• Biomolecules & Therapeutics
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• v.27 no.5
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• pp.474-483
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• 2019

Vascular endothelial growth factor (VEGF) plays a pivotal role in pathologic ocular neovascularization and vascular leakage via activation of VEGF receptor 2 (VEGFR2). This study was undertaken to evaluate the therapeutic mechanisms and effects of the tetrapeptide Arg-Leu-Tyr-Glu (RLYE), a VEGFR2 inhibitor, in the development of vascular permeability and choroidal neovascularization (CNV). In cultured human retinal microvascular endothelial cells (HRMECs), treatment with RLYE blocked VEGF-A-induced phosphorylation of VEGFR2, Akt, ERK, and endothelial nitric oxide synthase (eNOS), leading to suppression of VEGF-A-mediated hyper-production of NO. Treatment with RLYE also inhibited VEGF-A-stimulated angiogenic processes (migration, proliferation, and tube formation) and the hyperpermeability of HRMECs, in addition to attenuating VEGF-A-induced angiogenesis and vascular permeability in mice. The anti-vascular permeability activity of RLYE was correlated with enhanced stability and positioning of the junction proteins VE-cadherin, ${\beta}$-catenin, claudin-5, and ZO-1, critical components of the cortical actin ring structure and retinal endothelial barrier, at the boundary between HRMECs stimulated with VEGF-A. Furthermore, intravitreally injected RLYE bound to retinal microvascular endothelium and inhibited laser-induced CNV in mice. These findings suggest that RLYE has potential as a therapeutic drug for the treatment of CNV by preventing VEGFR2-mediated vascular leakage and angiogenesis.

• Archives of Plastic Surgery
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• v.43 no.6
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• pp.491-497
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• 2016

Background Hypertrophic scarring is a pathological condition that occurs after trauma or surgery. Angiogenesis occurs more often with hypertrophic scarring than with normotrophic scarring. The regulation of angiogenesis is one of the key factors in hypertrophic scar management. Vascular endothelial growth factor (VEGF) is an essential factor in the angiogenetic response. This study investigated whether decreasing the level of VEGF is effective for treating hypertrophic scarring. Methods Ten 8-week-old female New Zealand white rabbits were included. Four defects were created on each ear by using a 6-mm punch. Bevacizumab (Avastin, Roche Pharma, Basel, Switzerland) was administered in one ear and normal saline was administered in the other ear. Treatment was administered starting on day 2, every 2 days, until day 14. The levels of VEGF were measured using enzyme-linked immunosorbent assay on day 10 and histologic results were analyzed on day 40. Results Bevacizumab induced-defects showed less hypertrophic scarring when compared with the control group as measured by the scar elevation index (SEI) and loose collagen arrangement. The SEI in the experimental group was $1.89{\pm}0.13$, compared to $1.99{\pm}0.13$ in the control group (n=30, P=0.005). Additionally, the VEGF level was lower ($38.72{\pm}11.03pg$ vs. $82.50{\pm}21.64pg$, n=10, P=0.001) and fewer vessels existed ($8.58{\pm}0.76$ vs. $7.2{\pm}1.20$, n=10, P=0.007). Conclusions Preventing excessive angiogenesis is effective for preventing scar formation, especially with hypertrophic scarring. Although it is not an approach that is sufficient alone for the management of scarring, it may be one of several important strategies for scar treatment.

• Journal of Chest Surgery
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• v.39 no.11 s.268
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• pp.828-837
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• 2006

Background: Tissue hypoxia is characteristic of many human malignant neoplasm, and hypoxia inducible factor-1(HIF-1) plays a pivotal role in essential adaptive response to hypoxia, and activates a signal pathway for the expression of the hypoxia-regulated genes, resulting in increasing $O_2$ delivery or facilitating metabolic adaptation to hypoxia. Increased level of HIF-$1{\alpha}$ has been reported in many human malignancies, but in non-small cell lung carcinoma the influence of HIF-$1{\alpha}$ on tumor biology, including neovascularization, is not still defined. In present study the relationship of HIF-$1{\alpha}$ expression on angiogenetic factors, relationship between the tumor proliferation and HIF-$1{\alpha}$ expression, interaction of HIF-$1{\alpha}$ expression and p53, and relationship between HIF-$1{\alpha}$ expression and clinico-pathological prognostic parameters were investigated. Material and Method: Archival tissue blocks recruited in this study were retrieved from fifty-nine patients with primary non-small cell lung carcinoma, who underwent pneumonectomy or lobectomy from 1997 to 1999. HIF-$1{\alpha}$, VEGF(vascular endothelial growth factor), and p53 protein expression and Ki-67 labeling index in tumor tissues were evaluated, using a standard avidin-biotin-peroxidase complex(ABC) immunohistochemistry. Relationship between the HIF-$1{\alpha}$ expression and VEGF, p53 overexpression and correlation between the HIF-$1{\alpha}$ expresseion and Ki-67 index were analyzed. Clinico-pathologic prognostic parameters were also analyzed. Result: HIF-$1{\alpha}$ expression in cancer cells was found in 24 of 59 cases of non-small cell lung carcinoma(40.7%). High HIF-$1{\alpha}$ expression was significantly associated with several pathological parameters, such as pathological TMN stage(p=0.004), pT stage(p=0.020), pN stage (p=0.029), and lymphovascular invasion(p=0.019). High HIF-$1{\alpha}$ expression was also significantly associated with VEGF immunoreactivity(p<0.001), and aberrant p53 expression(p=0.040). but was marginally associated with Ki-67 labeling index(p=0.092). The overall 5-year survival rate was 42.3%. The survival curve of patients with a high HIF-$1{\alpha}$ expression was worse than that of patients with low-expression(p=0.002). High HIF-$1{\alpha}$ expression was independent unfavorable factors with a marginal significance in multivariate analysis performed by Cox regression. Conclusion: It is suggested that high HIF-$1{\alpha}$ expression may be associated with intratumoral neovascularization possibly through HIF-VEGF pathway, and high HIF-$1{\alpha}$ expression could be associated with lymph node metastasis and post operative poor prognosis in patients with non-small cell lung carcinoma.

