Fibrosis and hypoxia-inducible factor-1α-dependent tumors of the soft tissue on loss of von Hippel-Lindau in mesenchymal progenitors.
Fibrosis and hypoxia-inducible factor-1α-dependent tumors of the soft tissue on loss of von Hippel-Lindau in mesenchymal progenitors.
复制标题
间充质祖细胞中 von Hippel-Lindau 损失的软组织纤维化和缺氧诱导因子 1α 依赖性肿瘤。
DOI：
10.1016/j.ajpath.2015.07.008
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Schipani,Ernestina
中科院分区：
文献类型：
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作者：
Mangiavini,Laura;Merceron,Christophe;Araldi,Elisa;Khatri,Richa;Gerard-O'Riley,Rita;Wilson,TremikaL;Sandusky,George;Abadie,Jerome;Lyons,KarenM;Giaccia,AmatoJ;Schipani,Ernestina
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.
