Abstract
BackgroundVasculogenic mimicry (VM) is a novel tumor blood supply in some highly aggressive malignant tumors. Recently, we reported VM existed in gallbladder carcinomas (GBCs) and the formation of the special passage through the activation of the PI3K/MMPs/Ln-5γ2 signaling pathway. GBC is a highly aggressive malignant tumor with disappointing treatments and a poor prognosis. Norcantharidin (NCTD) has shown to have multiple antitumor activities against GBCs, etc; however the exact mechanism is not thoroughly elucidated. In this study, we firstly investigated the anti-VM activity of NCTD as a VM inhibitor for GBCs and its underlying mechanisms.MethodsIn vitro and in vivo experiments to determine the effects of NCTD on proliferation, invasion, migration, VM formation, hemodynamic and tumor growth of GBC-SD cells and xenografts were respectively done by proliferation, invasion, migration assays, H&E staining and CD31-PAS double stainings, optic/electron microscopy, tumor assay, and dynamic micro-MRA. Further, immunohistochemistry, immunofluorescence, Western blotting and RT-PCR were respectively used to examine expression of VM signaling-related markers PI3-K, MMP-2, MT1-MMP and Ln-5γ2 in GBC-SD cells and xenografts in vitro and in vivo.ResultsAfter treatment with NCTD, proliferation, invasion, migration of GBC-SD cells were inhibited; GBC-SD cells and xenografts were unable to form VM-like structures; tumor center-VM region of the xenografts exhibited a decreased signal in intensity; then cell or xenograft growth was inhibited. Whereas all of untreated GBC-SD cells and xenografts formed VM-like structures with the same conditions; the xenograft center-VM region exhibited a gradually increased signal; and facilitated cell or xenograft growth. Furthermore, expression of MMP-2 and MT1-MMP products from sections/supernates of 3-D matrices and the xenografts, and expression of PI3-K, MMP-2, MM1-MMP and Ln-5γ2 proteins/mRNAs of the xenografts were all decreased in NCTD or TIMP-2 group; (all P < 0.01, vs. control group); NCTD down-regulated expression of these VM signaling-related markers in vitro and in vivo.ConclusionsNCTD inhibited tumor growth and VM of human GBCs in vitro and in vivo by suppression of the PI3-K/MMPs/Ln-5γ2 signaling pathway. It is firstly concluded that NCTD may be a potential anti-VM agent for human GBCs.
Highlights
Vasculogenic mimicry (VM) is a novel tumor blood supply in some highly aggressive malignant tumors
The results showed that NCTD inhibits tumor growth and VM of human gallbladder carcinomas (GBCs) by suppression of the PI3-K/ MMPs/Ln-5γ2 signaling pathway in vitro and in vivo
We found that the cultured GBC-SD cells began to growth at 6th hr, maturated at 24th hr, which were predominantly of shuttle-shape or accumulation, with abundant cytoplasm, clear nuclei in control group; after NCTD treatment, the morphology of GBC-SD cells showed visible cell aggregation, float, nuclear condensation or fragmentation, cataclysm, apoptotic bodies, or even death (Figure 1A)
Summary
Vasculogenic mimicry (VM) is a novel tumor blood supply in some highly aggressive malignant tumors. Gallbladder carcinoma (GBC) is the most common biliary tract cancer (BTC), the fifth or sixth common malignant neoplasm of the digestive tract and the leading cause of cancer-related deaths in West countries and China [1,2,3,4,5] It commonly presents at an advanced stage, and has limited therapeutic options such as low surgical resection rate, disappointing chemotherapy and radiotherapy; diagnostic delay, high local recurrence and distant metastasis, and biological behavior of the tumor, the prognosis is very poor [1,6,7,8,9,10,11,12,13]. It should be considered to develop new antivascular therapeutic agents that target both angiogenesis and VM, in especial, anti-VM therapy for tumor VM
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