High Vascular Endothelial Growth Factor Expression Research Articles

Predicting Outcomes of Patients With Intracranial Meningiomas Using Molecular Markers of Hypoxia, Vascularity, and Proliferation

The natural history of surgically treated intracranial meningiomas can be quite variable. Recurrence and patient outcome cannot currently be predicted with accuracy. To explore the potential roles of tumor hypoxia-regulated biological markers, preoperative imaging, measures of proliferation, and angiogenesis in predicting patient outcome. Tissue from 263 patients (average follow-up, 75 months) was examined for molecular markers hypoxia-inducible factor-1α (HIF-1α), carbonic anhydrase-IX (CA-IX), and glucose transporter-1 (Glut-1); vascular endothelial growth factor (VEGF); proliferation (MIB-1); and microvascular density (MVD) (Factor VIII). Preoperative magnetic resonance images were also examined for tumor size and peritumoral brain edema (PTBE). VEGF, HIF-1α, CA-IX, and Glut-1 are positively correlated (P < .001-.005). PTBE was associated with higher grade (P = .03), larger tumors (P = .02), and log of MVD (P = .004). Progression-free survival (PFS) was associated with higher grade (P < .001), subtotal resection (P = .004), VEGF expression (P = .004), and log of MIB-labeling index (P < .001) on pairwise comparisons. Using multivariate analysis, PFS was associated with subtotal resection (HR 2.71, P = .027), higher grade (HR 6.29, P < .001), higher VEGF expression (HR 1.52, P = .038), and log of MIB-labeling index (HR 1.68, P = .005). Shorter overall survival was associated with subtotal resection (HR 3.23, P = .002), higher grade (HR 4.47, P < .001), higher expression of HIF-1α (HR 1.56, P < .001) and Glut-1 (HR 1.39, P = .02), and log of MIB-labeling index (HR 1.87, P < .001) when controlled for age. HIF, VEGF, and MIB-1 are significantly correlated with tumor recurrence. With further study, these molecular markers may be used to predict outcome for patients with intracranial meningiomas.

Co-expression of VEGF and CA9 in ovarian high-grade serous carcinoma and relationship to survival

Poor prognosis in ovarian high-grade serous carcinoma (HGSC) is largely related to resistance to chemotherapy. Tumour hypoxia is known to be associated with chemotherapy resistance. Stabilisation of hypoxia-inducible factor-1α upregulates the expression of downstream genes such as carbonic anhydrase 9 (CA9) and vascular endothelial growth factor (VEGF). This study was undertaken to analyse the hypoxia profile as indicated by the co-expression of VEGF and CA9 and its correlation with survival. VEGF and CA9 expressions were examined in tissue microarray of 97 cases of ovarian high-grade serous carcinoma using immunohistochemistry. High expression of either VEGF or CA9, individually, was associated with decreased overall survival (p = 0.006 and p = 0.05 respectively). Combined high expression of both markers, to give a 'hypoxia profile', was associated with chemotherapy resistance (p = 0.036) and showed worse overall survival with a significant p value (p = 0.001). Using multivariate analysis, hypoxia profile was an independent prognostic factor for overall survival (p = 0.028). The combined high expression CA9 and VEGF phenotype, described as high hypoxia profile group, was significantly associated with increased resistance to chemotherapy and poor overall survival. This group may benefit from combined targeted therapy for effective response in ovarian HGSC.

Correlation of CT Perfusion Images with VEGF Expression in Solitary Brain Metastases

To obtain permeability surface (PS) values using multi-slice helical CT perfusion imaging and to evaluate the spatial distribution correlation between PS values and vascular endothelial growth factor (VEGF) expression in solitary brain metastases. Imaging was performed on 21 patients, PS values being calculated from the central, border and peripheral parts of tumours. VEGF expression was determined by immunohistochemical staining. Rim enhancement was found in 16 cases, the border of the tumour featuring PS elevation with high VEGF expression in 13 cases. In the 5 cases with nodular enhancement, the border and the central part had high permeability and VEGF expression was high in all cases, the correlation being significant (P<0.01) . VEGF expression in brain metastases positively correlates with PS values from CT perfusion imaging, so that the latter can be used in the surveillance of angiogenic activity in brain metastases.

