• Asian Pacific Journal of Cancer Prevention
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• v.13 no.9
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• pp.4453-4458
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• 2012

Angiogenesis plays a significant role in colorectal cancer (CRC) and cyclooxygenase-2 (COX-2) appears to be involved with multiple aspects of CRC angiogenesis. Our aim was to investigate the inhibitory effects of Tan II-A (Tanshinone II-A, Tan II-A) on tumor growth in mice, as well as alteration of expression of COX-2 and VEGF in CRC. We established the mice xenograft model of C26 CRC cell line, and injected 0.5, 1, 2mg/kg of Tan II-A and 1mg/kg of 5-FU in respectively in vivo. Then, we assayed tumor weight and volume, and evaluated microvascular density and expression of VEGF. COX-2 promoter and COX-2 plasmids were transfected into HCT-116 cells, followed by detection of COX-2 promoter activity by chemiluminescence, and detection of COX-2 mRNA expression by fluorescence quantitative PCR. Taken together, the results showed Tan II-A could inhibit tumor growth and suppress the VEGF level in vivo. HCT-116 cell experiments showed marked inhibitory effects of Tan II-A on COX-2 and VEGF in a dose-dependent manner. The results indicate that Tan II-A can effectively inhibit tumor growth and angiogenesis of human colorectal cancer via inhibiting the expression level of COX-2 and VEGF.

• Journal of Radiopharmaceuticals and Molecular Probes
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• v.6 no.1
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• pp.3-9
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• 2020

Tetraiodothyroacetic acid (tetrac) is a derivative of thyroid hormone T₄ and causes anti-angiogenesis by blocking T₄ binding to integrin α_vβ₃. In this study, we synthesized [^99mTc]Tc-Cys-Asp-Gly(CDG)-tetrac and evaluated it in vitro as a tumor angiogenesis imaging ligand. The CDG was conjugated to tetrac as a chelator for technetium-99m labeling. The cold vial containing CDG-tetrac, sodium glucoheptonate, and reducing agent was completed under nitrogen-filled atmospheric glove bag. [^99mTc]Tc-CDG-tetrac was synthesized in quantitative yield by heating the cold vial with [^99mTc]TcO₄^- at 100℃ for 30 min. In vitro serum stability of [^99mTc]Tc-CDG-tetrac was measured by incubating the radioligand in 50% fetal bovine serum at 37℃ and analyzing the incubation mixture by radio-TLC, which showed high stability over 6 h (≥ 98%). Cell binding study was carried out by incubating [^99mTc]Tc-CDG-tetrac with human umbilical vein endothelial (HUVE) cells at 37℃ for 6 h. The cell binding of the radioligand increased from 100% at 0.5 h to 293.7% at 6 h in a time-dependent manner. For blocking study, the cells were incubated with the radioligand in the presence of either tetrac (20 μM) or cRGDyK (20 μM) at 37℃ for 4 h. The results demonstrated that the cell binding of the radioligand was inhibited by tetrac (19.1%) or cRGDyK (35.6%), indicating specific binding of the radioligand to integrin α_vβ₃. Thus, this study suggests that [^99mTc]Tc-CDG-tetrac may be a potential radioligand for tumor angiogenesis imaging.

• Molecules and Cells
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• v.40 no.10
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• pp.761-772
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• 2017

