• Journal of Gastric Cancer
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• 제11권1호
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• pp.16-22
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• 2011

Purpose: Eupatilin is an antioxidative flavone and a phytopharmaceutical derived from Artemisia asiatica. It has been reported to possess anti-tumor activity in some types of cancer including gastric cancer. Eupatilin may modulate the angiogenesis pathway which is part of anti-inflammatory effect demonstrated in gastric mucosal injury models. Here we investigated the anti-tumor effects of eupatilin on gastric cancer cells and elucidated the potential underlying mechanism whereby eupatilin suppresses angiogenesis and tumor growth. Materials and Methods: The impact of eupatilin on the expression of angiogenesis pathway proteins was assessed using western blots in MKN45 cells. Using a chromatin immunoprecipitation assay, we tested whether eupatilin affects the recruitment of signal transducer and activator of transcription 3 (STAT3), aryl hydrocarbon receptor nuclear translocator (ARNT) and hypoxia-inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$) to the human VEGF promoter. To investigate the effect of eupatilin on vasculogenesis, tube formation assays were conducted using human umbilical vein endothelial cells (HUVECs). The effect of eupatilin on tumor suppression in mouse xenografts was assessed. Results: Eupatilin significantly reduced VEGF, ARNT and STAT3 expression prominently under hypoxic conditions. The recruitment of STAT3, ARNT and HIF-$1{\alpha}$ to the VEGF promoter was inhibited by eupatilin treatment. HUVECs produced much foreshortened and severely broken tubes with eupatilin treatment. In addition, eupatilin effectively reduced tumor growth in a mouse xenograft model. Conclusions: Our results indicate that eupatilin inhibits angiogenesis in gastric cancer cells by blocking STAT3 and VEGF expression, suggesting its therapeutic potential in the treatment of gastric cancer.

• Journal of Ginseng Research
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• 제36권2호
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• pp.135-145
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• 2012

Previously, we reported that Helicobacter pylori-associated gastritis and gastric cancer are closely associated with increased levels of hydrogen sulfide ($H_2S$) and that Korean red ginseng significantly reduced the severity of H. pylori-associated gastric diseases by attenuating $H_2S$ generation. Because the incubation of endothelial cells with $H_2S$ has been known to enhance their angiogenic activities, we hypothesized that the amelioration of $H_2S$-induced gastric inflammation or angiogenesis in human umbilical vascular endothelial cells (HUVECs) might explain the preventive effect of Korean red ginseng on H. pylori-associated carcinogenesis. The expression of inflammatory mediators, angiogenic growth factors, and angiogenic activities in the absence or presence of Korean red ginseng extracts (KRGE) were evaluated in HUVECs stimulated with the $H_2S$ generator sodium hydrogen sulfide (NaHS). KRGE efficiently decreased the expression of cystathionine ${\beta}$-synthase and cystathionine ${\gamma}$-lyase, enzymes that are essential for $H_2S$ synthesis. Concomitantly, a significant decrease in the expression of inflammatory mediators, including cyclooxygenase-2 and inducible nitric oxide synthase, and several angiogenic factors, including interleukin (IL)-8, hypoxia inducible factor-1a, vascular endothelial growth factor, IL-6, and matrix metalloproteinases, was observed; all of these factors are normally induced after NaHS. An in vitro angiogenesis assay demonstrated that NaHS significantly increased tube formation in endothelial cells, whereas KRGE pretreatment significantly attenuated tube formation. NaHS activated p38 and Akt, increasing the expression of angiogenic factors and the proliferation of HUVECs, whereas KRGE effectively abrogated this $H_2S$-activated angiogenesis and the increase in inflammatory mediators in vascular endothelial cells. In conclusion, KRGE was able to mitigate $H_2S$-induced angiogenesis, implying that antagonistic action against $H_2S$-induced angiogenesis may be the mechanism underlying the gastric cancer preventive effects of KRGE in H. pylori infection.