1068 VASCULAR ENDOTHELIAL GROWTH FACTOR EXPRESSION IN SCHISTOSOMIASIS-ASSOCIATED BLADDER CANCER, CORRELATION WITH HISTOPATHOLOGICAL FEATURES AND SCHISTOSOMIASIS

You have accessJournal of UrologyBladder Cancer: Basic Research III1 Apr 20121068 VASCULAR ENDOTHELIAL GROWTH FACTOR EXPRESSION IN SCHISTOSOMIASIS-ASSOCIATED BLADDER CANCER, CORRELATION WITH HISTOPATHOLOGICAL FEATURES AND SCHISTOSOMIASIS Hosni Khairy Salem, Hala Ragab, and Nabila Abd El Maksoud Hosni Khairy SalemHosni Khairy Salem Cairo, Egypt More articles by this author , Hala RagabHala Ragab Cairo, Egypt More articles by this author , and Nabila Abd El MaksoudNabila Abd El Maksoud Cairo, Egypt More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.1174AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Vascular Endothelial growth factor (VEGF) is a principle growth factor mediating angiogenesis. The high expression of VEGF within bladder tumor is associated with poor prognosis. We determined tissue, plasma and urinary levels of VEGF in patients with bladder cancer to study their correlation with classical clinicopathological factors and to assess its potential role in the evaluation of bladder cancer patients METHODS VEGF was measured by enzyme-linked immunosorbent assay in the tissue, plasma and urine of 100 bladder cancer patients and in corresponding 40 healthy volunteers. Tumor tissue samples were standardized to the protein content and urine samples were normalized for creatinine content. RESULTS Tissue, plasma and urinary VEGF levels were significantly elevated in bladder cancer patients compared to healthy controls (p<0.001). The highest VEGF levels were noted in patients with invasive and poorly differentiated bladder cancer compared to those with superficial and well or moderately differentiated individuals followed by healthy controls. Similarly, we detected the same observation in patients with lymph node metastases signifying that VEGF increases with tumor progression. Also, VEGF levels for schistosomal bladder cancer patients were elevated compared to non-scistosomasl ones (although they were insignificantly different) and healthy controls as they correlated significantly together suggesting that schistosomiasis maybe participates in angiogenic switch. VEGF levels were superior to urine cytology and combined sensitivity between them was the highest (100%) when urine cytology combined with plasma or urinary VEGF. Tissue, plasma and urinary VEGF were significantly correlated together implying that the tumor is the source of plasma and urinary VEGF. CONCLUSIONS Our study demonstrates that strongly expressed VEGF may be relevant for diagnosis of bladder cancer patients, and it is implicated in the pathogenesis of bladder cancer progression. Quantification of urinary VEGF may provide a novel noninvasive marker for the early detection of bladder cancer as well as therapy target. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e433-e434 Peer Review Report Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hosni Khairy Salem Cairo, Egypt More articles by this author Hala Ragab Cairo, Egypt More articles by this author Nabila Abd El Maksoud Cairo, Egypt More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Expression of Tumor-Derived Vascular Endothelial Growth Factor and Its Receptors Is Associated With Outcome in Early Squamous Cell Carcinoma of the Lung

Antiangiogenic therapies targeting the vascular endothelial growth factor (VEGF) pathway have yielded more modest clinical benefit to patients with non-small-cell lung cancer (NSCLC) than initially expected. Clinical data suggest a distinct biologic role of the VEGF pathway in the different histologic subtypes of lung cancer. To clarify the influence of histologic differentiation in the prognostic relevance of VEGF-mediated signaling in NSCLC, we performed a concomitant analysis of the expression of three key elements of the VEGF pathway in the earliest stages of the following two principal histologic subtypes: squamous cell carcinoma (SCC) and adenocarcinoma (ADC). We evaluated tumor cell expression of VEGF, VEGF receptor (VEGFR) 1, and VEGFR2 using automatic immunostaining in a series of 298 patients with early-stage NSCLC recruited as part of the multicenter European Early Lung Cancer Detection Group project. A score measuring the VEGF signaling pathway was calculated by adding the tumor cell expression value of VEGF and its two receptors. The results were validated in two additional independent cohorts of patients with NSCLC. The combination of high VEGF, VEGFR1, and VEGFR2 protein expression was associated with lower risk of disease progression in early SCC (univariate analysis, P = .008; multivariate analysis, hazard ratio, 0.62; 95% CI, 0.42 to 0.92; P = .02). The results were validated in two independent patient cohorts, confirming the favorable prognostic value of high VEGF signaling score in early lung SCC. Our results clearly indicate that the combination of high expression of the three key elements in the VEGF pathway is associated with a good prognosis in patients with early SCC but not in patients with ADC.

