Expressions of nuclear factor KB, inducible nitric oxide synthase and vascular endothelial growth factor in adenoid cystic carcinoma of salivary glands: Correlationswith the angiogenesis and clinical outcome
To evaluate the expressions of nuclear factor kappaB (NF-kappaB p65), inducible nitric oxide synthase enzyme (iNOS), and vascular endothelial growth factor (VEGF) in relation to angiogenesis (microvessel density, MVD) and clinical outcomes in adenoid cystic carcinoma (ACC) of salivary glands.
Immunohistochemical staining was used to quantify the protein expression levels of NF-kappaB p65, iNOS, and VEGF in 80 surgically resected ACCs and 20 normal salivary tissues. In all cases of ACCs, MVD was evaluated by counting CD34-reactive endothelial cells or endothelial cell clusters.
The nuclear localization of NF-kappaB p65 was only detected in ACC cells. Both iNOS and VEGF staining activities in ACCs were more significant than those in normal gland tissues (P < 0.01). MVD had significant correlations with NF-kappaB p65, iNOS, and VEGF expressions (P < 0.01). In three histologic types of ACCs, the NF-kappaB, iNOS, VEGF expressions, and MVD were significantly higher in solid type than in cribriform and tubular types (P < 0.01). The NF-kappaB, iNOS, VEGF expressions, and MVD were significantly correlated with clinical stage, tumor size, vascular invasion, recurrence, and metastasis (P < 0.05). Multivariate analysis showed NF-kappaB, iNOS and VEGF expression, MVD, solid histotype, and perineural invasion had an independent prognostic effect on overall survival.
The expressions of NF-kappaB p65, iNOS, and VEGF were related with MVD. Clinical outcomes raised the possibility that the overexpression of these cytokines might contribute to tumor angiogenesis and have prognostic value in ACCs.
"After being mounted in a xylene-based medium (VWR International, Radnor, PA, USA), the sections were examined under a light microscope (Leica DMLB; Leica Biosystems, Nussloch, Germany). Microvessel density (MVD) was evaluated according to the guidelines already published elsewhere [21–23]. Positive staining of a single endothelial cell or cluster of endothelial cells was defined as microvessel. "
[Show abstract][Hide abstract] ABSTRACT: Bioengineered bone substitutes might represent alternatives to autologous bone grafts in medically compromised patients due to reduced operation time and comorbidity. Due to the lack of an inherent vascular system their dimension is limited to the size of critical bone size defect. To overcome this shortcoming, the experiment tried to create heterotopic bone around vessels. In vivo, a two-component fibrin and thrombin gel containing recombinant bone morphogenic protein (rhBMP-2) and transglutamate vascular endothelial growth factor (TG-VEGF) in different ratios, respectively, was injected into a dimensionally stable membrane tube, wrapped around the femoral vessel bundle in twelve New Zealand white rabbits. Sacrifice occurred eight weeks postoperatively. Microcomputed tomography of the specimens showed significantly increased bone volume in the rhBMP-2 to TG-VEGF ratio of 10 to 1 group. Histology showed new bone formation in close proximity to the vessel bundle. Immunohistochemistry detected increased angiogenesis within the newly formed bone in the rhBMP-2 to TG-VEGF ratios of 3 to 1 and 5 to 1. Heterotopic bone was engineered in vivo around vessels using different rhBMP-2 and TG-VEGF ratios in a fibrin matrix injected into a dimensionally stable membrane tube which prevented direct contact with skeletal muscles.
[Show abstract][Hide abstract] ABSTRACT: According to recent studies, the function of Slug in hypoxia induced cadherin switch differs from cancer to cancer. Whether Slug is an essential mediator of the tumor hypoxia induced cadherin switch in head and neck squamous cell carcinoma (HNSCC) and the prognostic role of Slug in HNSCC patients are not elucidated. The aim of this study is to investigate the role of the Slug in cadherin switch induced by hypoxia in HNSCC.
Two HNSCC cell lines and 119 HNSCC specimens were selected for the present experiments. E/N-cadherins expression and tumor cell invasion responding to hypoxia/HIF-1α overexpression and the silence of Slug/SnaI2 gene were detected in vitro. HNSCC specimens were analyzed by immunohistochemistry staining to correlate the expressions of Slug, HIF-1α and E/N-cadherins with clinical outcomes.
Our research evidenced that Slug was extremely elevated in the HNSCC cells in response to hypoxia/HIF-1α overexpression. Suppressing Slug expression impaired HIF-1α induced cadherin switch and tumor invasion. In HNSCC tissues, relatively high expression of Slug was detected to be associated with endogenous HIF-1α overexpression, cadherin switch, the risk of lymph node metastasis, and a more advanced TNM stage. Additionally, aberrant Slug expression combined with HIF-1α overexpression and cadherin switch was significantly correlated with shorter HNSCC patient survival. In conclusion, Slug is necessary for hypoxia-induced cadherin switch in HNSCC and may be used as a potential risk marker in predicting HNSCC clinical outcomes.
"Aberrant activation of the NF-κB pathway has been identified in various types of cancer, including both solid and hematopoietic malignancies (22). Zhang et al revealed that an activated NF-κB pathway was significantly correlated with advanced clinical stage, high frequencies of tumor angiogenesis and perineural invasion, aggressive locoregional recurrence and distant metastasis in ACC, all of which predict an adverse prognostic prospect (23). Sustained activation of the NF-κB pathway has been demonstrated to promote survival in tumor cells with radiotherapy by permitting cells to repair DNA damage and to escape elimination by apoptosis, which is induced by the destruction of DNA double-strand (24). "
[Show abstract][Hide abstract] ABSTRACT: The constitutive activation of the nuclear factor κB (NF-κB) signaling pathway is involved in oncogenesis, invasive growth, metastasis and induced resistance to radiation and chemotherapy. Selective inhibition of the NF-κB signaling pathway, either by a mutant inhibitor or pharmacological agents, improves the therapeutic efficiency of irradiation. In the present study, the changes in NF-κB expression and the rate of apoptosis were investigated following irradiation of cells of an adenoid cystic carcinoma cell line (ACC-M) in which NF-κB expression had been inhibited by transient transfection with a mutant IκBα plasmid. ACC-M cells were transiently transfected with the mutant IκBα plasmid using Lipofectamine and the expression of this mutant IκBα gene was verified. The presence of the mutant IκBα gene alone did not result in a reduction in cell proliferation. Furthermore, a significant inhibition of translocation and synthesis of NF-κB protein in the transfected cells was observed after irradiation. NF-κB protein was activated by different doses of irradiation in a dose- and time-dependent manner with concordant changes in the radiosensitivity of ACC-M cells. We conclude that the mutant IκBα gene selectively inhibited the NF-κB pathway, which may be a promising method to improve the radiosensitivity of adenoid cystic carcinomas.
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