대퇴골두 무혈성 괴사에서 알코올이 골아세포의 VEGF-A, PEDF, VEGFR-2의 발현에 미치는 영향

이우석(Woo-Suk Lee),정환용(Whan-Young Chung),김우식(Woo-Sik Kim),전택수(Taek-Soo Jeon),김상범(Sang-Bum Kim),김성훈(Sung-Hun Kim),김선홍(Sun-Hong Kim),임지혁(Ji-Hyuk Lim),한창동(Chang-Dong Han) 대한정형외과학회 2006 대한정형외과학회지 Vol.41 No.1

목적: 배양된 골아세포에 알코올을 투여하여 vascular endothelial growth factor A (VEGF-A), pigmented epithelium-derived factor (PEDF), vascular endothelial growth factor receptor 2 (VEGFR-2)의 발현에 미치는 영향을 분석하고자 하였다. 대상 및 방법: 대퇴골두 무혈성 괴사와 골절부의 대퇴골 전자간부에서 분리 배양한 골아세포에 알코올을 투여하고, 알코올 농도와 배양시기에 따른 세포 증식률, VEGF-A mRNA, PEDF mRNA, VEGFR-2 mRNA 발현을 측정하였다. 결과: 알코올을 투여한 골아세포는 조기에 세포수가 증가하였고, 이후에는 감소하거나 변화가 없었다(p<0.005). 골괴사군 중 고농도의 알코올(l00, 150 mM)을 투여한 군에서는 VEGF-A/PEDF 비는 감소하였고, 대조군에서는 VEGF-A/PEDF 비가 증가하였다(p<0.05). 결론: 골아세포 배양에서 알코올은 골아세포의 증식을 억제하고, VEGF-A/PEDF 비의 불균형을 유발하여, 골괴사 조직에서 신생혈관 형성을 억제할 것으로 생각되었다. Purpose: The aim of this study was to determine the effect of alcohol on the expression of VEGF-A, PEDF, and VEGFR-2 in human osteoblasts. Materials and Methods: Human osteoblasts primarily derived from the intertrochanteric region of the femur with osteonecrosis and fracture (control) were cultured with alcohol (0, 20, 100, 150 mM). The level of cell proliferation and the expression levels of VEGF-A mRNA, PEDF mRNA, and VEGFR-2 mRNA was evaluated according to the alcohol concentrations and the culture periods. Results: Osteoblasts with the added alcohol showed an early increase in cell population, and a subsequent decrease or steady level thereafter compared with those without alcohol (p < 0.05). The osteoblasts in the osteonecrosis group showed an increase in VEGF-A mRNA and PEDF mRNA expression at high alcohol concentrations (100, 150 mM), resulting in an decreased VEGF-A/PEDF ratio, while those in the control group showed an increase in VEGF-A mRNA expression and a decrease in PEDF mRNA expression, resulting in an increase in the VEGF-A/PEDF ratio (p<0.05). Conclusion: Alcohol stops the proliferation of osteoblasts and can cause an imbalance between VEGF-A and PEDF, thereby inhibiting the neovascularization of osteonecrosis.

No Association of Vascular Endothelial Growth Factor-A (VEGF-A) and VEGF-C Expression with Survival in Patients with Gastric Cancer

이수정,김종광,손상균,배한익,정호영,유완식,채의수,문준호,김시내 대한암학회 2009 Cancer Research and Treatment Vol.41 No.4

Purpose Although the vascular endothelial growth factor (VEGF) superfamily has been identified to critically influence tumor-related angiogenesis, the prognostic significance of a VEGF expression in gastric cancer is still controversial. Accordingly, the present study analyzed the VEGF-A and VEGF-C expressions and their impact on the prognosis of patients with gastric cancer. Materials and Methods Three hundred seventy-five consecutive patients who underwent surgical resection for gastric adenocarcinoma with a curative intent were enrolled in the present study. Immunohistochemical staining for VEGF-A and VEGF-C was performed using the formalin fixed, paraffin embedded tumor tissues. Results Positive VEGF-A and VEGF-C expressions were observed in 337 (90.1%) and 278 (74.9%) cases, respectively. The survival analysis showed that the expression of VEGF-A and VEGF-C had no effect on the OS and DFS. On the multivariate analysis that included age, gender and the TNM stage, no significant association between the grade of the VEGF-A or VEGF-C expression and survival was observed. Conclusion The current study suggests that the tissue expression of VEGF-A or VEGF-C alone is not an independent prognostic marker for patients with surgically resected gastric adenocarcinoma.

