*3.2.2.5 Effect of statins on invasive behavior*

Statins, increasing the non-isoprenylated cytosolic form of Ras [64], and helped by its antiangiogenic effect and inhibition of the ECM degradation, reduce sarcoma cell invasive ability [74]. Therefore, in osteosarcoma, statin decreases the expression of the angiogenic factors secreted by the tumor VEGF, bFGF, HGF, and TGF-β [75] and inhibits the neo-vascularization. Moreover, statins inhibit invasiveness [68, 76] by MMP-3, −13, −2, −9, −14 and TIMP-2 genes down-regulation, involved in the ECM degradation, in the chondrosarcoma cell line SW1353 and in HT1080 fibrosarcoma cells [76, 77]. Among some signaling pathways [32], the RhoA-JNK-c-Jun-MMP2 pathway [76] or the Jak2/Stat5/SOCS3 pathway [74] controlled by GGPP-prenylated RhoA [78]. In animal models, statins inhibit the growth of primary tumor fibrosarcoma [50] and prevent tumor growth and pulmonary metastatic development of rat fibrosarcoma [60]. Besides, statins enhance the effect of doxorubicin or cisplatin [67]. In a xenograft model of osteosarcoma, simvastatin synergistically potentiates the action of methotrexate, enhancing tumor volume reduction, decreasing side effects, and drastically reducing lung metastases [33].
