title: Effect of prolyl hydroxylase domain-2 haplodeficiency on the hepatocarcinogenesis in mice.
abstract: OBJECTIVE
  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--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.
authors.affiliation: Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Femke
authors.initials: F
authors.lastname: Heindryckx
authors.forename: Anna
authors.initials: A
authors.lastname: Kuchnio
authors.forename: Christophe
authors.initials: C
authors.lastname: Casteleyn
authors.forename: Stephanie
authors.initials: S
authors.lastname: Coulon
authors.forename: Kim
authors.initials: K
authors.lastname: Olievier
authors.forename: Isabelle
authors.initials: I
authors.lastname: Colle
authors.forename: Anja
authors.initials: A
authors.lastname: Geerts
authors.forename: Louis
authors.initials: L
authors.lastname: Libbrecht
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Hans
authors.initials: H
authors.lastname: Van Vlierberghe
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D001650:Bile Duct Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D018281:Cholangiocarcinoma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D004052:Diethylnitrosamine / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D005838:Genotype; D006505:Hepatitis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology; D010641:Phenotype; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000502:physiology
chemical_list: D000477:Alkylating Agents; D004052:Diethylnitrosamine; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases