c-myc-induced hepatocarcinogenesis in the absence of IGF-I receptor

被引:20
作者
Cadoret, A
Desbois-Mouthon, C
Wendum, D
Leneuve, P
Perret, C
Tronche, F
Housset, C
Holzenberger, M
机构
[1] Hop St Antoine, Fac Med, INSERM U 402, F-75571 Paris 12, France
[2] Hop St Antoine, Serv Anatomopathol, F-75571 Paris 12, France
[3] Hop St Antoine, INSERM U515, F-75571 Paris 12, France
[4] Inst Cochin, Dept Genet Dev & Pathol Mol, Paris, France
[5] Coll France, CNRS, FRE 2401, F-75231 Paris, France
关键词
hepatocellular carcinoma; IGF-I receptor; transgenic mouse; tumour growth; liver;
D O I
10.1002/ijc.20805
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. At 9 months, all c-myc transgenic mice displayed well-differentiated multifocal tumours, regardless of whether their livers-and their tumours-were able to produce IGF-IR. Levels of IRS-1 and IRS-2 were elevated in all tumours in the presence or absence of IGF-IR, suggesting that the signalling pathway downstream of IGF-IR is activated via IGF-IR-independent mechanisms in HCC. In conclusion, the deregulation of IGF signalling pathways, which often occurs during liver tumorigenesis, does not necessarily require IGF-IRs, and hepatic IGF-IR alone may not play a determinant role in c-myc-induced hepatocarcinogenesis. (C) 2004 Wiley-Liss, Inc.
引用
收藏
页码:668 / 672
页数:5
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