• 대한암한의학회지
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• 제13권1호
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• pp.13-24
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• 2008

Objective: To evaluate the effects of Bikihaun (BKH) on angiogenesis. Method: We examined the anti-angiogenic effect of BKH in invasion assay model. We performed proliferation assay, migration assay, tube formation assay and Chicken Chorioallantoic Membrane (CAM) assay. Results: In proliferation assay, at lower dose under 125 ${\mu}g/m{\ell}$ anti-angiogenesis effect of the group treated BKH made no difference with the control group. But, at the dose of 250 ${\mu}g/m{\ell}$ or more anti-angiogenesis effect of the group treated BKH showed more effective as compared to the control group. In migration assay, BKH did not affect migration of vascular endothelial cell. In tube formation assay, at lower dose under 100 ${\mu}g/m{\ell}$ showed mild effect of anti-tube formation. But, at the dose of 1000 ${\mu}g/m{\ell}$ showed more effective anti-tube formation. In CAM assay, BKH showed anti-angiogenesis effect at the dose of 10 ${\mu}g/m{\ell}$. Conclusion: BKH has antiangiogenetic properties in vitro.

• Tuberculosis and Respiratory Diseases
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• 제43권6호
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• pp.894-902
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• 1996

연구배경: Tumor angiogenesis란 종양 내에서 및 종양을 향한 새로운 혈관 증식을 말하는 것으로 암의 중식과 전이의 원인이 되며, 주로 유방암과 전립선암에서 암세포 조직 내에서의 angiogenesls와 전이의 상관관계가 보고되었으며, angiogenesls의 정도가 암의 독립적인 중요한 예후인자로 보고되었다. 본 연구는 폐암 조직에서 anglogenesls의 정도를 측정하여 예후인자로서의 가치를 평가하고자하였다. 방법: 1990년 1월 부터 1994년 12월 까지 이화여대 부속 동대문병원에서 원발성 폐암으로 진단받고 치료성적 및 생존여부를 알고 있는 비소세포폐암(non-small cell lung cancer) 환자의 기관지내시경 조직의 paraffin embedded block을 이용하여 CD31에 대한 antibody인 JC70을 사용하여 면역세포화학적 방법으로 endothelial cell을 염색하였다. 결과: 1) 전체 29예에서 microvessel의 수는 $32.7{\pm}20.8$(9-96)개 였다. 2) Microvessel의 수와 폐암의 조직학적 유형, T staging 간에는 유의한 상관관계가 없었으며, 임파선 전이 (N staging) 및 혈성 전이 (M staging) 와도 관계가 없었다(p>0.05). 3) 대상환자의 평균 추적기간은 15개월(2-46)로 microvessel의 수가 20개 이상인 군(20예)과 이하인(9예) 군으로 나누어 보았을때 1년 생존률 각각 50%, 46%, 2년 생존율 각각 30%, 0%로 유의한 차이가 없었다(p>0.05). 결론: Tumor angiogenesis는 임파선 및 원발 전이의 가능성을 시사하는 중요한 예후 예측인자일 것으로 생각되나 폐암의 기관지내시경 조직검사 조직을 이용하여서 angiogenesis의 정도를 측정하는 것은 조직이 적절하지 못하고 측정이 제한적이었으며, 아직까지는 우리나라에서 폐암에서의 angtogenesls에 관한 연구가 없는 상태로 수술조직을 이용한 더 많은 연구가 필요할 것으로 생각된다.

• 한국한의학연구원논문집
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• 제4권1호통권4호
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• pp.129-138
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• 1998

Angiogenesis, the formation of new blood vessels, is considered to be involved in many pathological symptoms such as diabetic retinopathy, arthritis, inflammation and solid tumour. In particular, it is thought that angiogenesis is critical for development and growth of solid tumour. Recent study shows that there is a highly significant association of microvessel density with overall survival and relapse-free survival in patients with breast tumour In this study, the inhibition effect of angiogenesis of traditional herbs used for the treatment of cancer was examined. It was found out that the extract of Agaricus blazei by boiling water is a possible inhibitor of angiogenesis. It inhibited normal developmental angiogenesis In the chorioallantoic membrane of chick embryos and also inhibited capillary-like tube formation by endotherial cells on matrigel in vitro. These results suggest that Agaricus blazei can be a potent angiogenesis inhibitor.