Abstract 3440: A Mouse Model of Germinal Matrix Hemorrhage based on Interactions between Vascular Endothelial Growth Factor (VEGF) and Pericellular Proteases

A Mouse Model of Germinal Matrix Hemorrhage based on Interactions between Vascular Endothelial Growth Factor (VEGF) and Pericellular Proteases Dianer Yang, Jessica Baumann, Hung-Chi Liang, Chia-Yi Kuan Division of Developmental Biology and Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA. Introduction: Germinal Matrix-Intraventricular Hemorrhaging (GMH-IVH) is a major threat to premature infants with a high incidence of neonatal mortality and life-long neurological deficits. The etiology of GMH-IVH is complex and involves both vascular and extravascular factors . However, there are few animal models of GMH-IVH and none addresses the interaction between vasculature and endogenous proteases in pathogenesis. Hypothesis: We hypothesize that over-expression of the vascular endothelial growth factor (VEGF) in the germinal matrix is able to induce pericellular proteases (tissue-type plasminogen activator, matrix metalloproteinse, or cathepsins) leading to hemorrhage in mouse embryos. Methods: We used a tetracycline-controlled transcriptional activator (tTA) system (bi-transgenic GFAP-tTA: TetO-VEGF165 embryos/mice) to over-express VEGF in the cortical ventricular zone from mid-gestation, when no doxycycline was administered. In the first set of investigation, we examined the cortical vasculature in E15-18 bi-transgenic embryos and sibling controls. The focus is to evaluate the density of blood vessels and the distribution of CD31+ endothelial cells and NG2+ pericytes. Microarray and in-situ hybridization were used to explore the downstream mediators of VEGF. Biochemical assays were used to compare the activity of various proteases. In the second set of study, doxycycline was administered to bi-transgenic embryos from E8 to E18 to adjust the timing of VEGF-induced angiogenesis. Results: The majority of bi-transgenic GFAP-tTA: TetO-VEGF165 embryos die before birth. In situ hybridization confirmed increased expression of VEGF in the cortical ventricular zone in bi-transgenic embryos, which exhibited overgrowth of blood vessels, CD31+ endothelial cells, and NG2+ pericytes at E16. The abnormal vessels showed glomeruloid microvascular proliferation-like morphology. Biochemical analysis revealed significantly increased Cathepsin B activity in the cortex of E16 embryos. Microarray and in-situ hybridization confirmed elevated expression of multiple Cathepsins. By E18, the bi-transgenic embryos exhibited spontaneous hemorrhage into the dilated ventricular space. Conclusions: High expression of VEGF in the ventricular zone of developing cerebral cortex is sufficient to induce vascular overgrowth and pericellular protease activity, leading to GMH-IVH-like outcomes. These results suggest that anti-VEGF or anti-Cathepsin treatment may interrupt this pathological process.

Bevacizumab activity in gastric cancer cells with high expression of VEGF.

