[Molecular mechanisms of progression in human hepatocarcinogenesis].
Hepatocellular carcinoma (HCC) is one of the most frequent malignant tumors worldwide with poor prognosis. Based on high-throughput screening technology, we and others have identified factors and pathways that are pivotal for tumor progression including transcription factors and microtubule-interacting proteins. In addition, aberrant activation of the IGF signalling pathway is frequently observed in HCCs which is predominantly based on high level expression of its ligand IGF-II. Because protumorigenic effects of IGF-II such as proliferation, anti-apoptosis, and migration are transmitted through its receptor IGF-1R, selective inhibition of this tyrosine kinase by small molecule compounds might reduce IGF-II-driven tumor growth. Indeed, administration of IGF-1R-selective inhibitors reduces IGF-II-induced effects and was associated with a significant reduction of tumor growth in a xenograft transplantation model. In conclusion, the IGF-II/IGF-1R signalling pathway is critically involved in the regulation of tumor growth and tumor cell dissemination, representing a promising therapeutic target structure in the treatment of HCC.
Breuhahn
K
K
Institut für Pathologie, Universitätsklinik Heidelberg, Im Neuenheimer Feld 220/221, 69120 Heidelberg. kai.breuhahn@med.uni-heidelberg.de
D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D009368:Neoplasm Transplantation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
C035170:IGF2 protein, human; D007335:Insulin-Like Growth Factor II; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1