Vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) is a hypoxia-inducibleangiogenesis and vascular permeability factor which is expressedin high amounts in perinecrotic palisading cells inhuman glioblastomas. In vitro VEGF gene expression isenhanced approximately ten times by hypoxia. Current evidencesuggests, that hypoxia is also the driving forcefor VEGF gene expression in glioblastoma cells invivo and represents the most important trigger fortumor angiogenesis and edema. Our approaches to inhibittumor angiogenesis and edema formation in glioblastoma patientswill concentrate on the disruption of VEGF/VEGF receptorsignal transduction pathway in vivo.     

血管内皮生长因子及其受体与骨肉瘤关系的研究进展

血管内皮生长因子（ＶＥＧＦ）是一种序列高度保守、高度特异性的促血管内皮细胞生长因子,广泛分布于人和动物体内的大脑、肾脏、肝脏、脾脏、胰腺和骨骼等组织中,对内皮细胞具有强烈的促有丝分裂作用,刺激血管内皮细胞增殖和血管通透性增加,促进新生血管形成。ＶＥＧＦ通过与血管内皮细胞表面受体（ＶＥＧＦＲ）特异性结合发挥生物学效应。抑制ＶＥＧＦ及ＶＥＧＦＲ的活性可以减缓或阻滞骨肉瘤侵袭和转移。研究表明,ＶＥＧＦ及ＶＥＧＦＲ对肿瘤血管及淋巴管的生成及肿瘤侵袭和转移起重要作用。本文对ＶＥＧＦ及ＶＥＧＦＲ与骨肉瘤血管与淋巴管生成及其侵袭与转移的关系作一综述。     

血管内皮生长因子及其受体与恶性胸腹水

血管内皮生长因子(VEGF)是调控恶性胸腹水发生、发展的关键介质.抑制VEGF及其受体表达,可以降低恶性胸腹水生成.现综述VEGF及其受体在恶性胸腹水诊断、治疗中的作用.     

血管内皮生长因子在胶质瘤中的表达

目的：研究人脑胶质瘤组织中血管内皮生长因子mRNA的表达，同时分析肿瘤间质血管增生的情况，并探讨两者之间的关系。方法：采用半定量逆转录－聚合酶链反应（RT－PCR）方法，对49例人脑胶质瘤手术切除标本，U251等3株胶质瘤细胞以及12例脑外伤内减压术中得到的正常脑组织检测了VEGF mRNA表达水平水平。另外，用免疫组化SP法对组织中的微血管密度（MVD）进行了分析。结果：胶质瘤组织中的VEGF mRNA表达水平达65．3％，随着病理分级的提高其表达水平有升高趋势，HUVEC及3株胶质瘤细胞亦表达水平较高，而正常脑组织表达水平及表达率较低，胶质瘤中的微血管密度（MVD）与胶质瘤级别之间有等级相关性，VEGF mRNA表达同MVD呈正相关。结论：VEGF、MVD对胶质瘤的恶性质瘤的恶性生物学行为的评估有重要意义，VEGF的高表达导致肿瘤组织血管增生，在胶质瘤侵袭过程中发挥重要作用。     

Vascular endothelial growth factor in esophageal cancer

Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis of many solid malignancies. The influence of angiogenesis and VEGF expression on progression and recurrence of esophageal cancer has been investigated over the last years. This article reviews the prognostic significance of VEGF expression, microvessel density (MVD), and lymphangiogenic factors in squamous cell carcinoma (SCC), Barrett's dysplasia, and adenocarcinoma (AC) of the esophagus, their predictive value for treatment response to chemo-radiotherapy and new anti-angiogenic treatment strategies.     

血管内皮生长因子与肿瘤

血管形成是肿瘤生长和转移的重要条件 ,而血管内皮生长因子 (VEGF)对肿瘤的血管形成具有很突出的作用 ,就VEGF与肿瘤予以综述     

Vascular endothelial growth factor in ovarian cancer

Tumor growth requires nutrients and oxygen. Both nutrients and oxygen are provided via the vasculature. Thus, when a tumor increases in volume, new blood vessels must form and invade the expanding tumor. This process, called angiogenesis, has theoretical significance in the context of ovarian cancer for two reasons. First, the process of angiogenesis and vessel regression occurs in a tightly controlled way as part of normal ovarian function. This suggests that at least some ovarian cells are primed to produce the paracrine stimulus needed for new blood vessel growth and that, on tranformation, this capability is present early in tumor development. Second, the characteristically large size of ovarian tumors indicates that angiogenesis is mandatory to sustain the tumor. In this article, we review the experimental and clinical correlative data that support the hypothesis that ovarian cancers are highly angiogenic. Because a critical component of angiogenesis is the paracrine and autocrine production of vascular endothelial cell growth factor, there is substantial focus on this topic.     