64 Background: Metastasis of cancer cells is associated with numerous activating molecules, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and tumor necrosis factor (TNF)-α. Excess VEGF production induces hematogenous metastasis in gastric cancer (GC) cells. To understand the anti-metastatic effect of bevacizumab, an anti-VEGF monoclonal antibody developed for selective inhibition of tumor angiogenesis, we investigated VEGF-induced expression of key adhesion molecules in human umbilical vein endothelial cells (HUVECs) and the inhibitory effect of bevacizumab on the adhesion of GC cells expressing high levels of VEGF. Methods: We measured the soluble VEGF (sVEGF) produced by 7 GC cells by ELISA. We evaluated intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin expression in HUVECs pretreated with SNU-1-conditioned medium (SNU-1 CM) or recombinant VEGF (rhVEGF) at different time points by western blotting. Results: We identified that SNU-1 cells secreted the highest sVEGF concentration in 7 GC cells. After rhVEGF pretreatment, ICAM-1 and E-selectin expression were highest at 4–6 h and 2 h, respectively, but VCAM-1 expression was unchanged. Bevacizumab cotreatment markedly decreased VCAM-1 and E-selectin expression to basal levels, whereas ICAM-1 expression was unaffected. The SNU-1 adherent cell percentage decreased following bevacizumab cotreatment of SNU-1 CM- or rhVEGF-pretreated HUVECs. Investigation of SNU-1-cell invasiveness through activated HUVECs revealed less than 10 invasive adherent cells, whereas no cells were found after bevacizumab cotreatment. Conclusions: Our preclinical data suggests that bevacizumab, might contribute to anti-metastasis by inhibiting SNU-1 cell adhesion to HUVECs by reducing E-selectin and VCAM-1 expression.

Cyclooxygenase Isoenzyme-2 and Vascular Endothelial Growth Factor are Associated with Poor Prognosis in Esophageal Adenocarcinoma

BackgroundCyclooxygenase isoenzyme-2 (COX-2) and vascular endothelial growth factor (VEGF) contribute to angiogenesis and are overexpressed in various malignancies. The aim of the study was to evaluate expression, prognostic value and correlation between COX-2 and VEGF expression in esophageal adenocarcinoma (EAC). MethodsSurgical specimens of 154 patients with EAC were used to construct a tissue micro array (TMA). TMA sections were immunohistochemically stained for COX-2 and VEGF and scored on intensity of staining. ResultsEstimated 5-year cancer specific survival was 37%. High COX-2 and VEGF expression was observed in 39 (26.5%) and in 77 (53.8%) tumors, respectively. Both markers were associated with poor cancer specific survival (p = .022 and p = .004, respectively, log rank). No significant correlation was found between VEGF and COX-2 expression (r = 063; p = .455). In multivariate analysis, high COX-2 expression (HR 1.65; 95% CI 1.04–2.61; p = .034) was associated with overall survival. In patients with T3 tumors, COX-2 expression was an independent prognostic factor for cancer specific survival (HR 1.81 95% CI 1.10–2.95; p = .019). ConclusionsThis is the first study that evaluated the prognostic value and correlation of COX-2 and VEGF expression in a large and homogenous population of patients with EAC. No correlation between COX-2 and VEGF expression was found. Both markers were expressed in EAC and were associated with poor prognosis. The findings support the use of COX-2 and VEGF inhibitors in future clinical studies.

Ras homolog gene family, member A promotes p53 degradation and vascular endothelial growth factor‐dependent angiogenesis through an interaction with murine double minute 2 under hypoxic conditions

Tumor neovascularization (TNV) is a common pathologic basis for malignant growth and metastasis. However, the mechanism of TNV pathogenesis is not fully understood. Ras homolog gene family, member A (RhoA), a Rho guanosine triphosphatase (GTPase) family member, may be involved in a hypoxia-induced vascular endothelial growth factor (VEGF) pathway that regulates TNV angiogenesis through an unclear mechanism. The regulation of RhoA on p53, the p53 binding protein homolog murine double minute 2 (MDM2), and VEGF was analyzed in hypoxic MCF-7 cells using Western blot analysis, real-time polymerase chain reaction (PCR) analysis, coimmunoprecipitation, and immunofluorescence staining assays. Changes in proliferation, invasion, migration, stress fiber formation, and tube formation were detected in an MCF-7 human umbilical vein endothelial cell (HUVEC) coculture system. Correlations of RhoA expression with MDM2, wild-type p53 (wt-p53), and VEGF expression in breast cancer tissues and relations between RhoA and breast cancer clinical features were analyzed by immunohistochemistry. Activated RhoA down-regulated p53 protein, which increased VEGF expression in hypoxic MCF-7 cells; whereas p53 messenger RNA levels were not altered. In addition, the ubiquitin-mediated degradation of p53 was enhanced by active RhoA. RhoA and MDM2 colocalized in the cytoplasm of hypoxic MCF-7 cells and interacted with each other physically. Furthermore, nutlin-3, a specific MDM2 inhibitor, was capable of reducing activated RhoA-induced p53 protein stability and attenuating VEGF accumulation. In an MCF-7-HUVEC coculture system, nutlin-3 effectively inhibited HUVEC proliferation, invasion, migration, stress fiber formation, and tube formation mediated by activated RhoA under hypoxic conditions. Data from 129 clinical breast cancer specimens with wt-p53 revealed that high RhoA expression was correlated with high MDM2 expression, low wt-p53 expression, and high VEGF expression. The current data suggested that activated RhoA promotes VEGF expression and hypoxia-induced angiogenesis through the up-regulation of MDM2 to decrease p53 stability.

