Back to Search
Start Over
c-myc-induced hepatocarcinogenesis in the absence of IGF-I receptor.
- Source :
-
International journal of cancer [Int J Cancer] 2005 Apr 20; Vol. 114 (4), pp. 668-72. - Publication Year :
- 2005
-
Abstract
- 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.
- Subjects :
- Alleles
Animals
Blotting, Western
Cell Proliferation
Genotype
Hepatocytes cytology
Hepatocytes metabolism
Immunohistochemistry
Liver metabolism
Liver Neoplasms etiology
Mice
Mice, Transgenic
Mutation
Promoter Regions, Genetic
Recombination, Genetic
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Time Factors
Liver Neoplasms genetics
Proto-Oncogene Proteins c-myc metabolism
Receptor, IGF Type 1 genetics
Receptor, IGF Type 1 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0020-7136
- Volume :
- 114
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- International journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 15609331
- Full Text :
- https://doi.org/10.1002/ijc.20805