LRP5 Signaling in Osteosarcomagenesis: a Cautionary Tale of Translation from Cell Lines to Tumors

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• 作者：Logan Horne^* ; ^&dagger ; ; ³ ; Frank R. Avilucea^* ; ³ ; Huifeng Jin^* ; ^&dagger ; ; Jared J. Barrott^* ; ^&dagger ; ; Kyllie Smith-Fry^* ; ^&dagger ; ; Yanliang Wang^* ; ^&dagger ; ; Bang H. Hoang^&Dagger ; ; Kevin B. Jones^* ; ^&dagger ; ; ^{kevin.jones@hci.utah.edu" class="auth_mail" title="E-mail the corresponding author}
• 刊名：Translational Oncology
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：9
• 期：5
• 页码：438-444
• 全文大小：1172 K

文摘

Previous reports document expression of low-density lipoprotein receptor-related protein 5 (LRP5) in osteosarcoma (OS) tissue. Expression of this Wnt receptor correlated with metastatic disease and poor disease-free survival. Forced expression of dominant-negative LRP5 (dnLRP5), which lacks the membrane binding domain of the native protein and therefore functions as a soluble receptor-sponge for Wnt ligands, reduced in vitro cellular invasion and in vivo xenograft tumor growth for osteosarcoma cell lines. Here, we use a genetically engineered mouse model of osteosarcomagenesis with and without expression of dnLRP5 to assess to what degree tumorigenesis is affected and whether Wnt/β-catenin signaling is circumvented or maintained. Each cohort of mice developed osteosarcoma at a similar ultimate prevalence, but after a slightly increased latency in those also expressing dnLRP5. On histology, there was no difference between groups, despite previous reports that the dnLRP5 osteosarcoma cells specifically undergo a mesenchymal-to-epithelial transition in vitro. Finally, immunohistochemistry showed the presence of cytosolic and nuclear β-catenin and nuclear Cyclin D1, markers consistent with preserved Wnt/β-catenin signaling despite constitutive blockade of the cell surface receipt of Wnt signaling ligand. These data suggest that canonical Wnt signaling plays a role in OS progression and that while blockade of singular nodes in signaling pathways can have dramatic effects on individual cell lines, real tumors readily evade such focused attacks.