Esophageal cancer is one of the common malignant tumors with high incidence and poor prognosis. Angiogenesis-related pathways play an important role in the occurrence and development of esophageal cancer. Vascular endothelial growth factor (VEGF) is the main mediator of angiogenesis. In addition to promoting angiogenesis and maintaining the survival of neovascularization, VEGF can also directly act on esophageal cancer cells and promote the occurrence and development of tumors. This article reviews the biology of VEGF and its effect on blood vessels, the expression of VEGF in esophageal cancer cells and its influencing factors, the role of VEGF in esophageal cancer cells, the immunomodulatory activity of VEGF and the clinical study of VEGF inhibitors. The purpose of this study is to provide a basis for more rational use of VEGF inhibitors in the treatment of esophageal cancer.
【Abstract】 Objective Sonic hedgehog (Shh) signaling pathway is involved in an important part of regulating angiogenesis. To investigate the effects of recombinant Shh N-terminant (rShh-N) on the expression and secretion of angiogenesis-related factor—vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Methods Bone marrow mesenchymal stem scells (BMSCs) were isolated from 3-day-old healthy Sprague Dawley rats and cultured to passage 3 in vitro. rShh-N at the concentrations of 0, 10, 100, and 200 ng/mL were applied to culture BMSCs in groups A, B, C, and D, respectively. At 12, 24, 48, and 72 hours of culture, the expressions of VEGF and bFGF mRNA and the levels of VEGF and bFGF in supernatant were measured with real-time quantitative PCR and ELISA, respectively. Results At the gene level, compared with group A, the expressions of VEGF and bFGF mRNA were enhanced in group D (P lt; 0.05) and the upregulation was more significant at 12 and 48 hours than 24 and 72 hours (P lt; 0.01). In group C, bFGF mRNA expression was substantially promoted at 12-72 hours (P lt; 0.05) and VEGF mRNA level was upregulated at 24-72 hours (P lt; 0.05), and both reached peak at 72 hours (P lt; 0.01). In group B, VEGF mRNA expression was inhibited at 12 hours (P lt; 0.05), but the level increased at 48 and 72 hours (P lt; 0.05); bFGF mRNA expression was obviously promoted at 12-48 hours (P lt; 0.05) and the maximum appeared at 48 hours (P lt; 0.01). At the protein level, the secretion of VEGF and bFGF in group D was significantly increased at 12-72 hours, as compared with group A (P lt; 0.05). In group C, VEGF and bFGF secretion was increased at 24-72 hours (P lt; 0.05). The secretion of VEGF in group B was inhibited at 12 and 48 hours (P lt; 0.05) and was promoted at 24 hours (P lt; 0.05); bFGF secretion was up-regulated at 24 and 48 hours (P lt; 0.05). The secretion of VEGF and bFGF in supernatant at 【Abstract】 Objective Sonic hedgehog (Shh) signaling pathway is involved in an important part of regulating angiogenesis. To investigate the effects of recombinant Shh N-terminant (rShh-N) on the expression and secretion of angiogenesis-related factor—vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Methods Bone marrow mesenchymal stem scells (BMSCs) were isolated from 3-day-old healthy Sprague Dawley rats and cultured to passage 3 in vitro. rShh-N at the concentrations of 0, 10, 100, and 200 ng/mL were applied to culture BMSCs in groups A, B, C, and D, respectively. At 12, 24, 48, and 72 hours of culture, the expressions of VEGF and bFGF mRNA and the levels of VEGF and bFGF in supernatant were measured with real-time quantitative PCR and ELISA, respectively. Results At the gene level, compared with group A, the expressions of VEGF and bFGF mRNA were enhanced in group D (P lt; 0.05) and the upregulation was more significant at 12 and 48 hours than 24 and 72 hours (P lt; 0.01). In group C, bFGF mRNA expression