Numerous tumours, including hepatocarcinomas, produce IGFs, and some depend on these growth factors in a paracrine or autocrine fashion. We have shown that c-myc-induced experimental hepatocarcinogenesis is associated with enhanced production of IGF-II. To assess the role of the IGF-I receptor (IGF-IR) in hepatocarcinogenesis, we generated conditional mutant mice that overexpressed c-myc and were knocked out for IGF-IR specifically in the liver. We compared these mice with littermate controls that also overexpressed c-myc but had wild-type IGF-IR alleles. We found that the pretumoral phase, induced by early c-myc expression and characterised by increased cell proliferation, was largely unaffected by the lack of IGF-IR. To our further surprise, hepatocellular carcinomas (HCCs) lacking IGF-IR readily developed and progressed at the same rate as control HCCs. Key words: hepatocellular carcinoma; IGF-I receptor; transgenic mouse; tumour growth; liver IGF-IR, the major receptor for both IGF-I and IGF-II, plays an important role in normal cell growth and development. It consists of 2 extracellular ␣ subunits, containing the ligand-binding domain, and 2 transmembrane  subunits with TK activity. IGF binding causes receptor autophosphorylation and activates TK activity, which subsequently phosphorylates a multitude of intracellular substrates, including IRSs and Shc. This leads to the downstream regulation of multiple signalling cascades, such as the MAPK and PI3K/Akt pathways. IGF-IR levels are constitutively very low in normal adult murine or human livers. Abnormal IGF-IR signalling is implicated in the development of different types of tumour, including HCC. Increased IGF-II levels have been observed in human HCC 1,2 and in tumoral liver tissue from several transgenic cancer models. 3,4 IGF-IR is overproduced in many HCC cell lines, allowing IGF-II to exert its mitogenic activity. 5 Moreover, IRS-1 is upregulated in human liver tumours and HCC cell lines. 6 Several authors have designed strategies to inhibit the IGF axis with the aim of preventing or treating HCC. Antisense therapy against IGF-I suppressed the tumorigenicity of a rat hepatoma cell line and caused regression of established tumours. 7 Injection of mice implanted with HCC with a methylated oligonucleotide downregulated IGF-II and prolonged survival. 8 Furthermore, transgenic mice that overproduce the SV40 large T antigen and that are null for IGF-II (secondarily to the disruption of the paternal Igf2 allele) develop fewer and smaller liver tumours than those carrying the normal Igf2 allele. 9 By targeting the IGF ligands, these studies highlight the importance of IGF signalling in hepatocarcinogenesis. However, they do not show whether blockade of the cognate receptor can produce similar effects. Here, we evaluated the outcome of nonreversible, Cre-lox-mediated and liver-specific IGF-IR knockout on hepatocellular tumorigenesis.
Material and methods
MicePK-myc transgenic mice (backcrossed with the 129/Sv genetic background for this study) express the c-m...