title: VHL and PTEN loss coordinate to promote mouse liver vascular lesions.
abstract: Von Hippel-Lindau (VHL) inactivation develops a tumor syndrome characterized by highly vascularized tumors as a result of hypoxia inducible factors (HIF) stabilization. The most common manifestation is the development of hemangioblastomas typically located in the central nervous system and other organs including the liver. PTEN (Phosphatase and tension homologue deleted on chromosome 10) inactivation also upregulates HIF-1alpha and may take part in promoting vascular lesions in tumors. The coordinate effect of loss of these tumor suppressors on HIF levels, and the subsequent effect on vascular lesion formation would elucidate the potential for mechanisms to modify HIF dosage supplementally and impact tumor phenotype. We therefore employed models of somatic conditional inactivation of Vhl, Pten, or both tumor suppressor genes in individual cells of the liver by Cre-loxP recombination to study the cooperativity of these two tumor suppressors in preventing tumor formation. Nine months after tumor suppressor inactivation, Vhl conditional deletion (Vhl (loxP/loxP)) mice showed no abnormalities, Pten conditional deletion (Pten (loxP/loxP)) mice developed liver steatosis and focal nodular expansion of hepatocytes containing lipid droplet and fat. Vhl and Pten conditional deletion (Vhl (loxP/loxP);Pten (loxP/loxP)) mice, however, developed multiple cavernous liver lesions reminiscent of hemangioblastoma. Liver hemangioblastomas in VHL disease may, therefore, require secondary mutation in addition to VHL loss of heterozygosity which is permissive for vascular lesion development or augments levels of HIF-1alpha.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 27599-7295, USA.
authors.forename: Shufen
authors.initials: S
authors.lastname: Chen
authors.forename: Christie A
authors.initials: CA
authors.lastname: Sanford
authors.forename: Junjiang
authors.initials: J
authors.lastname: Sun
authors.forename: Vivian
authors.initials: V
authors.lastname: Choi
authors.forename: Terry
authors.initials: T
authors.lastname: Van Dyke
authors.forename: R Jude
authors.initials: RJ
authors.lastname: Samulski
authors.forename: W Kimryn
authors.initials: WK
authors.lastname: Rathmell
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D000229:Dependovirus; D017353:Gene Deletion; D018014:Gene Transfer Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D050356:Lipid Metabolism; D008099:Liver / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000378:metabolism*; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011995:Recombination, Genetic; D015854:Up-Regulation / Q000235:genetics; D014652:Vascular Diseases / Q000201:enzymology* / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C494469:VHL protein, mouse