科研之友
微信
新浪微博
Facebook
分享链接
摘要
Vasculogenic mimicry (VM) is a tumor microcirculation pattern in highly aggressive gallbladder cancers (GBCs). We recently reported the anti-VM activity of norcantharidin (NCTD) in highly aggressive GBC-SD cells and xenografts. In this study, we further investigated that NCTD enhanced tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) anti-VM activity for GBCs and the underlying mechanisms. In vivo and in vitro experiments were performed to determine the effects of NCTD in combination with TIMP-2 on tumor growth, host survival, VM formation, hemodynamic of GBC-SD xenografts, and VM-like networks and malignant phenotypes of GBC-SD cells. Expression of matrix metalloproteinase (MMP)-2 and membrane type 1-MMP (MT1-MMP) among human GBCs, GBC-SD cells and xenografts were determined, respectively. The results showed that expression of MMP-2 and MT1-MMP in human GBCs, GBC-SD cells and xenografts was significantly related to VM in GBCs; a shorter survival time of VM-positive patients with high expression of MMP-2 or MT1-MMP compared to that of the patients with low expression. After treatment with NCTD+TIMP-2, tumor growth, VM formation, VM hemodynamic of the xenografts in vivo were significantly inhibited as compared to control, NCTD or TIMP-2 group, with a prolonged survival time of the xenograft mice (log-rank test, P=0.0115); and these observations were confirmed by VM-like networks by 3-D matrices and showed that proliferation, apoptosis, invasion, migration of GBC-SD cells in vitro were markedly affected. Furthermore, expression of MMP-2 and MT1-MMP in VM formation of the xenografts in vivo and GBC-SD cells in vitro was downregulated as compared to control, NCTD or TIMP-2 group. Thus, we concluded that NCTD enhances TIMP-2 antitumor and anti-VM activities in GBCs through downregulating MMP-2 and MT1-MMP.
- 出版日期2015-2
- 单位同济大学; 上海市徐汇区大华医院
