Abstract 236: DKK-3, a secreted Wnt antagonist, suppresses tumorigenic potential and lung metastasis of osteosarcoma

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