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Sarcoma
Volume 2013 (2013), Article ID 147541, 11 pages
http://dx.doi.org/10.1155/2013/147541
Research Article

Dkk-3, a Secreted Wnt Antagonist, Suppresses Tumorigenic Potential and Pulmonary Metastasis in Osteosarcoma

1Department of Oncology, CHOC Children’s Hospital, 455 South Main Street, Orange, CA 92868, USA
2Department of Orthopaedic Surgery, University of California, Irvine, 101 The City Drive South, Orange, CA 92868, USA
3Department of Obstetrics and Gynecology, University of California, Irvine, 101 The City Drive South, Building 56, Suite 260, Orange, CA 92868, USA
4Department of Urology, University of California, Irvine, 101 The City Drive South, Building 55, Suite 302, Orange, CA 92868, USA
5Department of Pharmaceutical Sciences, University of California, Irvine, 101 The City Drive South, Orange, CA 92868, USA
6Department of Orthopaedic Surgery and Chao Family Comprehensive Cancer Center, University of California, Irvine, 101 The City Drive South, Orange, CA 92868, USA

Received 7 July 2012; Revised 10 December 2012; Accepted 16 December 2012

Academic Editor: H. Gelderblom

Copyright © 2013 Carol H. Lin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Osteosarcoma (OS) is the most common primary bone malignancy with a high propensity for local invasion and distant metastasis. Despite current multidisciplinary treatments, there has not been a drastic change in overall prognosis within the past 2 decades. Dickkopf-3 protein (Dkk-3/REIC) has been known to inhibit canonical Wnt/β-catenin pathway, and its expression has been shown to be downregulated in OS cell lines. Using in vivo and in vitro studies, we demonstrated that Dkk-3-transfected 143B cells inhibited tumorigenesis and metastasis in an orthotopic xenograft model of OS. Inoculation of Dkk-3-transfected 143B cell lines into nude mice showed significant decreased tumor growth and less metastatic pulmonary nodules (88.7%) compared to the control vector. In vitro experiments examining cellular motility and viability demonstrated less anchorage-independent growth and decreased cellular motility for Dkk-3-transfected 143B and SaOS2 cell lines compared to the control vector. Downstream expressions of Met, MAPK, ALK, and S1004A were also downregulated in Dkk-3-transfected SaOS2 cells, suggesting the ability of Dkk-3 to inhibit tumorigenic potential of OS. Together, these data suggest that Dkk-3 has a negative impact on the progression of osteosarcoma. Reexpressing Dkk-3 in Dkk-3-deficient OS tumors may prove to be of benefit as a preventive or therapeutic strategy.