직장 결장암의 간전이 환자에서 VEGF-A, C, D 발현의 비교연구

전광식(Kwang-Sik Chun),이경하(Kyung-Ha Lee),송인상(In-Sang Song),김지연(Ji-Yeon Kim),김제룡(Je-Ryong Kim),안문상(Moon-Sang Ahn),이상일(Sang-Il Lee),박종현(Jong-Hyun Park),최송이(Song-E Choi),강대영(Dae-Young Kang),송규상(Kyu-Sang Son 대한외과학회 2009 Annals of Surgical Treatment and Research(ASRT) Vol.76 No.5

Purpose: We aimed to investigate the correlations between expressions of angiogenic cytokines VEGF-A, C, D of primary colorectal cancer and liver metastasis. Methods: We examined paraffin-embedded primary colorectal cancer tissue from 45 patients who had liver resection due to colorectal liver metastasis (metastasis group) and 37 patients who had surgical resection due to colorectal cancer only (control group). In the control group, local recurrence and distant metastasis had not occurred. Immunohistochemical staining for VEGF-A, C and D was performed. We analysed the correlations between expression of VEGF-A, C and D in primary colorectal cancer tissues and clinicopathologic parameters. Results: VEGF-A expressions of primary colorectal carcinoma were not different between the two groups. VEGF-C was more frequently expressed in the metastasis group (P=0.008) but VEGF-D was more expressed in the control group (P=0.003). Patients with VEGF-C negative and VEGF-D positive expression were predominant in the control group (P=0.020). Tumor location, T stage, lymph node metastasis and tumor differentiation were not related with the expressions of VEGF-A, C, D but only preoperative CEA was positively correlated with VEGF-A and C expression. Conclusion: Expressions of VEGF-C in primary tumor were more frequent in metastatic colorectal cancer and expressions of VEGF-D were more frequent in nonmetastatic colorectal cancer. More large-scale prospective studies for VEGF-C and D expression in colorectal cancer are necessary.

Serum Vascular Endothelial Growth Factor-A (VEGF-A) as a Biomarker in Squamous Cell Carcinoma of Head and Neck Patients Undergoing Chemoradiotherapy

Srivastava, Vikas Kumar,Gara, Rishi Kumar,Rastogi, Namrata,Mishra, Durga Prasad,Ahmed, Mohd Kaleem,Gupta, Shalini,Goel, Madhu Mati,Bhatt, Madan Lal Brahma Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.7

Background: To evaluate serum VEGF-A levels in squamous cell carcinoma of head and neck (SCCHN) patients and relationships with response to therapy. Materials and Methods: Serum VEGF-A levels in patients (n=72) treated with radiotherapy (RT) or radio-chemotherapy (RCT) and controls (n=40) were measured by ELISA. Results: Serum VEGF-A levels of the SCCHN cases were significantly higher (p=0.001) than in healthy controls, and in patients with positive as compared to negative lymph node status (p=0.004). Similarly, patients with advanced stage (Stage III-IV) disease had more greatly elevated levels of serum VEGF-A level than their early stage (Stage I-II) counterparts (p=0.001). In contrast, there was no significant difference (p=0.57) in serum level of VEGF-A in patients with advanced T-stage (T3-4) as compared to early stage (T1-2). Similarly, patients with distant metastasis had no significant (p=0.067) elevation in serum VEGF-A level as compared to non-metastatic disease. However, the non-responder patients had significantly higher serum VEGF-A level as compared to responders (p=0.001). Conclusions: Our results suggest that the serum VEGF-A level may be a useful biomarker for the prediction of response to therapy in SCCHN.

