Fibrosis and hypoxia-inducible factor-1α-dependent tumors of the soft tissue on loss of von Hippel-Lindau in mesenchymal progenitors.
The hypoxia-inducible factor (Hif)-1α (Hif-1α) and Hif-2α (Epas1) have a critical role in both normal development and cancer. von Hippel Lindau (Vhl) protein, encoded by a tumor suppressor gene, is an E3 ubiquitin ligase that targets Hif-1α and Epas1 to the proteasome for degradation. To better understand the role of Vhl in the biology of mesenchymal cells, we analyzed mutant mice lacking Vhl in mesenchymal progenitors that give rise to the soft tissues that form and surround synovial joints. Loss of Vhl in mesenchymal progenitors of the limb bud caused severe fibrosis of the synovial joints and formation of aggressive masses with histologic features of mesenchymal tumors. Hif-1α and its downstream target connective tissue growth factor were necessary for the development of these tumors, which conversely still developed in the absence of Epas1, but at lower frequency. Human tumors of the soft tissue are a very complex and heterogeneous group of neoplasias. Our novel findings in genetically altered mice suggest that activation of the HIF signaling pathway could be an important pathogenetic event in the development and progression of at least a subset of these tumors.
Department of Orthopaedic Surgery and the Division of Endocrinology, Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Division of Endocrinology, Department of Medicine, Indiana University, Indianapolis, Indiana; Endocrine Unit, Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts; Department of Orthopaedic and Traumatology, Milano-Bicocca University, Milan, Italy.
Laura
L
Mangiavini
Department of Orthopaedic Surgery and the Division of Endocrinology, Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Division of Endocrinology, Department of Medicine, Indiana University, Indianapolis, Indiana; INSERM, UMRS 791-LIOAD, Centre for Osteoarticular and Dental Tissue Engineering, Group STEP (Skeletal Tissue Engineering and Physiopathology), Nantes, France; Faculty of Dental Surgery, l'Universite Nantes Angers le Mans (LUNAM), Nantes, France.
Christophe
C
Merceron
Endocrine Unit, Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts.
Elisa
E
Araldi
Endocrine Unit, Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts.
Richa
R
Khatri
Division of Endocrinology, Department of Medicine, Indiana University, Indianapolis, Indiana.
Rita
R
Gerard-O'Riley
Department of Orthopaedic Surgery and the Division of Endocrinology, Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Division of Endocrinology, Department of Medicine, Indiana University, Indianapolis, Indiana; Endocrine Unit, Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts.
Tremika L
TL
Wilson
Department of Pathology, School of Medicine, Indiana University, Indianapolis, Indiana.
George
G
Sandusky
Oniris Animal Cancers, Models for Comparative Oncology Research (AMaROC), l'Universite Nantes Angers le Mans (LUNAM), Nantes, France.
Jerome
J
Abadie
Department of Orthopaedic Surgery, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California. Electronic address: klyons@mednet.ucla.edu.
Karen M
KM
Lyons
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, California. Electronic address: giaccia@stanford.edu.
Amato J
AJ
Giaccia
Department of Orthopaedic Surgery and the Division of Endocrinology, Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Division of Endocrinology, Department of Medicine, Indiana University, Indianapolis, Indiana; Endocrine Unit, Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts. Electronic address: eschipan@med.umich.edu.
Ernestina
E
Schipani
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction; D012983:Soft Tissue Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C494469:VHL protein, mouse