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

Laura Mangiavini, Christophe Merceron, Elisa Araldi, Richa Khatri, Rita Gerard-O'Riley, Tremika L. Wilson, George Sandusky, Jerome Abadie, Karen M. Lyons, Amato J. Giaccia, Ernestina Schipani

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3090-3101
Number of pages12
JournalAmerican Journal of Pathology
Volume185
Issue number11
DOIs
StatePublished - Nov 1 2015

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Hypoxia-Inducible Factor 1
Fibrosis
Neoplasms
Joints
Connective Tissue Growth Factor
Limb Buds
Ubiquitin-Protein Ligases
Proteasome Endopeptidase Complex
Tumor Suppressor Genes
Cell Biology
Proteins

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Mangiavini, L., Merceron, C., Araldi, E., Khatri, R., Gerard-O'Riley, R., Wilson, T. L., ... Schipani, E. (2015). Fibrosis and hypoxia-inducible factor-1α-dependent tumors of the soft tissue on loss of von Hippel-Lindau in mesenchymal progenitors. American Journal of Pathology, 185(11), 3090-3101. https://doi.org/10.1016/j.ajpath.2015.07.008

Fibrosis and hypoxia-inducible factor-1α-dependent tumors of the soft tissue on loss of von Hippel-Lindau in mesenchymal progenitors. / Mangiavini, Laura; Merceron, Christophe; Araldi, Elisa; Khatri, Richa; Gerard-O'Riley, Rita; Wilson, Tremika L.; Sandusky, George; Abadie, Jerome; Lyons, Karen M.; Giaccia, Amato J.; Schipani, Ernestina.

In: American Journal of Pathology, Vol. 185, No. 11, 01.11.2015, p. 3090-3101.

Research output: Contribution to journalArticle

Mangiavini, L, Merceron, C, Araldi, E, Khatri, R, Gerard-O'Riley, R, Wilson, TL, Sandusky, G, Abadie, J, Lyons, KM, Giaccia, AJ & Schipani, E 2015, 'Fibrosis and hypoxia-inducible factor-1α-dependent tumors of the soft tissue on loss of von Hippel-Lindau in mesenchymal progenitors', American Journal of Pathology, vol. 185, no. 11, pp. 3090-3101. https://doi.org/10.1016/j.ajpath.2015.07.008
Mangiavini, Laura ; Merceron, Christophe ; Araldi, Elisa ; Khatri, Richa ; Gerard-O'Riley, Rita ; Wilson, Tremika L. ; Sandusky, George ; Abadie, Jerome ; Lyons, Karen M. ; Giaccia, Amato J. ; Schipani, Ernestina. / Fibrosis and hypoxia-inducible factor-1α-dependent tumors of the soft tissue on loss of von Hippel-Lindau in mesenchymal progenitors. In: American Journal of Pathology. 2015 ; Vol. 185, No. 11. pp. 3090-3101.
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