title: Inhibition of tumor vasculogenic mimicry and prolongation of host survival in highly aggressive gallbladder cancers by norcantharidin via blocking the ephrin type a receptor 2/focal adhesion kinase/paxillin signaling pathway.
abstract: Vasculogenic mimicry (VM) is a newly-defined tumor microcirculation pattern in highly aggressive malignant tumors. We recently reported tumor growth and VM formation of gallbladder cancers through the contribution of the ephrin type a receptor 2 (EphA2)/focal adhesion kinase (FAK)/Paxillin signaling pathways. In this study, we further investigated the anti-VM activity of norcantharidin (NCTD) as a VM inhibitor for gallbladder cancers and the underlying mechanisms. In vivo and in vitro experiments to determine the effects of NCTD on tumor growth, host survival, VM formation of GBC-SD nude mouse xenografts, and vasculogenic-like networks, malignant phenotypes i.e., proliferation, apoptosis, invasion and migration of GBC-SD cells. Expression of VM signaling-related markers EphA2, FAK and Paxillin in vivo and in vitro were examined by immunofluorescence, western blotting and real-time polymerase chain reaction (RT-PCR), respectively. The results showed that after treatment with NCTD, GBC-SD cells were unable to form VM structures when injecting into nude mouse, growth of the xenograft was inhibited and these observations were confirmed by facts that VM formation by three-dimensional (3-D) matrix, proliferation, apoptosis, invasion, migration of GBC-SD cells were affected; and survival time of the xenograft mice was prolonged. Furthermore, expression of EphA2, FAK and Paxillin proteins/mRNAs of the xenografts was downregulated. Thus, we concluded that NCTD has potential anti-VM activity against human gallbladder cancers; one of the underlying mechanisms may be via blocking the EphA2/FAK/Paxillin signaling pathway.
authors.affiliation: Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Tongji University, Shanghai, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Surgery, Shanghai Pudong New Area People's Hospital, Shanghai, P.R. China.
authors.forename: Wen-Zhong
authors.initials: WZ
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Shanghai Yangpu Geriatric Hospital, Shanghai, P.R. China.
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Ge
authors.affiliation: Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, P.R. China.
authors.forename: Jing-Tao
authors.initials: JT
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, P.R. China.
authors.forename: Zhong-Yan
authors.initials: ZY
authors.lastname: Liu
authors.affiliation: Department of Surgery, Tongji Hospital, Tongji University School of Medicine, Tongji University, Shanghai, P.R. China.
authors.forename: Yue-Zu
authors.initials: YZ
authors.lastname: Fan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D036383:Ephrin-A2 / Q000378:metabolism; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D005706:Gallbladder Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008833:Microcirculation / Q000187:drug effects*; D051419:Paxillin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D036383:Ephrin-A2; D051419:Paxillin; C069741:norcantharidin; D051416:Focal Adhesion Protein-Tyrosine Kinases