• Toxicological Research
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• v.11 no.2
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• pp.175-180
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• 1995

We found that bufalln, one of the prominent components of the bufadlenolides in the Chinese medicine chan'su, has the potent inhibitory effects on growth and proliferation of the cultured bovine aortlc endothelial (BAE) and human umbilical vein endothelial (HUVE) cells. All naturally-occuring bufadienolides used in this study inhibited the cell growth in a dose-dependent manner. Particularly, bufalin among the bufadienolides showed the strongest inhibitory activity for the cell growth. The order of growth inhibition by bufadienolides on BAE cells was as follows: bufalin > gamabufotalln > bufotalln > cinobufagin > cinobufotalin > resibufogenin. The $IC_50$ values (50% inhibition of cell growth) of bufalin as determined by XTT assay were the range of 1-10 nM in BAE and HUVE cells. Bufalin exhibited a higher sensitivity towards cultured bovine aortic endothelial cells than human umbilical vein endothelial cells.

• Molecules and Cells
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• v.37 no.6
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• pp.487-496
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• 2014

Angiotensinogen (AGT), the precursor of angiotensin I, is known to be involved in tumor angiogenesis and associated with the pathogenesis of coronary atherosclerosis. This study was undertaken to determine the role played by AGT in endothelial progenitor cells (EPCs) in tumor progression and metastasis. It was found that the number of EPC colonies formed by AGT heterozygous knockout ($AGT^{+/-}$) cells was less than that formed by wild-type (WT) cells, and that the migration and tube formation abilities of $AGT^{+/-}$ EPCs were significantly lower than those of WT EPCs. In addition, the gene expressions of vascular endothelial growth factor (VEGF), Flk1, angiopoietin (Ang)-1, Ang-2, Tie-2, stromal derived factor (SDF)-1, C-X-C chemokine receptor type 4 (CXCR4), and of endothelial nitric oxide synthase (eNOS) were suppressed in $AGT^{+/-}$ EPCs. Furthermore, the expressions of hypoxia-inducible factor (HIF)-$1{\alpha}$and $-2{\alpha}$ were downregulated in $AGT^{+/-}$ early EPCs under hypoxic conditions, suggesting a blunting of response to hypoxia. Moreover, the activation of Akt/eNOS signaling pathways induced by VEGF, epithelial growth factor (EGF), or SDF-$1{\alpha}$ were suppressed in $AGT^{+/-}$ EPCs. In $AGT^{+/-}$ mice, the incorporation of EPCs into the tumor vasculature was significantly reduced, and lung tumor growth and melanoma metastasis were attenuated. In conclusion, AGT is required for hypoxia-induced vasculogenesis.

• BMB Reports
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• v.51 no.2
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• pp.73-78
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• 2018

Vascular endothelial growth factor and its receptor (VEGF-VEGFR) system play a critical role in the regulation of angiogenesis and lymphangiogenesis in vertebrates. Each of the VEGF has specific receptors, which it activates by binding to the extracellular domain of the receptors, and, thus, regulates the angiogenic balance in the early embryonic and adult stages. However, de-regulation of the VEGF-VEGFR implicates directly in various diseases, particularly cancer. Moreover, tumor growth needs a dedicated blood supply to provide oxygen and other essential nutrients. Tumor metastasis requires blood vessels to carry tumors to distant sites, where they can implant and begin the growth of secondary tumors. Thus, investigation of signaling systems related to the human disease, such as VEGF-VEGFR, will facilitate the development of treatments for such illnesses.

• IMMUNE NETWORK
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• v.24 no.1
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• pp.10.1-10.17
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• 2024

In this review, we will explore the intricate roles of cytokines and vascular endothelial growth factors in autoimmune diseases (ADs), with a particular focus on rheumatoid arthritis (RA) and multiple sclerosis (MS). AD is characterized by self-destructive immune responses due to auto-reactive T lymphocytes and Abs. Among various types of ADs, RA and MS possess inflammation as a central role but in different sites of the patients. Other common aspects among these two ADs are their chronicity and relapsing-remitting symptoms requiring continuous management. First factor inducing these ADs are cytokines, such as IL-6, TNF-α, and IL-17, which play significant roles in the pathogenesis by contributing to inflammation, immune cell activation, and tissue damage. Secondly, vascular endothelial growth factors, including VEGF and angiopoietins, are crucial in promoting angiogenesis and inflammation in these two ADs. Finally, placental growth factor (PlGF), an emerging factor with bi-directional roles in angiogenesis and T cell differentiation, as we introduce as an "angio-lymphokine" is another key factor in ADs. Thus, while angiogenesis recruits more inflammatory cells into the peripheral sites, cytokines secreted by effector cells play critical roles in the pathogenesis of ADs. Various therapeutic interventions targeting these soluble molecules have shown promise in managing autoimmune pathogenic conditions. However, delicate interplay between cytokines, angiogenic factors, and PlGF has more to be studied when considering their complementary role in actual pathogenic conditions. Understanding the complex interactions among these factors provides valuable insights for the development of innovative therapies for RA and MS, offering hope for improved patient outcomes.

