinase (MAPK) and PI3 kinase (PI3K) pathways. MAPK pathway leads to activation of Ras and then ERK, and PI3K pathway activates AKT/mTOR, both then stimulate signals for mitogens.