miR-29a suppresses growth and invasion of gastric cancer cells in vitro by targeting VEGF-A

( Ling Chen ),( Hong Xiao ),( Zong Hua Wang ),( Yi Huang ),( Zi Peng Liu ),( Hui Ren ),( Hang Song ) 생화학분자생물학회 2014 BMB Reports Vol.47 No.1

Increasing data shows miR-29a is a key regulator of oncogenic processes. It is significantly down-regulated in some kind of human tumors and possibly functionally linked to cellular proliferation, survival and migration. However, the mechanism remains unclear. In this study, we report miR-29a is significantly under-expressed in gastric cancer compared to the healthy donor. The microvessel density is negatively related to miR-29a expression in gastric cancer tissues. The ectopic expression of miR-29a significantly inhibits proliferation and invasion of gastric cancer cells. Furthermore, western blot combined with the luciferase reporter assays demonstrate that vascular endothelial growth factor A (VEGF-A) is direct target of miR-29a. This is the first time miR-29a was found to suppress the tumor microvessel density in gastric cancer by targeting VEGF-A. Taken together, these results suggest that miR-29a is a tumor suppressor in gastric cancer. Restoration of miR-29a in gastric cancer may be a promising therapeutic approach. [BMB Reports 2014; 47(1): 39-44]

위암의 내시경하 생검 조직에서 CD105 (Endoglin), D2- 40, Vasc ular Endothelial Growth Fac tor- A와 D의 발현을 통한 침습성의 예측

김성수(Sungsoo Kim),이태진(Tae Jin Lee),김범규(Beom Kyu Kim),차성재(Sung Jae Cha),박성준(Sung Jun Park),장인택(In Taek Chang),박성일(Sung Il Park) 대한외과학회 2007 Annals of Surgical Treatment and Research(ASRT) Vol.72 No.5

Purpose: CD105 (endoglin) has been shown to be a more useful marker to identify the proliferating endothelium involved in tumor angiogenesis than are the panendothelial markers. The monoclonal antibody D2-40 is a specific lymphatic endothelial marker. Methods: We investigated CD105, lymphatic vessel marker (D2-40), vascular endothelial growth factor (VEGD)-A and the VEGF-D expressions as possible prognostic markers in the endoscopic biopsy tissue of stomach cancer patients. The pre-operative endoscopic biopsies and surgical biopsies from 73 patients were immunostained for CD105, D2-40, VEGF-A and VEGF-D. Positively stained microvessels were counted in densely vascular foci (hot spots) at a ×200 field in each specimen. Results: The microvessel density (MVD) and lymphatic vessel density (LVD), according to the CD105 and D2-40 expressions of the endoscopic biopsies, showed a statistically significant correlation with the surgical biopsies. The MVD via CD105 a showed statistically significant correlation with the histologic differentiation, T-stage, nodal metastasis and stage in the endoscopic biopsies and surgical biopsies, respectively. The lympathic vessel density (LVD) via D2-40 showed a statistically significant correlation with T-stage, nodal metastasis and stage in the endoscopic biopsies. The expressions of VEGF-A and VEGF-D showed a statistically significant correlation with the MVD and LVD. Conclusion: The MVD, as determined by the CD105 expression and the LVD as determined by the D2-40 expression may be useful markers for predicting the invasiveness with using a pre-operative endoscopic biopsy of stomach cancer.