• Preventive Nutrition and Food Science
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• v.11 no.1
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• pp.1-5
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• 2006

Conjugated linoleic acid (CLA) is a group of positional and geometric isomers of linoleic acid that have been used to reduce the incidence, growth and metastasis of breast, colon, prostate and gastric cancer in animals. CLA could reduce tumor growth by altering angiogenesis; a process requiring associated angiogenic factors such as vascular endothelial growth factor (VEGF). In this study, we determined whether CLA could modulate the expression of VEGF in murine mammary tumor cells and adipocytes. The c9, t11-CLA isomer reduced VEGF transcripts and protein when mammary tumor cells were stimulated with PMA. That isomer also reduced VEGF expression in un stimulated mouse 3T3-L1 adipocytes. Since VEGF can be regulated by cyclooxygenase-2 (COX-2), we determined whether CLA could alter COX-2 enzyme expression and $PGE_2$ production. The c9, t11-CLA isomer reduced not only COX-2 enzyme expression but also $PGE_2$ production. Thus, c9, t11-CLA could modulate neovascularization by alteration of VEGF expression from mammary tumor cells and adipocytes by reducing COX-2 metabolites.

• Korean Journal of Pharmacognosy
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• v.28 no.1
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• pp.54-58
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• 1997

The cytotoxic activities of methanolic extract and its fractions of Ailanthi Cortex Radicis and column chromatographic eluates of its dichloromethane fraction (DCM fr.) were investigated. DCM fr. Showed the strongest cytotoxicity against hepatoma cells. Furthermore, the active equates 1-3, 8 and 9 were obtained. Effects on free radical generation and the growth of vascular endothelial cells were tested to elucidate the action mechanism of anticancer activity. Eluates 1-3 stimulated free radical generation, while eluates 8 and 9 showed no changes. Especially, eluates 8 and 9 efffectively inhibited the proliferation of vascular endothelial cells in a dose- dependant manner. It is speculated that the anticancer effects of eluates 1-3, 8 and 9 might be due to free radical generation and inhibition of endothelial cell growth, respectively.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.11
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• pp.4549-4553
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• 2015

Background: Colorectal carcinoma (CRC) is one of the major causes of cancer death worldwide. Data from the literature indicate differences between the proliferation rate of endothelial cells relative to the morphology growth type, possibly due to origin of specimens (autopsy material, surgery fragments) or quantification methods. Vascular endothelial growth factor (VEGF) is a factor that stimulates the proliferation of endothelial cells. It is expressed in more than 90% of cases of metastatic CRC. Aim: The aim of this study was to evaluate the endothelial cell proliferation and VEGF expression in primary tumors and corresponding liver metastases. Materials and Methods: Our study included 24 recent biopsies of primary tumors and corresponding liver metastases of CRC cases. CD34/Ki67 double immunostaining and RNA scope assay for VEGF were performed. Results: In the primary tumors analysis of VEGFmRNA expression indicated no significant correlation with differentiation grade, proliferative and non-proliferative vessels in the intratumoral and peritumoral areas. In contrast, in the corresponding liver metastases, VEGFmRNA expression significantly correlated with the total number of non-proliferative vessels and total number of vessels. CD34/Ki67 double immunostaining in the cases with poorly differentiated carcinoma indicated a high number of proliferating endothelial cells in the peritumoral area and a low number in the intratumoral area for the primary tumor. Moderately differentiated carcinomas of colon showed no proliferating endothelial cells in the intratumoral area in half of the cases included in the study, for both, primary tumor and liver metastasis. In well differentiated CRCs, in primary tumors, a high proliferation rate of endothelial cells in the intratumoral area and a lower proliferation rate in the peritumoral area were found. A low value was found in corresponding liver metastasis. Conclusions: The absence of proliferative endothelial cells in half of the cases for the primary tumors and liver metastases in moderately differentiated carcinoma suggest a vascular mimicry phenomenon. The mismatch between the total number of vessels and endothelial proliferation in primary tumors indicate that a functional vascular network is already formed or the existence of some mechanisms influenced by other angiogenic factors.

