Abstract
Abstract Osteosarcoma (OS) is the most common primary malignancy of bone. Current therapeutic protocols focus on intensive chemotherapy and radical surgical resection. However, 5-year survival rate remains low when patients present with pulmonary metastasis, suggesting a need for more effective targeted therapies. In this study, we examined the in vivo anti-tumor effects of Dickkopf-3 (Dkk-3), a secreted Wnt antagonist, in a mouse model of osteosarcoma. Osteosarcoma 143B cells over-expressing Dkk-3(143B/Dkk-3) was established by stable gene transfection. To examine the effects of Dkk-3 on tumorigenesis and lung metastasis of osteosarcoma, nude mice were injected subcutaneously or orthotopically in the proximal tibia with 143B/Dkk-3-transfected vs. control cells to establish local tumor and lung metastasis. Dkk-3 dramatically inhibited local tumor growth in engrafted mice. In the orthotopic intratibial injection model, 143B/Dkk-3 cells formed significantly fewer lung nodules than control cells. In order to determine the potential molecular mechanism underlying the anti-tumor effect of DKK3 on osteosarcoma, we examined the reversal of EMT (Epithelial Mesenchymal Transition) and the expression of c-Met and MMPs (Matrix metalloproteinase) by real time PCR and western blot. Dkk-3 significantly reversed the epithelial-mesenchymal transition of osteosarcoma cells by inducing expression of epithelial markers (E-cadherin, keratin 8, and keratin18) and repressing the expression of mesenchymal markers (N-cadherin, Vimentin, and fibronectin). Dkk-3 also inhibited the expression and proteolytic activity of metalloproteinases and down-regulated oncogenic c-Met expression. Our study suggested that Dkk-3 effectively inhibits both local tumor growth and lung metastasis by suppressing multiple oncogenic pathways. Therefore, over-expressing DKK3 may represent a novel therapeutic strategy for osteosarcoma patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 236. doi:10.1158/1538-7445.AM2011-236
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