Am J Pathol. 2015 Nov;185(11):3090-101. doi: 10.1016/j.ajpath.2015.07.008. Epub 2015 Sep 6.

Fibrosis and hypoxia-inducible factor-1α-dependent tumors of the soft tissue on loss of von Hippel-Lindau in mesenchymal progenitors.

Mangiavini L¹, Merceron C², Araldi E³, Khatri R³, Gerard-O'Riley R⁴, Wilson TL⁵, Sandusky G⁶, Abadie J⁷, Lyons KM⁸, Giaccia AJ⁹, Schipani E¹⁰.

Author information

1: 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.
2: 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.
3: Endocrine Unit, Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts.
4: Division of Endocrinology, Department of Medicine, Indiana University, Indianapolis, Indiana.
5: 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.
6: Department of Pathology, School of Medicine, Indiana University, Indianapolis, Indiana.
7: Oniris Animal Cancers, Models for Comparative Oncology Research (AMaROC), l'Universite Nantes Angers le Mans (LUNAM), Nantes, France.
8: 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.
9: 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.
10: 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.

Abstract

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.