Osteosarcoma is the main malignant primary bone tumor in children and adolescents for whom the prognosis remains poor, especially when metastases are present at diagnosis (survival rate drops to 20% when lung metastases were detected). Because TGF-β has been shown to promote metastases in many solid tumors, we investigated the effects of inhibition of the TGF-β/Smad cascade on osteosarcoma behavior. To this end, two independent procedures, a pharmacological approach with TGF-β receptor I inhibitor (SD-208) and a molecular approach using the natural Smad inhibitor (Smad7), was used. The impact of these procedures was assessed on tumor growth, tumor microenvironment, bone remodeling and lung metastases development by using a mouse model of osteosarcoma induced by paratibial injection of osteosarcoma cells, in accordance with the institutional guidelines of the French Ethical Committee.
We also showed that Smad7 slows the growth of the primary tumor and increases mice survival. In this context, we demonstrated that Smad7 expression does not affect osteosarcoma cell proliferation but affects the microarchitectural parameters of bone. In addition, Smad7-osteosarcoma bone tumors expressed lower levels of osteolytic factor RANKL, suggesting that Smad7 overexpression affects the vicious cycle established between tumor cells and bone cells by its ability to decrease osteoclast activity. Interestingly, we finally showed that Smad7 overexpression in osteosarcoma cells and SD-208 inhibits the development of lung metastases. These effects are correlated to the fact that Smad7 and SD-208 reduced two key functions in tumor progression, cell migration and invasion, in part by inhibiting the ability of TGF-β to stimulate the expression and activity of MMP2.These results suggest that the inhibition of TGF-β/Smad signaling pathway could be a promising therapeutic strategy against the tumor progression of osteosarcoma.
17 May 2014 - 20 May 2014