Glioblastoma is the most frequent and most aggressive brain tumor in adults. Solute carrier family 8 member 2 (SLC8A2) is only expressed in normal brain, but not present in other human normal tissues or in gliomas. Therefore, we hypothesized that SLC8A2 might be a glioma tumor suppressor gene and detected the role of SLC8A2 in glioblastoma and explored the underlying molecular mechanism. The glioblastoma U87MG cells stably transfected with the lentivirus plasmid containg SLC8A2 (U87MG-SLC8A2) and negative control (U87MG-NC) were constructed. In the present study, we found that the tumorigenicity of U87MG in nude mice was totally inhibited by SLC8A2. Overexpression of SLC8A2 had no effect on cell proliferation or cell cycle, but impaired the invasion and migration of U87MG cells, most likely through inactivating the extracellular signal-related kinases (ERK)1/2 signaling pathway, inhibiting the nuclear translocation and DNA binding activity of nuclear factor kappa B ($NF-{\kappa}B$), reducing the level of matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (uPA)-its receptor (uPAR) system (ERK1/2-$NF-{\kappa}B$-MMPs/uPA-uPAR), and altering the protein levels of epithelial to mesenchymal transitions (EMT)-associated proteins E-cardherin, vimentin and Snail. In addition, SLC8A2 inhibited the angiogenesis of U87MG cells, probably through combined inhibition of endothelium-dependent and endothelium-nondependent angiogenesis (vascular mimicry pattern). Totally, SLC8A2 serves as a tumor suppressor gene and inhibits invasion, angiogenesis and growth of glioblastoma.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.35 no.2
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• pp.66-73
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• 2009

Tumor angiogenesis is a process leading to formation of blood vessels within tumors and is crucial for maintaining a supply of oxygen and nutrients to support tumor growth and metastasis. Vascular endothelial growth factor(VEGF) plays a key role in tumor angiogenesis including induction of endothelial cell proliferation, migration, survival and capillary tube formation. VEGF binds to two distinct receptors on endothelial cells. VEGFR-2 is considered to be the dominant signaling receptor for endothelial cell permeability, proliferation, and differentiation. Bevacizumab(Avastin, Genetech, USA) is a monoclonal antibody against vascular endothelial growth factor. It is used in the treatment of cancer, where it inhibits tumor growth by blocking the formation of new blood vessels. The goal of this study is to identify the anti-tumor effect of Bevacizumab(Avastin) for oral squamous cell carcinoma cell lines. Human squamous cell carcinoma cell line(HN4) was used in this study. We examined the sensitivity of HN4 cell line to Bevacizumab(Avastin) by using in vitro proliferation assays. The results were as follows. 1. In the result of MTT assay according to concentration of Bevacizumab(Avastin), antiproliferative effect for oral squamous cell carcinoma cell lines was observed. 2. The growth curve of cell line showed the gradual growth inhibition of oral squamous cell carcinoma cell lines after exposure of Bevacizumab(Avastin). 3. In the apoptotic index, groups inoculated Bevacizumab(Avastin) were higher than control groups. 4. In condition of serum starvation, VEGFR-2 did not show any detectable autophosphorylation, whereas the addition of VEGF activated the receptor. Suppression of phosphorylated VEGFR-2 and phosphorylated MAPK was observed following treatment with Bevacizumab(Avastin) in a dose-dependent manner. 5. In TEM view, dispersed nuclear membrane, scattered many cytoplasmic vacuoles and localized chromosomal margination after Bevacizumab(Avastin) treatment were observed. These findings suggest that Bevacizumab(Avastin) has the potential to inhibit MAPK pathway in proliferation of oral squamous cell carcinoma cell lines via inhibition of VEGF-dependent tumor growth.

• Korean Journal of Head & Neck Oncology
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• v.20 no.2
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• pp.128-134
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• 2004

