title: WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma.
abstract: Osteosarcoma is a highly metastatic form of bone cancer in adolescents and young adults that is resistant to existing treatments. Development of an effective therapy has been hindered by very limited understanding of the mechanisms of osteosarcomagenesis. Here, we used genetically engineered mice to investigate the effects of deleting the tumor suppressor Wwox selectively in either osteoblast progenitors or mature osteoblasts. Mice with conditional deletion of Wwox in preosteoblasts (WwoxΔosx1) displayed a severe inhibition of osteogenesis accompanied by p53 upregulation, effects that were not observed in mice lacking Wwox in mature osteoblasts. Deletion of p53 in WwoxΔosx1mice rescued the osteogenic defect. In addition, the Wwox;p53Δosx1double knockout mice developed poorly differentiated osteosarcomas that resemble human osteosarcoma in histology, location, metastatic behavior, and gene expression. Strikingly, the development of osteosarcomas in these mice was greatly accelerated compared with mice lacking p53 only. In contrast, combined WWOX and p53 inactivation in mature osteoblasts did not accelerate osteosarcomagenesis compared with p53 inactivation alone. These findings provide evidence that a WWOX-p53 network regulates normal bone formation and that disruption of this network in osteoprogenitors results in accelerated osteosarcoma. The Wwox;p53Δosx1double knockout establishes a new osteosarcoma model with significant advancement over existing models. Cancer Res; 76(20); 6107-17. ©2016 AACR.
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Israel.
authors.forename: Sara
authors.initials: S
authors.lastname: Del Mare
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Israel.
authors.forename: Hussam
authors.initials: H
authors.lastname: Husanie
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Israel.
authors.forename: Ortal
authors.initials: O
authors.lastname: Iancu
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Israel.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Abu-Odeh
authors.affiliation: Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Evangelou
authors.affiliation: Department of Cancer Biology and Genetics (CBG), The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.affiliation: Department of Biochemistry, University of Vermont College of Medicine, Burlington, Vermont.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gordon
authors.affiliation: Department of Pathology, Hadassah University Hospital, Jerusalem.
authors.forename: Gail
authors.initials: G
authors.lastname: Amir
authors.affiliation: Department of Biochemistry, University of Vermont College of Medicine, Burlington, Vermont.
authors.forename: Janet
authors.initials: J
authors.lastname: Stein
authors.affiliation: Department of Biochemistry, University of Vermont College of Medicine, Burlington, Vermont.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.affiliation: Department of Cancer Biology and Genetics (CBG), The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece. Biomedical Research Foundation of the Academy of Athens, Athens, Greece. Faculty Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Manchester Centre for Cellular Metabolism, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Gorgoulis
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
authors.affiliation: The Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Israel. Department of Cancer Biology and Genetics (CBG), The Ohio State University Wexner Medical Center, Columbus, Ohio. Department of Biochemistry, University of Vermont College of Medicine, Burlington, Vermont. ramiaq@ekmd.huji.ac.il.
authors.forename: Rami I
authors.initials: RI
authors.lastname: Aqeilan
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000209:etiology* / Q000235:genetics; D002454:Cell Differentiation; D019070:Cell Lineage; D050659:Core Binding Factor Alpha 1 Subunit / Q000502:physiology; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000502:physiology; D010012:Osteogenesis; D012516:Osteosarcoma / Q000209:etiology* / Q000235:genetics; D010088:Oxidoreductases / Q000502:physiology*; D010446:Peptide Fragments / Q000097:blood; D011347:Procollagen / Q000097:blood; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D010446:Peptide Fragments; D011347:Procollagen; C493709:RUNX2 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C047202:procollagen Type I N-terminal peptide; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human