title: LRP5 Signaling in Osteosarcomagenesis: a Cautionary Tale of Translation from Cell Lines to Tumors.
abstract: 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.
authors.affiliation: Department of Orthopaedic Surgery, University of Utah, Salt Lake City, UT, 84112; Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112.
authors.forename: Logan
authors.initials: L
authors.lastname: Horne
authors.affiliation: Department of Orthopaedic Surgery, University of Utah, Salt Lake City, UT, 84112.
authors.forename: Frank R
authors.initials: FR
authors.lastname: Avilucea
authors.affiliation: Department of Orthopaedic Surgery, University of Utah, Salt Lake City, UT, 84112; Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112.
authors.forename: Huifeng
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Orthopaedic Surgery, University of Utah, Salt Lake City, UT, 84112; Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112.
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Barrott
authors.affiliation: Department of Orthopaedic Surgery, University of Utah, Salt Lake City, UT, 84112; Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112.
authors.forename: Kyllie
authors.initials: K
authors.lastname: Smith-Fry
authors.affiliation: Department of Orthopaedic Surgery, University of Utah, Salt Lake City, UT, 84112; Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112.
authors.forename: Yanliang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, Albert Einstein College of Medicine, Bronx, NY, 10461.
authors.forename: Bang H
authors.initials: BH
authors.lastname: Hoang
authors.affiliation: Department of Orthopaedic Surgery, University of Utah, Salt Lake City, UT, 84112; Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112. Electronic address: kevin.jones@hci.utah.edu.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Jones