• Archives of Plastic Surgery
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• v.34 no.1
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• pp.13-17
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• 2007

Purpose: To understand the pathogenesis of the disease that presents abnormally proliferated vascular endothelial cells, a model of DMH(1,2-dimethylhydrazine)-induced abnormal proliferation of HUVECs(Human Umbilical Vein Endothelial Cells) was made. We indirectly determined that Protein Kinase C(PKC) restricts the cellular proliferation and inhibits the manifestation of growth factor by using several inhibiting substances of the transmitter through our previous studies. Thereupon, we attempted to observe direct enzymatic activities of PKC and its correlation with the abnormal proliferation of vascular endothelial cells. Methods: $10^5$ HUVECs cells were applied to 6 individual well plates in three different groups; A control group cultured without treatment, a group concentrated with $0.75{\times}10^{-8}M$ DMH only, and a group treated with DMH & $5{\times}10^{-9}M$ Calphostin C, inhibitor of PKC. In analyzing the formation of intracellular PKC enzyme, protein separation was performed, and separated protein was quantitatively measured. PKC enzyme reaction was analyzed through Protein Kinase C Assay System (Promega, USA), and the results were analyzed according to Beer's law. Results: Enzymatic activity of PKC presented the highest in all reaction time of a group concentrated only with DMH, and the lowest in the control group. The group treated with DMH and the inhibitor revealed statistically lower enzymatic activity than group only with DMH in all reaction time, although higher than the control group. Conclusion: From the enzymatic aspect, most active and immediate reaction of the PKC was observed in the group concentrated with DMH only. The group treated with DMH & PKC inhibitor showed meaningful decrease. Accordingly, PKC holds a significant role in DMH-induced abnormal proliferation of vascular endothelial cells.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.11
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• pp.5665-5669
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• 2012

Background: The vascular endothelial growth factor (VEGF) mediates vasculogenesis and angiogenesis through promoting endothelial cell growth, migration and mitosis, and has involvement in cancer pathogenesis, progression and metastasis. However, the prognostic value of VEGF in patients with prostate cancer remains controversial. Objectives: The aim of our study was to evaluate the prognostic value of VEGF in prostate cancer, and summarise the results of related research on VEGF. Methods: In accordance with an established search strategy, 11 studies with 1,529 patients were included in our meta-analysis. The correlation of VEGF-expression with overall survival and progression-free survival was evaluated by hazard ratio, either given or calculated. Results: The studies were categorized by introduction of the author, demographic data in each study, prostate cancer-relatived information, VEGF cut-off value, VEGF subtype, methods of hazard ratio (HR) estimation and its 95% confidence interval (CI). High VEGF-expression in prostate cancer is a poor prognostic factor with statistical significance for OS (HR=2.32, 95%CI: 1.40-3.24). However, high VEGF-expression showed no effect on poor PFS (HR=1.30, 95%CI: 0.88-1.72). Using Begg's, Egger's test and funnel plots, we confirmed lack of publication bias in our analysis. Conclusion: VEGF might be regarded as a prognostic maker for prostate cancer, as supported by our meta-analysis. To achieve a more definitive conclusion enabling the clinical use of VEGF in prostate cancer, we need more high-quality interventional original studies following agreed research approaches or standards.

• BMB Reports
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• v.39 no.5
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• pp.469-478
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• 2006

Vascular endothelial growth factor (VEGF)-A, a major regulator for angiogenesis, binds and activates two tyrosine kinase receptors, VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). These receptors regulate physiological as well as pathological angiogenesis. VEGFR2 has strong tyrosine kinase activity, and transduces the major signals for angiogenesis. However, unlike other representative tyrosine kinase receptors which use the Ras pathway, VEGFR2 mostly uses the Phospholipase-$C{\gamma}$-Protein kinase-C pathway to activate MAP-kinase and DNA synthesis. VEGFR2 is a direct signal transducer for pathological angiogenesis including cancer and diabetic retinopathy, thus, VEGFR2 itself and the signaling appear to be critical targets for the suppression of these diseases. VEGFR1 plays dual role, a negative role in angiogenesis in the embryo most likely by trapping VEGF-A, and a positive role in adulthood in a tyrosine kinase-dependent manner. VEGFR1 is expressed not only in endothelial cells but also in macrophage-lineage cells, and promotes tumor growth, metastasis, and inflammation. Furthermore, a soluble form of VEGFR1 was found to be present at abnormally high levels in the serum of preeclampsia patients, and induces proteinurea and renal dysfunction. Therefore, VEGFR1 is also an important target in the treatment of human diseases. Recently, the VEGFR2-specific ligand VEGF-E (Orf-VEGF) was extensively characterized. Interestingly, the activation of VEGFR2 via VEGF-E in vivo results in a strong angiogenic response in mice with minor side effects such as inflammation compared with VEGF-A, suggesting VEGF-E to be a novel material for pro-angiogenic therapy.