Cyclooxygenase-2 and vascular endothelial growth factor in chronic hepatitis, cirrhosis and hepatocellular carcinoma

Background/AimsCyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) are up-regulated in hepatocellular carcinoma (HCC). To investigate the levels of COX-2 and VEGF expression in chronic hepatitis (CH), cirrhosis, and HCC.MethodsThe immunohistochemical expressions of COX-2 and VEGF were evaluated in tissues from patients with CH (n=95), cirrhosis (n=38), low-grade HCC (LG-HCC; n=6), and high-grade HCC (HG-HCC; n=29).ResultsThe COX-2 expression scores in CH, cirrhosis, LG-HCC, and HG-HCC were 3.3±1.9 (mean±SD), 4.2±1.7, 5.5±1.0, and 3.4±2.4, respectively (CH vs. cirrhosis, P=0.016; CH vs. LG-HCC, P=0.008; LG-HCC vs. HG-HCC, P=0.004), and the corresponding VEGF expression scores were 0.9±0.8, 1.5±0.7, 1.8±0.9, and 1.6±1.1 (CH vs. cirrhosis, P<0.001; CH vs. LG-HCC, P=0.011; LG-HCC vs. HG-HCC, P=0.075). Both factors were correlated with the fibrosis stage in CH and cirrhosis (COX-2: r=0.427, P<0.001; VEGF: r=0.491, P<0.001). There was a significant correlation between COX-2 and VEGF in all of the tissue samples (r=0.648, P<0.001), and between high COX-2 and VEGF expression scores and survival (COX-2: P=0.001; VEGF: P<0.001).ConclusionsThe expressions of both COX-2 and VEGF are significantly higher in cirrhosis and LG-HCC than in CH. High COX-2 and high VEGF expressions are associated with a high survival rate.

Giant Cell Lesions of the Jaws: Does the Level of Vascularity and Angiogenesis correlate With Behavior?

To compare vascularity and angiogenic activity in aggressive and nonaggressive giant cell lesions (GCLs) of the jaws. This is a retrospective study of 14 GCLs treated at the University of California, San Francisco. Immunohistochemistry was used to determine of the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), CD34, and CD31. VEGF and bFGF expression in giant cells (GCs) and surrounding mononuclear stroma was classified into 1) high immunoreactivity (>50% staining) and 2) low immunoreactivity (<50% staining). CD31- and CD34-stained vessels were counted at 200× magnification. Clinical and radiographic records were reviewed to classify lesions as aggressive or nonaggressive. Of the lesions, 8 were aggressive and 6 were nonaggressive. High VEGF expression was found within the GCs in 4 of 8 aggressive lesions compared with 1 of 6 nonaggressive lesions. The stroma in both groups had low staining. High staining of the GCs for bFGF was found in 6 of 8 aggressive lesions compared with 3 of 6 nonaggressive lesions. The stroma of all aggressive cases showed high expression of bFGF compared with 3 of 6 nonaggressive cases. The aggressive group had a mean of 20.1 ± 5.4 vessels/high-powered field (hpf) stained for CD31 compared with 11.5 ± 5.6 vessels/hpf in the nonaggressive group. The aggressive group had 24.6 ± 7.0 vessels/hpf stained with CD34 compared with 18.5 ± 4.0 vessels/hpf in the nonaggressive group. The vascularity and level of angiogenesis within aggressive GCLs are higher than those in nonaggressive lesions.