Background and Objectives: Angiogenesis is the process of new blood vessel development from preexisting vessel. Angiogenenesis has been considered to be essential for the growth and expansion of a solid tumor. Vascular endothelial growth factor (VEGF), known as one of the most important vascular permeability factors, induces proliferation of endothelial cells, stiumulates angiogenesis, and increases vascular permeability. Several recents reports have documented that VEGF overexpression is associated with poor clinical outcomes in many maligmancies. The aims of this study were to determine whether microvessel density and VEGF expression are related to clinicopathologic factors such as age, sex, tumor size, tumor stage, and prognostic factors and to evaluate the relationship between VEGF expression and angiogenesis in benign and malignant thyroid tumors. Materials and Methods: The subjects were 65 patients (27 with papillary carcinoma, 27 with adenomatous hyperplasia, 11 with follicular adenoma) who underwent thyroidectomy from 1995 to 2001. Imuunohistochemistry was used to detect VEGF expression and microvessel density (MVD) in paraffin-embedded thryoid tumor specimens. Results: The intensity of the VEGF expression did not show stastically difference between benign and malignant thyroid tumors. There was no apparent correlation between VEGF expression and age, tumor size, T stage or scores of the AGES, AMES and MACIS systems. The neo-microvessel density was higher in the maligant tumor than the benign tumors. Also, higher neo-microvessel density was associated with metastases of the lymph nodes and scores of the AMES and AGES systems. Conclusion: Our results suggest that neo-microvessel vessel density may be a significant prognostic factor in the thyroid papillary carcinoma. But the VEGF expression does not appear to be an significant independent prognostic factor for thyroid papillary carcinoma.

• BMB Reports
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• v.41 no.4
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• pp.278-286
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• 2008

Angiogenesis, the formation of blood vessels, is essential for preparing a closed circulatory system in the body, and for supplying oxygen and nutrition to tissues. Major diseases such as cancer, rheumatoid arthritis, and atherosclerosis include pathological angiogenesis in their malignant processes, suggesting anti-angiogenic therapy to be a new strategy for suppression of diseases. However, until the 1970s, the molecular basis of angiogenesis was largely unknown. In recent decades, extensive studies have revealed a variety of angiogenic factors and their receptors, including vascular endothelial growth factor (VEGF)-VEGFRs, Angiopoietin-Tie, Ephrin-EphRs and Delta-Notch to be the major regulators of angiogenesis in vertebrates. VEGF and its receptors play a central role in physiological as well as pathological angiogenesis, and functional inhibitors of VEGF and VEGFRs such as anti-VEGF neutralizing antibody and small molecules that block the tyrosine kinase activity of VEGFRs have recently been approved for use to treat patients with colorectal, lung, renal and liver cancers. These drugs have opened a novel field of cancer therapy, i.e. anti-angiogenesis therapy. However, as yet they cannot completely cure patients, and cancer cells could become resistant to these drugs. Thus, it is important to understand further the molecular mechanisms underlying not only VEGF-VEGFR signaling but also the VEGF-independent regulation of angiogenesis, and to learn how to improve anti-angiogenesis therapy.

• Journal of Haehwa Medicine
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• v.9 no.2
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• pp.241-250
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• 2001

A study on relation of angiogenesis and blood stagnation in cancer was done, and the results were as follows. 1. Angiogenesis is a sequence of vascular proliferation and accomplished by regulation of anti-angiogenesis factor and indicating factor. These factors are secreted in the course of blood coagulation, inflammation, and regeneration. 2. Angiogenesis in cancer is a important action in growth of tumor and metastasis because it supply oxygen and nutrition. 3. The complicated processes, for example, platelet coagulation, action of coagulator factor & dissolution factor and interaction of variety factors are related to blood stasis and promoting blood circulation to remove blood stasis in oriental medicine. 4. Promoting blood circulation to remove blood stasis is expected to suppress angiogenesis, and we expect advanced study will be accomplished in future.

• The Journal of Internal Korean Medicine
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• v.29 no.2
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• pp.490-499
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• 2008

Objectives : This study was aimed to elucidate the effects of Trichosanthes kirilowii extract (TKE) on the angiogenesis and growth of tumor cells. Methods : Tube formation assay was performed by using human umbilical vein endothelial cells (HUVEC), and anchorage dependent colony assay was performed by using B16-F10 melanoma, Hep G2 and HT1080, CT-26 and SNU-1 cells. Results : For HUVEC, TKE at a level of more than 100 ${\mu}g/m{\ell}$ suppresses cell growth. For HUVEC at 100 ${\mu}g/m{\ell}$ and greater TKE density, the formation of tubes was suppressed in a dose-dependant manner. TKE controls the colony formations of B16-F10 melanoma cells, CT 26 cells, and Hep G2 cells, and its effect is proportional to density. In HT1080 cells and SNU-1 cells, formation is suppressed regardless of density. Conclusions : From these results, it could be concluded that TKE has significant properties on anti-angiogenesis and growth inhibiting of tumor cells. It is suggested that TKE will be a good candidate for new drugs or therapeutics for anti-angiogenesis.