• Nutrition Research and Practice
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• v.3 no.1
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• pp.3-8
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• 2009

The matrix metalloproteinases (MMP) play an important role in tumor invasion, angiogenesis and inflammatory tissue destruction. Increased expression of MMP was observed in benign tissue hyperplasia and in atherosclerotic lesions. Invasive cancer cells utilize MMP to degrade the extracellular matrix and vascular basement membrane during metastasis, where MMP-2 has been implicated in the development and dissemination of malignancies. The present study attempted to examine the antiangiogenic activity of the medicinal herbs of Aspergillus usamii var. shirousamii-transformed Angelicae Gigantis Radix and Zizyphus jujube (tAgR and tZj) with respect to MMP-2 production and endothelial motility in phorbol 12-myristate 13-acetate (PMA)- or VEGF-exposed human umbilical vein endothelial cells (HUVEC). Nontoxic tAgR and tZj substantially suppressed PMA-induced MMP-2 secretion. In addition, $25{\mu}g/mL$ tAgR and tZj prevented vascular endothelial growth factor-stimulated endothelial cell transmigration and tube formation. The results reveal that tAgR and tZj dampened endothelial MMP-2 production leading to endothelial transmigration and tube formation. tAgR and tZj-mediated inhibition of endothelial MMP may boost a therapeutic efficacy during vascular angiogenesis.

• Bulletin of the Korean Chemical Society
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• v.27 no.9
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• pp.1456-1458
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• 2006

• Journal of Applied Biological Chemistry
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• v.48 no.4
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• pp.178-182
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• 2005

Nitric oxide (NO) produced from endothelial cells plays a critical role in vascular physiology. The regulation of endothelial NO synthase (eNOS) involves various mechanisms including multiple Ser/Thr phosphorylations. Recently, eNOS-Ser617 was newly recognized to be phosphorylated in response to humoral factors including vascular endothelial growth factor. However, it remains unknown whether and how eNOS-Ser617 phosphorylation is stimulated by shear stress, the primary stimulus of endothelial NO production. This issue was explored in the present study using cultured bovine aortic endothelial cells (BAECs). Over-expression of a constitutively active protein kinase B(Akt) mutant in BAECs increased Ser617 phosphorylation while constitutively active protein kinase A mutant had no effect. When BAECs were subjected to an arterial level of laminar shear stress, eNOS-Ser617 phosphorylation was clearly increased in a time-dependent manner. Shear stress also stimulated Akt phosphorylation at Thr308, one of the key regulatory sites. The time courses of eNOS-Ser617 and Akt-Thr308 phosphorylations appeared to be very similar. These results suggested that eNOS-Ser617 phosphorylation, mediated by Akt, is a physiological response to the mechanical shear stress, involved in the regulation of NO production in endothelial cells.

• Journal of Korean Neurosurgical Society
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• v.30 no.6
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• pp.683-687
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• 2001

Objective : Angiogenesis, the proliferation of capillary endothelial cells, is a vital component in the development, progression, and metastasis of many human tumors. Vascular endothelial growth factor(VEGF) is an endothelial cell-specific mitogen and induces angiogenesis and vascular permeability. The features of glioblastoma, distinct from low grade astrocytomas, are the presence of necroses and vascular endothelial proliferation. In this study, we investigated VEGF expression in the different grades of astrocytomas and determined whether VEGF expression correlates with development of glioblastoma and progression of astrocytomas. Patients and Methods : Forty seven patients with astrocytic tumors(24 males and 23 females), aged 3 to 65 years, were evaluated. Immunohistochemical staining was carried out using labelled streptavidin biotin method and primary antibody was a antirabbit polyclonal Ab against N-terminus region of VEGF165(Oncogene research product, MA, USA). Immunoreactivity(IR) was classified into no IR(absent or a trace of stain), moderate IR and intense IR by level of staining amount and intensity. Results : Six pilocytic astrocytomas showed 3 no IR and 3 moderate IR, 10 astrocytomas showed 2 no IR, 6 moderate IR and 2 intense IR, 12 anaplastic astrocytomas showed I no IR, 7 moderate IR and 4 intense IR and 19 glioblastomas showed 1 no IR, 11 moderate IR and 7 intense IR. Immunoreactivity was significantly different between low and high grade of tumors but there was no significant difference between anaplastic astrocytomas and glioblastomas. Gemistocytic tumor cells represented the predominent VEGF-immunoreactive cell types, as compared with compactly-arranged small tumor cells. In glioblastomas VEGF IR was observed in both perinecrotic and vital tumor areas. Conclusion : VEGF seems to be a important angiogenic factor in anaplastic astrocytomas and glioblastomas and VEGF expression may contribute to neovascularization of human astrocytomas.