Pleiotrophin is a potential colorectal cancer prognostic factor that promotes VEGF expression and induces angiogenesis in colorectal cancer

Pleiotrophin (PTN) is an important developmental secretory cytokine expressed in many types of cancer and involved in angiogenesis and tumor growth; however, the significance of PTN expression in colorectal cancer (CRC) has not been established. Immunohistochemistry, western blot, and enzyme-linked immunosorbent assay were used to detect PTN expression in CRC patients. The relationship between PTN expression and clinicopathological characteristics and survival time was statistically analyzed, and the relationship between PTN and vascular endothelial growth factor (VEGF) in tumor angiogenesis was further analyzed. Of CRC tissues, 74.70% (62/83) stained positive, with a strong positive ratio of 60.24% (50/83). The expression of PTN in CRC tissues was much higher than in normal colorectal tissues. PTN serum levels in CRC patients (mean = 254.59 ± 261.76 pg/ml) were significantly higher than those of normal volunteers (mean = 115.23 ± 79.53 pg/ml; p < 0.001). PTN expression was related to CRC differentiation and TNM staging. High level of PTN is a predictor of a poor prognosis and high expression of PTN is accompanied by high expression of VEGF in CRC patients. Investigation of the relationship between PTN and VEGF revealed that PTN, through the PTN/RPTPβ/ζ signaling pathway, increased tyrosine phosphorylation of β-catenin, leading to an increase in VEGF. Our study identifies PTN as an essential growth factor for CRC. PTN promotes VEGF expression and cooperates with VEGF in promoting CRC angiogenesis. PTN could serve as a prognostic factor for this cancer. Considering that PTN shows very limited expression in normal tissue, it may represent an attractive new target for CRC therapy.

Effects of erythropoietin on angiogenesis after myocardial infarction in porcine

Erythropoietin (EPO) has recently been shown to confer cardioprotective effects via angiogenesis and antiapoptosis. The administration of EPO after myocardial infarction (MI) reduces infarct size and improves cardiac function in small animals. The purpose of this study is to investigate the protective effects of EPO in porcine MI. Each animal in the EPO group received four injections of recombinant human EPO (rhEPO; 6000 U per injection) at 2-day intervals, starting after coronary occlusion. Animals in the control group received saline. Left ventriculography was performed just after coronary occlusion and at 28 days. Time-course changes in serum levels of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and fibroblast growth factor (FGF) were measured. The number of vessels was calculated, and the mRNA expressions of VEGF and insulin-like growth factor (IGF) were examined. Left ventricular function was similar between the groups. The numbers of cells positive for anti-α-smooth muscle actin, von Willebrand factor, and c-kit were significantly higher in the EPO group than in the controls (P < 0.05). The EPO group exhibited significantly higher HGF and FGF concentrations (P < 0.05) and higher expression of VEGF and IGF mRNA (P < 0.05) compared with the controls. In conclusion, EPO accelerates angiogenesis via the upregulation of systemic levels such as HGF and FGF, and the local expression of VEGF and IGF, in porcine MI.

RAD001 reverses radio-resistance and exerts synergistic tumor inhibition with 5-fluorouracil

To explore the in vitro synergistic anti-tumor efficacy of mammalian target of rampamycin (mTOR) inhibitor (RAD001) and 5-fluorouracil (5-FU) for radio-resistant tumors. Radio-resistant cells of human pancreatic cancer cell and human colon cancer cell were established. The expression profiles of VEGF (vascular endothelial growth factor) and TP (thymidine phosphorylase) were compared between parental and radio-resistant tumor cells. The tumor proliferation was analyzed after 5-FU alone or in combination with a mTOR inhibitor. After several cycles of radiation induction (3 Gy), the radio-resistant cells of human pancreatic cancer (AsPCres) and colon cancer (HT29res) were established. There was a higher expression of VEGF in radio-resistant tumor cells than their parental cells. They were 1215 ± 67 pg/ml in AsPCres and 689 ± 25 pg/ml in HT29res respectively (P < 0.01). The up-regulation of TP was observed in both AsPC-res and HT29-res. The combined therapy of 5-FU plus a mTOR inhibitor might exert synergistic tumor inhibition. RAD001 decreases the radiation-induced expression of VEGF in tumor. And the post-radiation up-regulation of TP promotes the efficacy of 5-FU. The combined therapy of RAD001 and 5-FU may inhibit synergistically the growth of radio-resistant tumors.