was substantially promoted at 12-72 hours (P lt; 0.05) and VEGF mRNA level was upregulated at 24-72 hours (P lt; 0.05), and both reached peak at 72 hours (P lt; 0.01). In group B, VEGF mRNA expression was inhibited at 12 hours (P lt; 0.05), but the level increased at 48 and 72 hours (P lt; 0.05); bFGF mRNA expression was obviously promoted at 12-48 hours (P lt; 0.05) and the maximum appeared at 48 hours (P lt; 0.01). At the protein level, the secretion of VEGF and bFGF in group D was significantly increased at 12-72 hours, as compared with group A (P lt; 0.05). In group C, VEGF and bFGF secretion was increased at 24-72 hours (P lt; 0.05). The secretion of VEGF in group B was inhibited at 12 and 48 hours (P lt; 0.05) and was promoted at 24 hours (P lt; 0.05); bFGF secretion was up-regulated at 24 and 48 hours (P lt; 0.05). The secretion of VEGF and bFGF in supernatant at
Objective To observe the effects of immunologic cytokines or anti-angiogenesis gene transfer mediated by electroporation for choroidal melanoma cells.Methods The human embryo kidney cells and malignant choroidal melanoma cells were transfected with plasmids pNGVL-mIL2, pNGVL-mIL12, pCI-sFLK-1, pCR3.1-antiVEGF121,pCI-ExTek. Then the expression of mIL2, mIL12, sFLK-1, VEGF and ExTek were detected by enzymelinked immunosorbentassay (ELISA) and Western blot. Nude mice models of malignant choroidal melanoma were established and they were divided into four groups randomly. Each group was treated with 30 mu;l of 0.9% NaCl, 30 mu;g pNGVL, 30 mu;g antiVEGF121+sFLK-1+ExTek and 30 mu;g mIL2+mIL12 respectively by electroporation. Seven，14, 21, 28, 35 and 42 days after treatment, the tumor volumes were measured to calculate the tumor inhibition rate. Results ELISA and Western blot showed that mIL2，mIL12，sFLK-1 and ExTek were expressed after electroporation，VEGF expression was decreased remarkably. After treatment，the tumors of mIL2+mIL12 group were greatly inhibited with a tumor inhibition rate of 97.33%，while the tumors of antiVEGF121+sFLK-1+ExTek and pNGVL group were partially inhibited with tumor inhibition rates of 53.33% and 36.33% respectively.Conclusions Immunologic cytokines transfer mediated by electroporation can inhibit the growth of melanoma，but anti-angiogenesis only have a mild effects.
Objective To observe the effects of stromal cellderived factor 1alpha; (SDF-1alpha;) in secondary neovascular glaucoma (NVG) of proliferative diabetic retinopathy (PDR). Methods The vitreous specimens from 25 PDR patients (31 eyes) were collected with 13 NVG eyes and non-NVG 18 eyes. The concentrations of SDF-1alpha; and vascular endothelial growth factor (VEGF) in those specimens were measured by enzyme-linked immunosorbent assay （ELISA）. Human umbilical vein endothelial cells (HUVEC) were treated by different concentrations of SDF-1alpha;and vascular endothelial growth factor (VEGF) in vitro, and the formation of tube cavity-like structure, length of capillarylike structures and 5prime;-bromo-2prime;-deoxyuridine (BrdU) labeling of treated HUVEC were measured. Results The length of HUVEC tube-like and capillarylike structure formation in 10, 100, 1000 ng/ml SDF-1alpha; and 10 ng/ml VEGF groups were longer than that in the control group, the differences were statistically significant (P＜0.01). The A value of BrdU labeling of 10, 100, 1000 ng/ml SDF-1alpha; and 10 ng/ml VEGF groups were increased than that in the control group, the differences were statistically significant (P＜0.01). The vitreous levels of SDF-1alpha; and VEGF of NVG specimens were higher than those in the non-NVG group, the differences were statistically significant (P＜0.01). Conclusions SDF-1alpha; may promote the migration and proliferation of vascular endothelium cells, and participate in the neovascularization process in NVG patients with PDR.
