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.
Highlights
Hepatocellular carcinoma (HCC) is the 5th most common neoplasm worldwide with more than 600,000 cases per year and the 3rd leading cause of cancer-related death [1,2]
The insulin-like growth factor (IGF) axis has emerged as an important pathway in the development and progression of HCC and as a potential therapeutic target
In a study from Hong Kong, 30 HCC samples from patients examined using northern blot analysis showed more than 93% of the adult promoter insulin-like growth factor 2 (IGF-2) transcripts were repressed, while 93% of the adult type IGF-2 transcripts were detected in nontumourous tissues [68,69]
Summary
Hepatocellular carcinoma (HCC) is the 5th most common neoplasm worldwide with more than 600,000 cases per year and the 3rd leading cause of cancer-related death [1,2]. In a transgenic murine HCC model overexpressing the inhibitor of metalloproteinase (TIMP1), IGFBP-3 degradation was reduced, and serum level of IGFBP-3 was subsequently increased, which decreased the bioavailable IGF-2 ligand and its downstream signalling This resulted in reduced liver hyperplasia, despite the activation of IGF-2 by a strong oncogene such as SV40 T antigen [83]. Such ability was demonstrated in several human tumor cell lines, where phosphorylated IGF-1R and its downstream proteins, including ERK and p70s6k were all effectively inhibited by OSI-906 (OSI) [100]. The idea of combining IGF-1R inhibitors and agents such as erlotinib or everolimus could be a promising strategy in the management of advanced HCC
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