• Asian Pacific Journal of Cancer Prevention
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• 제16권15호
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• pp.6639-6643
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• 2015

Background: Prostate cancer is a major concern of public health. Microvascular density (MVD) is one of the prognostic markers for various solid cancers. Matrix metalloproteinase 11 (MMP11) plays an important role in angiogenesis and changes in its expression level are known to be associated with tumor progression and clinical outcome. Aim: To investigate the relationship between MVD and MMP11 expression in prostatic adenocarcinoma tissues. Materials and Methods: The expression levels of MMP11 and MVD were analyzed immunohistochemically for 50 specimens of prostatic adenocarcinoma. Results: MMP11 was mainly expressed in stromal cells but rarely seen in epithelial cells. Mean MVD was $36/mm^2$, and it was correlated significantly only with bone metastases. MVD was also significantly correlated with MMP11 expression (r=0.29, p=0.044). Conclusions: MMP11 may alter the stromal microenvironment of prostate cancer to stimulate tumor angiogenesis.

• Asian Pacific Journal of Cancer Prevention
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• 제14권12호
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• pp.7651-7656
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• 2013

Background: Breast cancer is the most common malignancy among women in both developed and developing countries. The burden is increasing in low-income and middle-income countries (LMCs) and threatens the public health of such societies. Introduction of expensive monoclonal antibodies to cancer treatment regimens poses a real challenge in the health systems of LMCs. Despite controversy of cost-effectiveness of bevacizumab in breast cancer, some studies indicate gain of patients from this drug. The present study aimed to propose a priority setting model for administration of anti-angiogenic agents in breast cancer via assessment of tumor angiogenesis by the microvessel density (MVD) method and associations with clinicopathological characteristics (including simultaneous mutations of TP53 and HER-2 genes). Materials and Methods: Age, axillary lymph nodes status, tumor size, stage and grade, estrogen and progesterone receptors status, HER-2/neu status (by immunohistochemistry and FISH test), TP53 mutation, Ki-67 (for proliferation assay) and CD34 (for angiogenesis assay) were assessed in 111 breast cancer patients. The molecular subtype of each tumor was also determined and correlations of simultaneous mutations of HER-2 and p53 genes with angiogenesis and other clinicopathological characteristics were evaluated. Results: There were significant associations between simultaneous mutations of HER-2 and p53 genes and all other parameters except tumor size. The degree of angiogenesis in the ERBB2 subtype was greater than the others. Younger patients showed a higher angiogenesis rate rather those older than 50 years. Conclusions: Our results demonstrated that patients with simultaneous mutations of HER-2 and p53 genes, those with ERBB2 molecular subtype and also younger women (often triple negative) seem more eligible for obtaining anti-angiogenic agents. These results suggest a model for priority setting of patients with breast cancer for treatment with anti-angiogenic drugs in LMCs.

• 생명과학회지
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• 제24권5호
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• pp.588-593
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• 2014

