Effect of prolyl hydroxylase domain-2 haplodeficiency on the hepatocarcinogenesis in mice

• Published in: Journal of hepatology 2012-07, Vol.57 (1), p.61-68
• Main Authors: Heindryckx, Femke, Kuchnio, Anna, Casteleyn, Christophe, Coulon, Stephanie, Olievier, Kim, Colle, Isabelle, Geerts, Anja, Libbrecht, Louis, Carmeliet, Peter, Van Vlierberghe, Hans
• Format: Article
• Language: English
• Subjects: Alkylating Agents - toxicity; Angiogenesis; Animals; Bile Duct Neoplasms - chemically induced; Bile Duct Neoplasms - genetics; Bile Duct Neoplasms - metabolism; Bile Ducts, Intrahepatic - metabolism; Biological and medical sciences; Carcinoma, Hepatocellular - chemically induced; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Cholangiocarcinoma; Cholangiocarcinoma - chemically induced; Cholangiocarcinoma - genetics; Cholangiocarcinoma - metabolism; Diethylnitrosamine - toxicity; Disease Models, Animal; Female; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation, Neoplastic - physiology; Genotype; Hepatic progenitor cells; Hepatitis - genetics; Hepatitis - metabolism; Hepatocellular carcinoma; Humans; Hypoxia; Hypoxia-Inducible Factor-Proline Dioxygenases; Liver Neoplasms, Experimental - chemically induced; Liver Neoplasms, Experimental - genetics; Liver Neoplasms, Experimental - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Mice; Neovascularization, Physiologic - physiology; Notch signaling; Phenotype; Precancerous Conditions - genetics; Precancerous Conditions - metabolism; Procollagen-Proline Dioxygenase - deficiency; Procollagen-Proline Dioxygenase - genetics; Procollagen-Proline Dioxygenase - metabolism; Signal Transduction - physiology; Stem Cells - physiology; Tumors
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2012.02.021

Background & Aims The two major primary liver cancers in adults are hepatocellular carcinoma and cholangiocarcinoma. These tumors rapidly outgrow their vascular supply and become hypoxic, resulting in the production of hypoxia inducible factors. Recently, interest has grown in the regulators of these factors. Several reports have been published describing the role of prolyl hydroxylase domains – the key oxygen sensor responsible for the degradation of hypoxia inducible factors – in tumor progression and vascularisation. The effect of prolyl hydroxylase domain 2 on the pathogenesis of liver cancer has never been studied. Methods A diethylnitrosamine-induced mouse model was used in this study, allowing primary hepatic tumors to occur as a result of chronic liver damage. Several parameters of prolyl hydroxylase domain 2-haplodeficient mice were compared to those of wild type mice, thereby focussing on the expression of angiogenic factors and on the hepatic progenitor cell activation and differentiation. Results This study shows that inhibiting prolyl hydroxylase domain 2 increases the hepatocarcinogenesis and stimulates the development of cholangiocarcinoma. Furthermore, PHD2 deficiency and the accompanying continuous HIF activation, selected for a more metastatic tumor phenotype. Conclusions The effect of prolyl hydroxylase domain 2 deficiency on hepatocarcinogenesis hold a great potential for therapeutic intervention, since hypoxia and the selection for a more aggressive cholangiocarcinoma phenotype might also have a repercussion on patients receiving long-term treatment with anti-angiogenic compounds.