Effects of Differential Distribution of Microvessel Density, Possibly Regulated by miR-374a, on Breast Cancer Prognosis

Li, Jian-Yi,Zhang, Yang,Zhang, Wen-Hai,Jia, Shi,Kang, Ye,Tian, Rui Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.3

Background: The discovery that microRNAs (miRNAs) regulate proliferation, invasion and metastasis provides a principal molecular basis of tumor heterogeneity. Microvessel distribution is an important characteristic of solid tumors, with significant hypoxia occurring in the center of tumors with low blood flow. The distribution of miR-374a in breast tumors was examined as a factor likely to be important in breast cancer progression. Methods: Breast tissue samples from 40 patients with breast cancer were classified into two groups: a highly invasive and metastatic group (HIMG) and a low-invasive and metastatic Group (LIMG). Samples were collected from the center and edge of each tumor. In each group, six specimens were examined by microRNA array, and the remaining 14 specimens were used for real-time RT-qPCR, Western blot and immunohistochemical analyses. Correlation analysis was performed for the miRNAs and target proteins. Follow-up was carried out during 28 months to 68 months after surgery, and survival data were analyzed. Results: In the LIMG, the relative content of miR-374a was lower in the center of the tumor than at its edge; in the HIMG, it was lower at the edge of the tumor, and miR-374a levels were lower in breast cancer tissues than in normal tissues. There was no difference between VEGF-A and VCAM-1 mRNA levels at the edge and center of the tumor; however, we observed a significant difference between VEGF-A and VCAM-1 protein expression levels in these two regions. There was a negative correlation between miR-374a and target protein levels. The microvessel density (MVD) was lower in the center of the tumor than at its edge in HIMG, but the LIMG vessels were uniformly distributed. There was a significant positive correlation between MVD and the number of lymph node metastases (Pearson correlation, r=0.912, P<0.01). The median follow-up time was 48.5 months. LIMG had higher rate of disease-free survival (100%, P=0.013) and longer median survival time (66 months) than HIMG, which had a lower rate of 75% and shorter median survival time (54 months). Conclusions: Our data demonstrated miR-374a to be differentially distributed in breast cancer; VEGF-A and VCAM-1 mRNA had coincident distribution, and the distribution of teh respective proteins was uneven and opposite to that for the miR-374a. These data might explain the differences in the distribution of MVD in breast cancer and variation in breast cancer prognosis.

무혈성 괴사에 이환된 대퇴골두 연골세포의 세포외 기질 mRNA 발현

정환용 ( Whan Young Chung ),이우석 ( Woo Suk Lee ),김상범 ( Sang Bum Kim ),배인탁 ( In Tak Bae ),박원기 ( Won Ki Park ) 대한고관절학회 2008 Hip and Pelvis Vol.20 No.4

목적: 대퇴골두 무혈성 괴사의 관절 연골세포에서 제2형 교원질, aggrecan, vascular endothelial growth factor A (VEGF-A), pigmented epithelium-derived factor (PEDF) mRNAs의 발현 정도를 분석하였다. 대상 및 방법: 대퇴골두 무혈성 괴사로 인공 고관절 전치환술을 시행한 환자의 대퇴골두 관절연골에서 분리 배양한 연골세포를 삼차원 배양하여 제 2형 교원질, aggrecan, VEGF-A mRNA, PEDF mRNA 발현을 실시간 중합효소 연쇄반응법(Real-time PCR)으로 측정하였다. 결과: 대퇴골두 무혈성 괴사군의 관절 연골세포에서 제2형 교원질과 aggrecan mRNA의 발현은 감소하였다(p<0.05). VEGF-A mRNA와 PEDF mRNA의 발현은 정상 연골에 비해 차이가 없었다(p>0.05). 결론: 무혈성 괴사에 이환된 대퇴골두 연골세포의 연골 기질 형성 능력이 떨어져 있었다. Purpose: The aim of this study was to evaluate the expression of type Ⅱ collagen, aggrecan, VEGF-A and PEDF mRNAs in the human chondrocytes derived from the articular cartilage of the femoral heads with avacular necrosis (AVN). Materials and Methods: We cultured human chondrocytes that were primarily derived from the articular cartilage of femoral heads with AVN. We evaluated the mRNA expression of type Ⅱ collagen, aggrecan, VEGF-A and PEDF. Results: The chondrocytes of the AVN group showed decreased expressions of type Ⅱ collagen mRNA and aggrecan mRNA (p<0.05). The expression of VEGF-A mRNA and PEDF mRNA in the AVN group was the same as that of the normal group (p>0.05). Conclusion: The cartilage matrix`s formation ability was found to be decreased in the chondrocytes of the femoral heads affected by AVN.