본 논문은 RLIP76 단백질이 암, 종양 혈관 신생 및 그 치료에 미치는 중요성을 보고함에 있다. 암의 연구에 있어서, 종양의 혈관 신생을 억제시키는 인자와 영향을 끼치는 인자를 밝혀내는 것은 암의 억제와 치료를 위한 분자 생물학적 기전에 중대한 영향을 미친다. 최근 연구에서, RLIP76 단백질이 혈관 신생에 영향을 끼치는 역할을 발견하였다. RLIP76 제거 마우스의 종양은 일반 종양과 비교하여 혈관의 크기가 작으며, 가늘고, 그 혈관의 수가 적고 길이가 짧은 것으로 보고되고 있다. 게다가, Matrigel plugs을 이용한 혈관 신생 실험에서, RLIP76이 제거된 마우스에서는 혈관 생성이 억제 되었으나, 일반 마우스에서는 혈관이 생성되었다. 또한, 혈관세포를 이용한 in vitro 실험에 있어서, proliferation, migration 및 cord formation 모두가 RLIP76에 의해서 조절되었다. 일반적으로 RLIP76은 대부분의 인간 조직과 종양에서 발현되며, 약의 저항 기전 연구에 이용되고 있기도 한다. 또한, 이RLIP76은 small GTPase R-Ras와 상호작용을 통하여 세포 spreading 및 migration에 관여하고 있다. 이러한 결과는 RLIP76와 암 연구의 중요성을 보고하고 있으며, 혈관 세포의 기능의 기전 및 종양의 혈관 신생을 위한 RLIP76 단백질의 중요성을 알리고 있고, RLIP76의 추가적인 연구를 통하여 종양의 혈관 신생의 기전을 밝히는 것이 필요함을 제안하는 바이다.

• Biomolecules & Therapeutics
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• 제17권4호
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• pp.422-429
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• 2009

Invasion and metastasis is the main cause of cancer mortality. Angiogenesis is a prerequisite for the tumor growth and metastasis. Matrix metalloproteinases (MMPs) are the key enzymes playing in the invasive growth and metastasis of cancer as well as angiogenesis. Xanthohumol, a prenylated chalcone of the Hop plant (Humulus lupulus L), has been reported to suppress cancer invasion and angiogenesis. In the present study, we investigated the antiinvasive effects of xanthohumol (1) and its synthetic derivatives, 4'-O-methylxanthohumol SEM ether (2), xanthohumol C (3), and xanthohumol C MOM ether (4) in relation to MMP expression in HT-1080 human fibrosarcoma cells. The compound 1 and its derivative, 3 and 4, significantly inhibited serum-induced HT-1080 cell invasion, and 12-O-tetradecanoylphorbol-13-acetate (TPA)-enhanced activity and expression level of MMP-2 and MMP-9 in a concentration-dependant manner. In addition, they inhibited TPA-enhanced expression of MT1-MMP with relatively weak inhibition in tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 level. The compound 1 significantly decreased the cell viability, whereas the derivatives, 2 and 3 showed no cytotoxicity, and compound 4 showed slight cytotoxicity in the cells. Furthermore, in a chick chorioallantoic membrane (CAM) assay, the derivatives 3 and 4 dose-dependently suppressed vascular endothelial growth factor (VEGF)-induced angiogenesis, which is similar to that of compound 1. Taken together, the results indicate that compounds 3 and 4 may be valuable anti-angiogenic agents in the treatment of chronic diseases such as cancer and inflammation working through suppression of MMP-2 and MMP-9.

• 한국가시화정보학회지
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• 제18권3호
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• pp.84-89
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• 2020

Cancer cells secrete angiogenic factors, and nearby vasculatures make new blood vessels essential for cancer development and metastasis in response to these soluble factors. Many efforts have been made to elucidate cancer-endothelial cell interactions in vitro. However, not much is known due to the lack of a suitable co-culture platform. Here, we introduce a 3D printing-based microfluidic system that mimics the in vivo-like cancer-endothelial cell interactions. The tumoroids and endothelial cells are co-cultured, physically separated by porous fibrin gel, allowing communication between two cell types through soluble factors. Using this microfluidic system, we were able to visualize new vessel formation induced by tumoroids of different origins, including liver, breast, and ovary. We confirmed that the ovarian tumoroids most induced angiogenesis while the other two cancer types suppressed it. Utilization of the proposed co-culture platform will help the researchers unveil the underlying mechanisms of the dynamic interplay between tumor and angiogenesis.