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Osteosarcoma(OS) is a highly aggressive bone cancer for which treatment has remained essentially unchanged for decades. Although OS is characterized by extensive genomic heterogeneity and instability, RB1and TP53have been shown to be the most commonly inactivated tumor suppressors in OS. We previously generated a mouse model with a double knockout (DKO) of Rb1and Trp53within cells of the osteoblastic lineage, which largely recapitulates human OS with nearly complete penetrance. SKP2 is a repression target of pRb and serves as a substrate recruiting subunit of the SCFSKP2complex. In addition, SKP2 plays a central role in regulating the cell cycle by ubiquitinating and promoting the degradation of p27. We previously reported the DKOAA transgenic model, which harbored a knock-in mutation in p27 that impaired its binding to SKP2. Here, we generated a novel p53-Rb1-SKP2triple-knockout model (TKO) to examine SKP2 function and its potential as a therapeutic target in OS. First, we observed that OS tumorigenesis was significantly delayed in TKO mice and their overall survival was markedly improved. In addition, the loss of SKP2also promoted an apoptotic microenvironment and reduced the stemness of DKO tumors. Furthermore, we found that small-molecule inhibitors of SKP2 exhibited anti-tumor activities in vivo and in OS organoids as well as synergistic effects when combined with a standard chemotherapeutic agent. Taken together, our results suggest that SKP2 inhibitors may reduce the stemness plasticity of OS and should be leveraged as next-generation adjuvants in this cancer.

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 vitrocellular invasion and in vivoxenograft 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.

Total hip arthroplasty with metal-on-polyethylene implants and metal-on-metal articulations have been an area of recent interest. This article describes a patient with a persistent small soft tissue mass on the anterior groin following total hip arthroplasty with negative findings on infection workup, including blood work and aspiration. Subsequent biopsy findings were consistent with organizing thrombus and necrosis. It then developed into an expansile soft tissue groin mass with significant femoral and pelvic bony destruction and soft tissue infiltration. Metallosis, the formation of a pseudocapsule, and aseptic lymphocyte vasculitis-associated lesions have also been an area of interest following adult hip reconstruction. Occasionally, the formation of subsequent lesions make revision surgery impossible to perform due to bony destruction and soft tissue limitations. Although few in number, most studies or cases that have linked metal-on-metal implants to pseudotumors have been treated with revision surgery and replacement of articulating surfaces. This case highlights a metal-on-polyethylene total hip arthroplasty with a mass presenting with pseudotumor-like characteristics. However, final histology demonstrated fibroadipose tissue with fat necrosis and fibrosis, thickened vascular vessels, and diffuse chronic inflammation with lymphocytic infiltrates, which are more consistent with an atypical inflammatory vascular tumor. The current case illustrates treatment difficulties and provides surgical options for when this event occurs. Although aseptic lymphocyte vasculitis-associated lesions have been observed with metal-on-polyethylene articulations, the multiorgan involvement in this case is unique. In this case, radical excision with hemipelvectomy and complex flap closure was a last resort treatment solution that staved off the prospect of patient mortality.

There is currently no consensus regarding the best techniques or surgical strategies with which to maximize intercalary allograft reconstruction outcomes. The purpose of the current study was to assess which techniques and methods are being utilized by North American orthopaedic oncologists.

Wnt proteins have been implicated in regulating growth and pattern formation in a variety of tissues during embryonic development. We previously identified Frzb-1, a gene which encodes a secreted protein with homology in the ligand binding domain to the Wnt receptor Frizzled, but lacking the domain encoding the putative seven transmembrane segments. Frzb-1 has recently been shown to bind to Wnt proteins in vitro, and to inhibit the activity of Xenopus Wnt-8 in vivo. We report now that mFrzb-1 and Wnt transcripts display both complementary and overlapping expression patterns at multiple sites throughout embryonic development. By Northern analysis, the expression of mFrzb-1 in the developing mouse embryo is greatest from 10.5 to 12.5 days postcoitum (dpc). In the early embryo, mFrzb-1 is expressed in the primitive streak, presomitic mesoderm, somites, and brain. Later, mFrzb-1 exhibits sharp boundaries of expression in the limb bud, branchial arches, facial mesenchyme, and in cartilaginous elements of the appendicular skeleton. We conclude from these experiments that Frzb-1is expressed at a time and location to modulate the action of Wnt family members during development of the limbs and central nervous system. Dev. Dyn. 1998;212:364–372. © 1998 Wiley-Liss, Inc.

Synovial sarcoma (SS) is an aggressive soft-tissue cancer with a poor prognosis and a propensity for local recurrence and distant metastasis. In this study, we investigated whether S phase kinase-associated protein (Skp2) plays an oncogenic role in tumor initiation, progression, and metastasis of SS. Our study revealed that Skp2 is frequently overexpressed in SS specimens and SS18-SSX transgenic mouse tumors, as well as correlated with clinical stages. Next, we identified that genetic depletion of Skp2 reduced mesenchymal and stemness markers, and inhibited the invasive and proliferative capacities of SS cell lines. Furthermore, Skp2 depletion markedly suppressed the growth of SS xenografts tumors. Treatment of SS cell lines with the skp2 inhibitor flavokawain A (FKA) reduced Skp2 expression in a dose-dependent manner and resulted in cell cycle arrest and apoptosis. FKA also suppressed the invasion and tumor-initiating properties in SS, similar to the effects of Skp2 knockdown. In addition, a combination of FKA and conventional chemotherapy showed a synergistic therapeutic efficacy. Taken together, our results suggest that Skp2 plays an essential role in the biology of SS by promoting the mesenchymal state and cancer stemness. Given that chemotherapy resistance is often associated with cancer stemness, strategies of combining Skp2 inhibitors with conventional chemotherapy in SS may be desirable.