VEGF-A regulated by progesterone governs uterine angiogenesis and vascular remodelling during pregnancy

Kim, Minah,Park, Hyeung Ju,Seol, Jae Won,Jang, Jeon Yeob,Cho, Young-Suk,Kim, Kyu Rae,Choi, Youngsok,Lydon, John P,DeMayo, Francesco J,Shibuya, Masabumi,Ferrara, Napoleone,Sung, Hoon-Ki,Nagy, Andras,Al Blackwell Publishing Ltd 2013 EMBO molecular medicine Vol.5 No.9

<P>The features and regulation of uterine angiogenesis and vascular remodelling during pregnancy are poorly defined. Here we show that dynamic and variable decidual angiogenesis (sprouting, intussusception and networking), and active vigorous vascular remodelling such as enlargement and elongation of ‘vascular sinus folding’ (VSF) and mural cell drop-out occur distinctly in a spatiotemporal manner in the rapidly growing mouse uterus during early pregnancy — just after implantation but before placentation. Decidual angiogenesis is mainly regulated through VEGF-A secreted from the progesterone receptor (PR)-expressing decidual stromal cells which are largely distributed in the anti-mesometrial region (AMR). In comparison, P<SUB>4</SUB>-PR-regulated VEGF-A-VEGFR2 signalling, ligand-independent VEGFR3 signalling and uterine natural killer (uNK) cells positively and coordinately regulate enlargement and elongation of VSF. During the postpartum period, Tie2 signalling could be involved in vascular maturation at the endometrium in a ligand-independent manner, with marked reduction of VEGF-A, VEGFR2 and PR expressions. Overall, we show that two key vascular growth factor receptors — VEGFR2 and Tie2 — strikingly but differentially regulate decidual angiogenesis and vascular remodelling in rapidly growing and regressing uteri in an organotypic manner.</P>

Relationships between Lymph Node Metastasis and Expression of CD31, D2-40, and Vascular Endothelial Growth Factors A and C in Papillary Thyroid Cancer

이상혁,이성진,진성민,이노희,김동훈,채승완,손진희,김원석 대한이비인후과학회 2012 Clinical and Experimental Otorhinolaryngology Vol.5 No.3

Objectives. To investigate the relationships between lymph node metastasis (LNM) and expression of CD31, D2-40 and vascular endothelial growth factors (VEGF)-A and -C in patients with papillary thyroid cancer (PTC). Methods. Paraffin-embedded thyroid tissues of 72 patients were evaluated, which included 25 patients with thyroid nodular hyperplasia (TNH), 24 PTC patients without LNM, and 23 PTC patients with LNM. Three pathologists, who were blinded to the patient’s clinical information, assessed the immunohistochemical staining results. The amount of expression was scored as high (>25% of cells stained) or low (0-25%). Results. A higher level of VEGF-A expression was observed in the PTC groups regardless of LNM when compared to the group with TNH (91.3%, 79.2%, 4.0%, respectively). VEGF-C expression in the PTC with LNM group was significantly higher than the other two groups (P<0.05). No difference in microvessel density (MVD) scores was observed using CD31 among the three groups. The lymphatic vessel density (LVD) score using D2-40 was significantly higher in patients having PTC with LNM than the other groups (P<0.05). Conclusion. VEGF-C and D2-40 were more highly expressed in patients having PTC with LNM than in patients having PTC without LNM or in those having TNH. Analysis of VEGF-C level and LVD using D2-40 may be helpful in the diagnosis of PTC and the evaluation of LNM potential in patients with PTC.