• Clinical and Experimental Reproductive Medicine
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• v.31 no.4
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• pp.235-244
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• 2004

Objective: The effects on spermatogenesis by expression of vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) were investigated. Materials and Methods: Testicular specimens were obtained from 40 infertile males due to primary testicular failure and from 10 fertile males with other urologic problems. The specimens of infertile males were devided into 4 groups according to histologic findings; Sertoli cell only syndrome (A), maturation arrest (B), hypospermatogenesis (C) and sloughing and disorganization (D). VEGF and ET-1 expression were detected with immunohistochemical stain. Results: VEGF expression on Leydig cell was detected in all cases. But, VEGF expression rates on germ cell were significantly higher in infertile group B, C, D compared to that of the control group (p<0.05). ET-1 expression rates on Leydig cell was significantly lower in all infertile group compared to that of the control group (p<0.05). But, ET-1 expression rates on Sertoli cell was significantly higher in all infertile group compared to that of the control group (p>0.05). In germ cell of infertile group, LH, FSH and prolactin were significantly decreased, and estradiol is increased in positive stain group on ET-1 immunohistochemical stain (p<0.05). VEGF and ET-1 expression were not correlated mean seminiferous tubule diameter (p>0.05). Conclusions: Abnormal spermatogenesis would be reflected in VEGF expression in germ cell.

• Journal of Life Science
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• v.34 no.2
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• pp.128-137
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• 2024

This review discusses the pivotal role of vascular endothelial growth factors (VEGF) in angiogenesis and lymphangiogenesis, vital processes influencing vascular permeability, endothelial cell recruitment, and the maintenance of tumor-associated blood and lymphatic vessels. VEGF exerts its effects through tyrosine-kinase receptors, VEGFR-1, VEGFR-2, and VEGFR-3. This VEGF-VEGFR system is central not only to cancer but also to diseases arising from abnormal blood vessel and lymphatic vessel formation. In the context of cancer, VEGF and its receptors are essential for the development of tumor-associated vessels, making them attractive targets for therapeutic intervention. Various approaches, such as anti-VEGF antibodies, receptor antagonists, and VEGF receptor function inhibitors, are being explored to interfere with tumor growth. However, the clinical efficacy of anti-angiogenic agents remains uncertain and necessitates further refinement. The article also highlights the physiological role of VEGFs, emphasizing their involvement in endothelial cell functions, survival, and vascular permeability. The identification of five distinct VEGFs in humans (VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PLGF) is discussed, along with the classification of VEGFRs as typical receptor tyrosine kinases with distinct signaling systems. The family includes VEGFR-1 and VEGFR-2, crucial in tumor biology and angiogenesis, and VEGFR-3, specifically involved in lymphangiogenesis. Overall, this review has provided a comprehensive overview of VEGF and VEGFR, detailing their roles in various diseases, including cancer. This is expected to further facilitate the utilization of VEGF and VEGFR as therapeutic targets.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.27 no.2
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• pp.110-122
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• 2005

Adenoid cystic carcinoma (ACC) of salivary glands has a protracted clinical course with perineural invasion, delayed onset of hematogenous metastasis, and poor responses to classical cytotoxic chemotherapic agents. Most deaths from salivary ACC are caused by lung metastases that are resistant to conventional therapy. Therefore, knowledge of cellular properties and tumor-host interactions that influence the dissemination of metastatic cells is important for the design of more effective therapy of salivary cancer. I determined in vitro expression of epidermal growth factor receptor (EGFR) and its downstream effectors and vascular endothelial growth factor receptor (VEGFR)-2 on a human salivary ACC cell line (ACC2). I also evaluated the expression of EGF and VEGF signaling molecules and metastasis-related proteins on human salivary ACC cells orthotopically growing in nude mice. In Western blot and immunohistochemical analyses, EGFR and VEGFR-2 were presented and phosphorylated in ACC2 cells. In human parotid cancer xenografts in nude mice, EGF and VEGF signaling molecules, IL-8, and MMP-9 were expressed at markedly higher levels than in normal parotid tissues. Moreover, tumor-associated endothelial cells of this orthotopic parotid tumor expressed phosphorylated VEGFR-2 and phosphorylated Akt, which is a cell-survival protein. These data show that those biomarkers can be molecular targets for therapy of salivary ACC, which has a propensity for delayed lung metastasis.