• Tuberculosis and Respiratory Diseases
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• v.43 no.6
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• pp.894-902
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• 1996

Background : Tumor angiogenesis is the growth of new vessels toward and within tumor. It has been demonstrated that the growth of tumor beyond a certain size requires angiogenesis and it is closely involved in tumor progression and metastasis. The finding that intensity of neovascularization correlates independently with metastasis may lead to identification of patients in whom radical surgery should be supplemented by systemic treatment. Method : We have collected paraffin blocks of bronchoscopic biopsy of patients with non-small cell lung cancer. We highlighted the vessel by staining endothelial cell with JC70 monoclonal antibody(to CD31) immunohistochemically and counted microvessels under 200 X field using light microscopy. Results : 1) The mean microvessel count was $32.7{\pm}20.8$ (9-96) in total 29 cases. 2) There were no correlations between microvessel counts and pathologic cell type, T staging, node melastasis(N) and hematogenous metastasis(M) (p>0.05). 3) The median follow-up duration was 15 months(2-46) and there was no correlation between the microvessel counts and survival rate of lung cancer patients (p>0.05). Conclusion : Tumor angiogenesis seems to be an important prognostic factor suggesting the probability of metastasis. But the microvessel count in the bronchoscopic biopsy specimen was inadequate and very limited. There has been no data about angiogenesis of lung cancer in korea yet So the study of tumor angiogenesis using resected lung tumor specimen would be demanded.

• Journal of the Korea Academia-Industrial cooperation Society
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• v.11 no.3
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• pp.1133-1138
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• 2010

The purpose of our study was to evaluate the correlation between expression of VEGF, HIF-$1{\alpha}$, E-cadherin, and p53 and pathologic stage. We retrospectively reviewed the medical records of the 101 patients who underwent surgery of thyroid nodules from 2000 to 2007. Expression of VEGF, HIF-$1{\alpha}$, E-cadherin, and p53 were examinated immunohistochemically. Papillary thyroid carcinoma in this study included 54 cases of more than 45 years old. Each expression of VEGF, HIF-$1{\alpha}$, E-cadherin, and p53 was analysed. Only expression loss of E-cadherin was associated with the stage. High HIF-1 expression was significantly associated with VEGF immunoreactivity (p<0.05). Expression loss of E-cadherin was independent unfavorable factors. It is suggested that high HIF-$1{\alpha}$ expression may be associated with intratumoral neovascularization possibly through HIF-VEGF pathway.

• Journal of Chest Surgery
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• v.36 no.10
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• pp.711-720
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• 2003

Bakground : Complete resection by the surgery has been selected as the treatment of choice in lung cancer patients, but in cases of recurrence after excision or inoperable cases, the importance of anticancer chemotherapy has been emphasized. If one can select a set of the sensitive chemotherapeutic agents before anticancer chemotherapy, it will give more favourable results. Subrenal capsular assay has been recognized as a useful in-vivo chemosensitivity test of thoracic and abdominal tumors and it can be done in a short time for a rapid interpretation of tumor responsiveness to anticancer chemotherapeutic drugs. It has been reported that various kinds of cancer cells can be implantable to the kidney, but so far there is no comparative study of xenogeneic cell implantation on liver, spleen and kidney. The author implanted the human lung cancer cells under the capsule of S.D rat's liver, spleen and kidney respectively and compared the pattern of growth and histology. Material and Method: After incubation of human lung cancer cell line (SW-900 G IV) in RPMI 1640 (Leibovitz L-15 medium) culture media, 3${\times}$3${\times}$3 mm size fibrin clots which contain 108 cancer cells were made. Thereafter the fibrin clots were implanted at subcapsule area of liver, spleen and kidney of S.D. female rat. For immune suppression, cyclosporin-A (80 mg/Kg) was injected subcutaneously daily from post-implantation first day to sixth day. The body weight was measured at pre and post implantation periods. The growth pattern and the size of tumor mass were observed and the pathologic examination and serum tumor marker tests were performed. Result: Body weight increased in both of control and experimental groups. Serum Cyfra 21-1 was not detected. Serum levels of CEA and NSE revealed no significant change. The SCC-Ag increased significantly in implanted group. The growth rate of human lung cancer cells which was implanted on spleen was higher than on liver or kidney. The surface area, thickness, and volume of tumor mass were predominant at spleen. The success rates of implantation were 80% on kidney, 76.7% on spleen and 43.3% on liver. Pathologic examination of implanted tumors showed characteristic findings according to different organs. Tumors that were implanted on kidney grew in a round shape, small and regular pattern. In the spleen, tumors grew well and microscopic neovascularization and tumor thrombi were also found, but the growth pattern was irregular representing frequent daughter mass. Human lung cancer cells that were implanted in the liver, invaded to the liver parenchyme, and had low success rate of implantation. Microscopically, coagulation necrosis and myxoid fibrous lesion were observed. Conclusion: The success rate of implantation was highest in the kidney. And the mass revealed regular growth that could be measured easily. The SCC-Ag was presented earlier than CEA or Cyfra21-1. The Cyfra21-1 was not detected at early time after implantation. The best model for tumor implantation experiment for chemosensitivity test was subrenal capsular analysis than liver and spleen and the useful serum tumor marker in early period of implantation was the SCC-Ag.