• Nutrition Research and Practice
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• v.8 no.4
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• pp.377-385
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• 2014

BACKGROUND/OBJECTIVES: Abundant consumption of seaweeds in the diet is epidemiologically linked to the reduction in risk of developing cancer. In larger cases, however, identification of particular seaweeds that are accountable for these effects is still lacking, hindering the recognition of competent dietary-based chemo preventive approaches. The aim of this research was to establish the antiproliferative potency and angiosuppressive mode of action of Stoechospermum marginatum seaweed methanolic extract using various experimental models. MATERIALS/METHODS: Among the 15 seaweeds screened for antiproliferative activity against Ehrlich ascites tumor (EAT) cell line, Stoechospermum marginatum extract (SME) was found to be the most promising. Therefore, it was further investigated for its anti-proliferative activity in-vitro against choriocarcinoma (BeWo) and non-transformed Human embryonic kidney (HEK 293) cells, and for its anti-migratory/tube formation activity against HUVEC cells in-vitro. Subsequently, the angiosuppressive activity of S. marginatum was established by inhibition of angiogenesis in in-vivo (peritoneal angiogenesis and chorioallantoic membrane assay) and ex-vivo (rat cornea assay) models. RESULTS: Most brown seaweed extracts inhibited the proliferation of EAT cells, while green and red seaweed extracts were much less effective. According to the results, SME selectively inhibited proliferation of BeWo cells in-vitro in a dose-dependent manner, but had a lesser effect on HEK 293 cells. SME also suppressed the migration and tube formation of HUVEC cells in-vitro. In addition, SME was able to suppress VEGF-induced angiogenesis in the chorio allantoic membrane, rat cornea, and tumor induced angiogenesis in the peritoneum of EAT bearing mice. A decrease in the microvessel density count and CD31 antigen staining of treated mice peritoneum provided further evidence of its angiosuppressive activity. CONCLUSIONS: Altogether, the data underline that VEGF mediated angiogenesis is the target for the angiosuppressive action of SME and could potentially be useful in cancer prevention or treatment involving stimulated angiogenesis.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.14
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• pp.5793-5798
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• 2014

Background: Golgi phosphoprotein-3 (GOLPH3) is implicated in cancer development and progression. The aim of this study was to evaluate the prognostic significance of GOLPH3 protein and its association with tumor angiogenesis in patients with early-stage NSCLC. Materials and Methods: Immunohistochemistry was performed to determine GOLPH3 protein expression and allow assessment of intratumoral microvessel density (MVD) by counting CD-34 positive immunostained endothelial cells. Correlations of expression with MVD, clinicopathologic features and clinical prognosis were analyzed. Results: A notably higher level of GOLPH3 expression was found in early-stage NSCC tissues at the protein level. However, we do not find any correlation between GOLPH3 expression and clinicopathologic features (p>0.05), although higher MVD was positively associated with GOLPH3 overexpression (p<0.001). Expression of GOLPH3 was found to be an independent prognostic factor in early-stage NSCLC patients, those expressing high levels of GOLPH3 exhibiting a substantially lower 5-year overall survival than GOLPH3-negative patients (adjusted HR =1.899, 95% CI: 1.021-3.532, p=0.043). Conclusions: High expression of the GOLPH3 protein is common in early-stage NSCC, and is closely associated with tumor progression, increased tumor angiogenesis, and poor survival. We conclude a possibility of its use as a diagnostic and prognostic marker in early-stage NSCC patients.