1. An evaluation of the role of insulin-like growth factors (IGF) and of type-I IGF receptor signalling in hepatocarcinogenesis and in the resistance of hepatocarcinoma cells against drug-induced apoptosis
- Author
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Ghislaine Schweizer-Groyer, Malika Lasfer, Guillaume Fallot, André Groyer, and Catherine Alexia
- Subjects
MAPK/ERK pathway ,medicine.medical_specialty ,Programmed cell death ,Carcinoma, Hepatocellular ,medicine.medical_treatment ,Cathepsin D ,Antineoplastic Agents ,Apoptosis ,Biology ,Biochemistry ,Receptor, IGF Type 1 ,Paracrine signalling ,Insulin-Like Growth Factor II ,Internal medicine ,Tumor Cells, Cultured ,medicine ,Humans ,Insulin-Like Growth Factor I ,Receptor ,Autocrine signalling ,Pharmacology ,Growth factor ,Liver Neoplasms ,Insulin-Like Growth Factor Binding Proteins ,Cell Transformation, Neoplastic ,Endocrinology ,Drug Resistance, Neoplasm ,Cancer research ,Signal Transduction - Abstract
Strong evidence emphasizes the role of the insulin-like growth factor (IGF) system and of type-I IGF receptor (IGF-IR) signalling in tumourigenesis. In this connection: (i) changes in the expression pattern of components of the IGF system (autocrine/paracrine expression of IGF-I and -II, overexpression of IGF-IR, decreased expression of IGF-binding proteins (IGFBPs) and of type-II IGF receptor/cation-independent mannose-6-phosphate receptor (IGF-II/M6PR) and (ii) increased serum concentrations of proteases that cleave the IGFBPs (e.g., cathepsin D) were observed in patients with hepatocellular carcinomas (HCC), in human hepatoma cell lines and in their conditioned culture medium, as well as in rodent models of hepatocarcinogenesis. Accordingly, studies carried out with animal models do suggest that the IGF system and IGF-IR signalling may play a role in hepatocarcinogenesis and in deregulated proliferation and apoptosis of HCC cells. Finally the instrumental role of Raf/MEK/ERK, one of the signalling cascades stimulated by IGF-IR, in anthracycline-induced apoptosis of HepG2 and Huh-7 human hepatoma cell lines emphasizes that care must be taken when designing combinations of antitumoural molecules for antineoplastic treatment. This review addresses the putative roles of the IGF system in primary HCC, with a special focus on the underlying molecular mechanisms. In a second part it emphasizes the putative interference of IGF-IR signalling with chemotherapeutic drug-induced apoptosis in human hepatoma cells.
- Published
- 2004