Contribution of VEGF polymorphisms to variation in VEGF serum levels in a healthy population

Vascular endothelial growth factor (VEGF) is a pro-angiogenic factor. Variability in VEGF expression, induced by specific VEGFA variants, are involved in angiogenesis-related disorders. This study examined the genotype distribution and functional role (VEGF expression) of rs699947, rs833061, rs1570360, rs2010963, rs833068, rs833070, rs3025020, and rs3025039 VEGFA variants and their haplotypes in 519 healthy Bahraini individuals of both genders. The distribution of the eight VEGFA polymorphisms screened was in Hardy-Weinberg equilibrium. The minor allele frequencies of rs699947 (0.42), rs833061 (0.32), rs1570360 (0.31), rs2010963 (0.33), rs833068 (0.37), rs833070 (0.42), rs3025020 (0.33), and rs3025039 (0.13) were generally compared to those established for Caucasians. Of the variants tested, rs3025020 was associated with increased VEGF serum levels (p=0.019), while rs3025039 was associated with decreased levels (p=0.038). Linkage analysis identified two VEGFA blocks, the first, spanning 16 kb, was not associated with altered VEGF levels, while the second, spanning 3 kb containing rs3025020 and rs3025039, was linked with higher VEGF expression, of which the (-583)T/(+936)T haplotype (p=0.008) was linked with higher VEGF levels compared to the (-583)C/(+936)C (all wild-type) haplotype. These results support the association of rs30250202 and rs3025039, and specific VEGF haplotypes, with altered VEGF serum levels, although the exact functional mechanisms remain to be elucidated.

Expression of VEGF and VEGFR-2 in patients with operable advanced laryngeal cancer treated with induction chemotherapy

Objective To assess the prognostic values of the immunohistochemical expression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2) in a cohort of patients with operable advanced laryngeal cancer who have been treated with induction chemotherapy. Methods VEGF and VEGFR-2 expression in the Forty-nine patients was quantified by an enzyme immunosorbent assay in a retrospective series.Results The moderate to high VEGF expression in 34 patients were found and low expression in 15 patients. VEGFR-2 expression was moderate to high in 31 patients and was low expression in 18. The probability of a complete response to induction chemotherapy was significantly higher in patients with none to low VEGF expression.Conclusion VEGF expression seems to be a significant predictor of complete response to induction chemotherapy. Key words: Laryngeal neoplasms; Vascular endothelial growth factor A; Drug therapy,combination; Prognosis

Clinical significance of tissue factor and vascular endothelial growth factor expressions on CD14+ monocytes in patients with non Hodgkin lymphoma

To explore the values of tissue factor (TF) and vascular endothelial growth factor (VEGF) expressions on peripheral CD14+ monocytes in disease assessment, prognosis, and short-term efficacy evaluation of non-Hodgkin lymphoma (NHL) patients. TF and VEGF expressions on CD14+monocytes in 47 NHL patients (disease group) before chemotherapy and after 4 chemotherapy cycles and in 30 healthy subjects (control group) were detected by flow cytometry, and the potential relationship among TF, VEGF, International Prognostic Index (IPI), and short-term efficacy were analyzed. TF and VEGF expressions on CD14 + monocytes in disease group were significantly higher than those in control group ( all P <0. 01) and positive correlation was showed between them (r = 0. 708, P = 0.00). TF and VEGF expressions in Ann Arbor stage III and IV (n = 22 and 19) , symptomatic (n = 22) , lactate dehydrogenase (LDH) increased (n = 21) , Eastern Cooperative Oncology Group (ECOG) score 2-4 (n = 12) and extranodal lesions >1 (n = 16) groups were significantly higher than those in Ann Arbor stage II (an = 6) , asymptomatic (an =25) , LDH normal (n = 26) , ECOG score 0-1 ( n = 35) and extranodal lesions ~1 ( na = 31) groups, respectively (all P <0.05). The expressions of TF and VEGF on CD14 + monocytes in high-risk (n = 7) or high-middle-risk (n = 11) groups were significantly increased compared with low-risk (n = 15) or low-middle-risk(n = 14) groups, respectively (all P <0. 01). TF and VEGF expressions in non-remission group before chemotherapy (n = 11) were both obviously higher than those in remission group (an = 36, all P <0. 01) , and after chemotherapy their expressions in remission group were significantly lower than those before chemotherapy (all P <0. 01) , while such significant changes were not observed in the non-remission group ( all P > 0. 05). The high expressions of TF and VEGF on peripheral CD14 + monocytes can be useful markers in dis-ease assessment, prognosis evaluation and short-term efficacy observation of NHL patients.

