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Wang H.,Tongji University | Sun W.,Tongji University | Zhang W.-Z.,Shanghai Pudong New area Peoples Hospital | Ge C.-Y.,Shanghai Yangpu Geriatric Hospital | And 3 more authors.
PLoS ONE | Year: 2014

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. © 2014 Wang et al.

Lu H.,Shanghai JiaoTong University | Zheng P.,Shanghai Pudong New area Peoples Hospital | Zhang W.,Shanghai JiaoTong University
Journal of NeuroInterventional Surgery | Year: 2013

Object: Patients with symptomatic atherosclerotic stenosis of the intracranial vertebrobasilar artery (VBA) have a poor prognosis, and those with coexistent intracranial and extracranial stenoses have worse outcomes despite medical therapy. A study was undertaken to investigate the long-term outcome and restenosis rates of patients with symptomatic atherosclerotic stenoses at the intracranial VBA and the vertebral artery ostium (VAO) after drug-eluting stent (DES) placement. Methods: From July 2004 to July 2008, 24 consecutive patients (mean age 65 years) with this condition underwent DES placement. Technical success was defined as stent placement of both the VAO and intracranial VBA stenoses with complete stent coverage of the lesions and residual stenosis of ≤30%. The study end point was a composite of stroke or death within 30 days and ischemic stroke in the VBA territory after 30 days. Results: Technical success was obtained in all patients without any stroke or death within 30 days. During a median follow-up duration of 35 months, recurrent in-stent restenosis developed in two cases (10%) at 12-month follow-up. These two patients were free from stroke recurrence. Thus, the annual stroke rate in the VBA territory (including any stroke or death within 30 days) was 0. Conclusions: This pilot study confirms that DES placement for patients with symptomatic atherosclerotic stenoses at the intracranial VBA and VAO has an acceptable long-term outcome and may be considered as an alternative to medical therapy.

Wang Y.,Capital Medical University | Zhao X.,Capital Medical University | Liu L.,Capital Medical University | Soo Y.O.Y.,Chinese University of Hong Kong | And 11 more authors.
Stroke | Year: 2014

Background and Purpose-We aimed to establish the prevalence, characteristics, and outcomes of intracranial atherosclerosis (ICAS) in China by a large, prospective, multicenter study. Methods-We evaluated 2864 consecutive patients who experienced an acute cerebral ischemia <7 days after symptom onset in 22 Chinese hospitals. All patients underwent magnetic resonance angiography, with measurement of diameter of the main intracranial arteries. ICAS was defined as £50% diameter reduction on magnetic resonance angiography. Results- The prevalence of ICAS was 46.6% (1335 patients, including 261 patients with coexisting extracranial carotid stenosis). Patients with ICAS had more severe stroke at admission and stayed longer in hospitals compared with those without intracranial stenosis (median National Institutes of Health Stroke Scale score, 3 versus 5 median length of stay, 14 versus 16 days both P<0.0001). After 12 months, recurrent stroke occurred in 3.27% of patients with no stenosis, in 3.82% for those with 50% to 69% stenosis, in 5.16% for those with 70% to 99% stenosis, and in 7.27% for those with total occlusion. Cox proportional hazards regression analyses showed that the degree of arterial stenosis, age, family history of stroke, history of cerebral ischemia or heart disease, complete circle of Willis, and National Institutes of Health Stroke Scale score at admission were independent predictors for recurrent stroke at 1 year. The highest rate of recurrence was observed in patients with occlusion with the presence of £3 additional risk factors. Conclusions-ICAS is the most common vascular lesion in patients with cerebrovascular disease in China. Recurrent stroke rate in our study was lower compared with those of previous clinical trials but remains unacceptably high in a subgroup of patients with severe stenosis.

Zhang J.-T.,Tongji University | Sun W.,Tongji University | Zhang W.-Z.,Shanghai Pudong New area Peoples Hospital | Ge C.-Y.,Shanghai Yangpu Geriatric Hospital | And 4 more authors.
BMC Cancer | Year: 2014

Background: Vasculogenic 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.Methods: In 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.Results: After 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.Conclusions: NCTD 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. © 2014 Zhang et al.; licensee BioMed Central Ltd.

Xi F.,Shanghai Pudong New area Peoples Hospital | Ye J.,China Pharmaceutical University
Oncology Research | Year: 2016

Hexokinase 2 (HK2) has been identified as an oncogene in some malignant diseases such as breast cancer and ovarian cancer. However, the role of HK2 in lung cancer remains unclear. In this study, we explored the functional role of HK2 in lung cancer cell proliferation and tumorigenesis and determine its expression profile in lung cancer. HK2 expression was increased in primary lung cancer tissues of patients. Knocking down HK2 expression by small interfering RNA (siRNA) inhibited cell proliferation in lung cancer cells and nude mice. Thus, HK2 is required for sustained proliferation and survival of tumor cells in vitro and in vivo, and its aberrant expression may contribute to the pathogenesis of lung cancer. Thus, our study provided evidence that HK2 functions as a novel oncogene in lung cancer and may be a potential therapeutic target for lung cancer. Copyright © 2016 Cognizant, LLC.

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