Vascular endothelial growth factor (VEGF) is a multifunctional factor that promotes blood vessel formation and increases vascular permeability. Its abnormal elevation plays a key role in common retinal diseases such as wet age-related macular degeneration and diabetic macular edema. Anti-VEGF therapy can inhibit angiogenesis, reduce vascular leakage and edema, thereby delaying disease progression and stabilizing or improving vision. Currently, the clinical application of anti-VEGF drugs has achieved satisfactory therapeutic effects, but there are also issues such as high injection frequency, heavy economy burden, potential systemic side effects, and non-responsiveness. To address these issues, current research and development mainly aim on biosimilars, multi-target drugs, drug delivery systems, oral anti-VEGF drugs, and gene therapy. Some drugs have shown great potential and are expected to turn over a new leaf for anti-VEGF treatment in ophthalmology.
Objective To detect the expressions of osteopontin （OPN）， breast tumor kinase （Brk）， and vascular endothelial growth factor （VEGF） in the breast cancer tissue， the adjacent （2cm） normal breast tissue， and the distal（＞5cm） normal breast tissue， and analyze their clinical significances. Method The immunohistochemical method was used to detect the expressions of OPN， Brk， and VEGF in the breast cancer tissue， the adjacent （2cm） normal breast tissue， and the distal （＞5cm） normal breast tissue from 40 cases of breast cancer. Results ① The expressions of OPN，Brk， and VEGF in the breast cancer tissue were significantly higher than those of the adjacent （2cm） normal breast tissue and the distal （＞5cm） normal breast tissue （P＜0.01）， the expression of Brk in the adjacent （2cm） normal breast tissue was significantly higher than that of the distal （＞5 cm） normal breast tissue （P＜0.05）. ② In the breast cancer tissue， the OPN and Brk protein expressions were not associated with age， tumor diameter， and histological grade （P＞0.05），were associated with lymph node metastasis and TNM stage （P＜0.05）. The VEGF protein expression was not associated with age and tumor diameter （P＞0.05）， but was associated with histological grade， lymph node metastasis， and TNM staging （P＜0.05）. ③ In the breast cancer tissue， OPN， Brk， and VEGF had positive correlation with each other （P＜0.05）， but not in the adjacent （2cm） normal breast tissue and the distal （＞5 cm） normal breast tissue （P＞0.05）. Conclusions The expressions of OPN and Brk from the same signal pathway increase by turns in the distal （＞5 cm） normal breast tissue， adjacent （2cm） normal breast tissue， and breast cancer tissue. OPN induced the adhesion and migration of endothelial cells to accelerate vascular repair through VEGF and Brk has correlation with the progress of tumor invasion and metastasis through participating in tumor vascularization.
Objective To investigate the inhibitory effects of fms-like typrosine kinase receptor sFlt-1 on retinal neovascularization (RNV).Methods Recombinant lentivirus sFlt-1（2-3）and sFlt-1（2-4）expressing the sFlt-1 (2-3) and (2-4) immunoglobulinlike regions of sFlt-1 were constructed. 96 seven-day-old C57/6J mice were randomly divided into 4 groups with 24 mice in each group. Group 1: normal control; group 2: experimental control; group 3: sFlt-1（2-3）; group 4: sFlt-1（2-4）.The mice in group 2-4 were exposed to hyperoxia with （75plusmn;2）% O2 for 5 days and then returned to normoxia with 21% O2;the mice received an intravitreal injection with 1 mu;l virus of empty vector, sFlt-1（2-3）,or sFlt-1（2-4）,respectively. Five days later, all mice underwent perfusion fluorecein angiography and retinal wholemont was made to observe the changes of retinal vessels; retinal sections were stained by hematoxylin and eosin and RNV endothelium cell nucleus were counted; vascular endothelial growth factor(VEGF) and VEGF receptor-2 (KDR/Flk-1) protein were measured by Western blot.Results Seventeen days after birth, the retinal area of fluorescein leakage and RNV, RNV nucleus which breaking through inner limiting membrane in group 3 and 4 were smaller or less than that in group 2（P＜0.01）; while VEGF protein didnprime;t changed much （P＞0.05）the expression of KDR/Flk-1 decreased significantly (P＜0.01). Conclusion sFlt-1（2-3）and sFlt-1（2-4）can inhibit the formation of oxygen-induced RNV,the former virus has a better effect.