Tumor-derived vascular endothelial growth factor (VEGF)-A facilitates tumor metastasis through the VEGF-VEGFR1 signaling pathway

Vascular endothelial growth factor (VEGF) and its receptors are involved in carcinogenesis, invasion and tumor angiogenesis, but the underlying mechanism by which VEGF promotes tumor metastasis is poorly understood. In this study, we show that in cancer patients high expression of VEGF is correlated with metastasis, and anti-VEGF treatment (bevacizumab) has clinical effects on tumor metastasis. Two human lung carcinoma cell lines (A549 and SPCA1 cells) with distinct VEGF expression were injected intravenously through the lateral tail vein of SCID mice and a murine model was developed. We investigated the association between the expression of VEGF and tumor metastasis by microvessel density, immunohistochemistry and whole mount staining. At sacrifice, in the high VEGF expression A549 cell line group, the induced tumor was distinctively larger in size and multiple metastatic lesions were found in lung tissues. Two specific neutralizing anti-mouse VEGFR1 and VEGFR2 antibodies were administered to the tumor-bearing mice; anti-VEGFR1, but not anti-VEGFR2 treatment produced inhibitive effects on VEGF-induced tumor metastasis. These findings demonstrate that the VEGF-VEGFR1 signaling pathway is crucial for tumor metastasis and the blockade of VEGF-VEGFR1-induced metastasis may provide a novel approach for the prevention and treatment of tumor metastasis.

Angiogenic markers in canine lymphoma tissues do not predict survival times in chemotherapy treated dogs

Angiogenesis, which is essential for malignancies to progress, depends on various signalling proteins including vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptors 1 and 2 (VEGFR-1 and VEGFR-2). Microvessel density (MVD) is frequently used to evaluate angiogenesis. This study assessed the relationship between expression of VEGF, VEGFR-1 and VEGFR-2, MVD and the survival time in dogs with lymphoma. VEGF, VEGFR-1 and VEGFR-2 expression was evaluated immunohistochemically and microvessel profiles were counted in 34 lymphoma samples. Seventy-nine percent of the samples showed high VEGF expression and 62% were highly positive for VEGFR-1; VEGFR-2 immunoreactivity was mostly negative. Dogs treated with chemotherapy had a median survival time of 266days, but no significant relationships were found between overall survival time, MVD and expression of VEGF, VEGFR-1 or VEGFR-2. In this study, VEGF its receptors and the MVD were no prognostic factors in dogs with lymphoma.

Inhibition of high glucose-induced VEGF and ICAM-1 expression in human retinal pigment epithelium cells by targeting ILK with small interference RNA

The aim of this study was to investigate the change of Integrin-linked kinase (ILK) expression of human retinal pigment epithelium (RPE) cells in response to high glucose, and the effect of targeting ILK with small interference RNA (siRNA) on the high glucose-induced expression of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1). The ILK mRNA and protein expression in human RPE cells were analyzed with RT-PCR and western blot after exposure to 5.5, 30, 40, 50 mM glucose, or 5.5 mM glucose+45.5 mM mannitol for 48 h. The expression of VEGF and ICAM-1 was also determined. Cells were treated with ILK siRNA, to determine the effect of ILK on VEGF and ICAM-1 expression following treatment with high glucose. High concentrations of glucose significantly up-regulated ILK mRNA and protein expression, and the ILK expression increased along with the glucose concentration. The changes of VEGF and ICAM-1 expression were similar to that of ILK expression. Knocking down ILK gene expression with siRNA inhibited the elevation of VEGF and ICAM-1 induced by high glucose treatment. These results suggested that ILK was involved in the response of RPE cells to high glucose and may therefore play a role in the pathogenesis of diabetic ophthalmology.