• Archives of Plastic Surgery
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• v.37 no.1
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• pp.7-11
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• 2010

Purpose: Vascular endothelial growth factor (VEGF) is known as a growth factor of endothelium and fibroblast. The purpose is to know the VEGF effects on fibroblast proliferation and fibroblast's notch receptor expression. Methods: CCD-986sk fibroblast was purchased from the Korean Cell Bank and was used in XTT assay for proliferation and wound healing assay for migration. Immunofluorescent (IF) staining and western blotting were used in testing notch expression of fibroblast. Semiquantitative RT-PCR was used in checking notch 1 mRNA production by fibroblast. Student-t test was used for analyzing results. Results: Cell proliferation assay using XTT showed significant higher proliferation in VEGF treated fibroblast, $2.324{\pm}0.0026$ vs. $2.463{\pm}0.017$ (p=0.002). Wound healing assay showed longer migration in VEGF treated fibroblast (p=0.062). The fluorescence was brighter in VEGF treated cells of notch 1 IF staining. Notch 1 expressions and mRNA productions increased more in VEGF treated cells. Conclusion: VEGF stimulates fibroblast to proliferate, migrate and to express Notch 1 simultaneously. Notch receptor could be related to VEGF mediated wound healing.

• BMB Reports
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• v.42 no.10
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• pp.685-690
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• 2009

Angiogenesis is essential for tumor growth and vascular endothelial cell growth factor (VEGF) plays a key role in this process. Conversely, sphingosine 1-phosphate (S1P) is a biologically active sphingolipid known to play a key role in cancer progression by regulating endothelial cell proliferation and migration. In this study, the authors found that S1P increases the level of VEGF mRNA in human umbilical vein endothelial cells (HUVECs) and immortalized HUVECs (iHUVECs). Additionally, S1P was found to increase VEGF promoter activity in MS-1 mouse pancreatic islet endothelial cells. Furthermore, a pharmacological inhibitory study revealed that $G_{\alpha i/o}$-mediated phospholipase C, Akt, Erk, and p38 MAPK signaling are involved in this S1P-induced expression of VEGF. A component of AP1 transcription factor is important for S1P-induced VEGF expression. Taken together, these findings suggest that S1P enhances endothelial cell proliferation and migrat ion by upregulating the expression of VEGF mRNA.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.28 no.3
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• pp.193-201
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• 2006

Squamous cell carcinoma(SCC) of head and neck(SCCHN) is the sixth most common human malignant tumor. However, despite advances in prevention and treatment of SCC, the five-year survival rates for patients remain still low. To improve the outcome for patients with SCCHN, novel treatment strategies are needed. Overexpression of the epidermal growth factor(EGF) and activation of its receptor(EGFR) are associated with progressive growth of SCCHN. Vascular endothelial growth factor(VEGF) signaling molecules are related with neoangiogenesis and vascular metastasis of SCC. In this study, we determined the therapeutic effect of AEE788(Novartis Pharma AG, Basel, Switzerland), which is a dual inhibitor of EGFR/ErbB2 and VEGFR tyrosine kinases, on human oral SCC. At first, we screened the expression of EGFR, c-ErbB2(HER-2) and VEGFR-2 in a series of human oral SCC cell lines. And then we evaluated the effects of AEE788 on the phosphorylation of EGFR and VEGFR-2 in a oral SCC cell line expressing EGFR/HER-2 and VEGFR-2. We also evaluated the effects of AEE788 alone, or with paclitaxel(Taxol) on the oral SCC cell growth and apoptosis. As a result, all oral SCC cells expressed EGFR and VEGFR-2. Treatment of oral SCC cells with AEE788 led to dose-dependent inhibition of EGFR and VEGFR-2 phosphorylation, growth inhibition, and induction of apoptosis. Moreover, AEE788 sensitizes the cells to paclitaxel-mediated toxicity and apoptosis. These data mean EGFR and VEGFR-2 can be reliable targets for molecular therapy of oral SCC, and therefore warrant clinical use of EGFR/VEGFR inhibition in the treatment of patients with recurrent or metastatic oral SCC.