Targeting the insulin-like growth factor pathway in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Only 30%-40% of the patients with HCC are eligible for curative treatments, which include surgical resection as the first option, liver transplantation and percutaneous ablation. Unfortunately, there is a high frequency of tumor recurrence after surgical resection and most HCC seem resistant to conventional chemotherapy and radiotherapy. Sorafenib, a multi-tyrosine kinase inhibitor, is the only chemotherapeutic option for patients with advanced hepatocellular carcinoma. Patients treated with Sorafenib have a significant increase in overall survival of about three months. Therefore, there is an urgent need to develop alternative treatments. Due to its role in cell growth and development, the insulin-like growth factor system is commonly deregulated in many cancers. Indeed, the insulin-like growth factor (IGF) axis has recently emerged as a potential target for hepatocellular carcinoma treatment. To this aim, several inhibitors of the pathway have been developed such as monoclonal antibodies, small molecules, antisense oligonucleotides or small interfering RNAs. However recent studies suggest that, unlike most tumors, HCC development requires increased signaling through insulin growth factor II rather than insulin growth factor I. This may have great implications in the future treatment of HCC. This review summarizes the role of the IGF axis in liver carcinogenesis and the current status of the strategies designed to target the IGF-I signaling pathway for hepatocellular carcinoma treatment.

Keywords: Hepatocellular carcinoma; Insulin; Insulin-like growth factor; Insulin-like growth factor receptor; Therapy; Tyrosine kinase inhibitor; Antibody therapy

Core tip: It is mandatory to develop alternative therapies for the successful treatment of hepatocellular carcinoma (HCC). One of the key drivers of hepatocarcinogenesis is the insulin-like growth factor (IGF) system. Therefore, several inhibitors of this pathway have been developed and their therapeutic potential is being tested in patients with HCC. However, recent studies suggest that IGF-II, a member of the pathway, may be more relevant for hepatocarcinogenesis than its close homologue IGF-I. The purpose of this review is to summarize these facts within a detailed description of the IGF axis and the alterations of the pathway that lead to HCC. The strategies designed to target the IGF-I signaling pathway for HCC treatment are also reviewed.