ObjectiveTo investigate the relationship between the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase9 (MMP9) and the recurrence or metastasis of hepatocellular carcinoma (HCC).MethodsThe expression of VEGF and MMP9 in 50 HCC tissues and in 30 normal liver tissues were examined by immunochemistry.ResultsThe positive rates of VEGF and MMP9 in HCC tissue were 86% and 68% respectively, and 53.3% and 33.3% respectively in normal liver tissue. The positive rates of VEGF and normal liver tissue (Plt;0.05). The correlation between expressions of MMP9 and VEGF was very significant (r=0.98，Plt;0.01). The positive rates of VEGF and MMP9 in HCC with metastasis were higher than that of HCC without metastasis.ConclusionVEGF and MMP9 are expressed cooperatively. Both of them play important role in the invasion and metastasis of HCC.
Objective
To observe the effect of celecoxib on the expression vascular endothelial growth factors (VEGF) in diabetic rats.
Methods
Thirty-six wistar rats were used to establish the diabetic models by intraperitoneal injection with streptozotocin. The diabetic rats were divided into 2 groups: diabetic group (n=18) and celecoxib group (n=18). Celecoxib (50 mg/kg) was administered orally to the rats in celecoxib group and the physiological saline with the same volume was given orally to the rats in diabetic group. Eighteen else rats were in normal control group. All of the rats were executed 3 months later. The expression of VEGF protein was detected by immunohistochemistry method. Reverse transcription-polymerase chain reaction（RT-PCR） analysis was used to examine the expression of retinal VEGF mRNA and cyclooxygenase-2 mRNA.
Results
Lower positive expression of VEGF mRNA and cyclooxygenase-2 mRNA, weakly positive action of immunohistochemistry of VEGF, and lower expression of VEGF protein were detected in normal control group; in the diabetic group, the expression of VEGF mRNA and cyclooxygenase-2 mRNA increased obviously comparing with which in the control group (Plt;0.05), and the bly positive action of immunohistochemistry of VEGF and increased expression of VEGF protein were detected (Plt;0.01); in celecoxib group, the expression of VEGF mRNA was lower than that in the diabetic group (Plt;0.05), the expression of cyclooxygenase-2 mRNA didnprime;t decrease much (Pgt;0.05), the positive action of immunohistochemistry of VEGF decreased, and the expression of VEGF protein decreased (Plt;0.01).
Conclusion
By inhibiting the activation of cyclooxygenase-2, celecoxib can inhibit the expression of retinal VEGF mRNA and protein in diabetic rats induced by streptozotocin.
(Chin J Ocul Fundus Dis,2007,23:265-268)
ObjectiveTo investigate the correlation between the expressions of matrix metalloproteinase-3 (MMP-3) and vascular endothelial growth factor (VEGF) in the three negative breast cancer (TNBC) and analyze their clinicopathologic significances.
MethodsOne hundred and twelve patients confirmed TNBC from January 2008 to January 2013 in this hospital were collected. The cases of luminal type with the similar pathological type and pathological staging were chosen as control. The expressions of MMP-3 and VEGF were detected by immunohistochemistry.
Results①The positive expression rates of MMP-3 and VEGF in the TNBC tissues were significantly higher than those in the luminal tissues[MMP-3:90.18%(101/112) versus 49.11%(55/112), P < 0.05;VEGF:84.82%(95/112) versus 48.21%(54/112), P < 0.05]. 2 The positive expressions of MMP-3 and VEGF in the TNBC tissues were correlated with age, menopausal status, tumor size, axillary lymph node metastasis, and TNM stage(P < 0.05).③The expression of MMP-3 was positively correlated with VEGF in the TNBC tissues(rs=0.711, P < 0.01).④The results of follow-up showed that the recurrence and metastasis rate within 3 years was 73.21%, the survival rate within 5 years was 36.61% in the patients with TNBC.
ConclusionsThere is a close relation between MMP-3 and VEGF in TNBC, the expressions of MMP-3 and VEGF may serve as important biomarkers for evaluating invasion and metastasis in TNBC. There is a higher metastasis rate within 3 years and a lower survival rate within 5 years in TNBC. According to intervening the expressions of MMP-3 and VEGF, and inhibiting cancer cells matrix degradation and vascular formation, then cancer cells metastasis could be blocked, it may be important to reduce the 3-year recurrence rate and improve 5-year survival rate.
