Norcantharidin enhances TIMP-2 anti-vasculogenic mimicry activity for human gallbladder cancers through downregulating MMP-2 and MT1-MMP

• Published in: International journal of oncology Vol. 46; no. 2; pp. 627 - 640
• Main Authors: ZHU, WEI, SUN, WEI, ZHANG, JING-TAO, LIU, ZHONG-YAN, LI, XIN-PING, FAN, YUE-ZU
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.02.2015; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Angiogenesis; Animals; anti-vasculogenic mimicry therapy; Antimitotic agents; Antineoplastic agents; Apoptosis - drug effects; Biomedical research; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Cancer therapies; Cell Line, Tumor; Cell Proliferation - drug effects; Drug therapy; Ethics; Gallbladder; Gallbladder cancer; gallbladder neoplasm; Gallbladder Neoplasms - genetics; Gallbladder Neoplasms - pathology; Gene Expression Regulation, Neoplastic - drug effects; Health aspects; Human subjects; Humans; Immunoglobulins; International organizations; Kinases; matrix metalloproteinase; Matrix Metalloproteinase 14 - biosynthesis; Matrix Metalloproteinase 2 - biosynthesis; Medical prognosis; Medical records; Medical research; Melanoma; Mice; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - pathology; norcantharidin; Physiological aspects; Prognosis; Proteases; Proteins; Studies; Survival analysis; Tissue Inhibitor of Metalloproteinase-2 - biosynthesis; Tumors; vasculogenic mimicry; Xenograft Model Antitumor Assays; China
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2014.2753

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.