Vascular endothelial growth factor levels and induction of permeability in malignant pleural effusions.

Vascular endothelial growth factor (VEGF) is an important mediator of angiogenesis and vascular permeability. We hypothesized that malignant pleural effusions may contain high levels of VEGF protein as well as other cytokines implicated in these processes. Pleural effusions cytologically proven to be malignant were collected from 39 patients with various types of cancer, and VEGF, interleukin-8, and angiogenin levels in the effusions were determined by immunoassay. Negative controls were nonmalignant ascites and serum samples from healthy individuals. VEGF levels were significantly higher than those of control samples in pleural effusions secondary to breast, mesothelioma, and non-small cell lung cancer and when all malignant pleural effusion samples were pooled. Neither interleukin-8 nor angiogenin levels were elevated in malignant pleural effusions relative to the control samples. Vascular permeability, which was measured by using the Miles assay in nude mice, was increased proportionately with VEGF levels in the malignant pleural effusions; this increase in permeability induced by injection of recombinant VEGF or the malignant effusions was reduced by pretreating the mice with a VEGF receptor antibody.     

Vascular endothelial growth factor and programmed death-1 pathway inhibitors in renal cell carcinoma

Advanced renal cell carcinoma has historically carried a poor prognosis with very limited treatment options. However, in recent years, the treatment landscape has changed drastically, with many new therapeutic options and improved survival for patients. Novel treatments consist of molecularly targeted agents against the vascular endothelial growth factor (VEGF) pathway as well as the immune checkpoint inhibitors, which stimulate an antitumor immune response. Recent strategy has focused on the development of combination therapy with the use of VEGF inhibitors and immune checkpoint inhibitors in the first-line setting. As more treatments are approved and the options for therapy expand further, there is a growing need for predictive biomarkers to personalize treatment choices for individual patients. Prospective clinical trials comparing the sequencing of treatments are needed to help determine the best therapeutic approach.     

Vascular endothelial growth factor in ovarian cyst fluid

BACKGROUND: The purpose of the current study was to determine vascular endothelial growth factor (VEGF) concentrations in cyst fluid from malignant, borderline, and benign ovarian tumors, and to correlate these data with preoperative serum VEGF concentrations and clinicopathologic characteristics. METHODS: One hundred seven ovarian cysts were removed and punctured for cyst fluid collection. Histologic diagnosis revealed 25 malignant, 12 borderline, and 70 benign ovarian tumors. The VEGF concentrations of all the cyst fluid specimens as well as in 37 preoperatively collected serum samples were determined by making use of a sandwich type double determinant enzyme linked immunoadsorbent assay based on a combination of 4 polyclonal antibodies. RESULTS: Statistically significantly higher VEGF concentrations were found in cyst fluid from malignant (median, 21.5 microg/L) compared with borderline (median, 3.2 microg/L; P = 0.01) or benign tumors (median, 1.3 microg/L; P < 0.0001). Preoperative serum VEGF concentrations were significantly higher in patients with malignant (median, 0.63 microg/L; range, 0.016-17.7 microg/L) compared with nonmalignant tumors (median, 0.28 microg/L; range, 0.016-0.89 microg/L; P = 0.008). A significant correlation of preoperative serum VEGF was found with VEGF cyst fluid concentrations (r = 0.38; P = 0.02). Significantly higher VEGF cyst fluid concentrations were found in serous malignant (median, 31.9 microg/L) compared with mucinous malignant tumors (median, 4.7 microg/L; P = 0.004). Not significant, though higher median VEGF cyst fluid concentrations were found in advanced International Federation of Gynecology and Obstetrics (FIGO) Stage II, III, and IV, histologic Grade 2 and 3, patients with residual tumor greater than 2 cm, with malignant cells in ascites or peritoneal washings, or with recurrent disease, as compared with FIGO Stage I, histologic grade 1, patients with less than or equal to 2-cm residual tumor, without malignant cells in ascites/peritoneal washings, or without recurrent disease, respectively. CONCLUSIONS: It has become clear from the increased study sample that ovarian tumors of different histologic etiology vary in VEGF cyst fluid concentrations, with the highest VEGF cyst fluid concentrations in malignant tumors. The prognostic significance of VEGF cyst fluid concentrations in advanced FIGO stage seems to be of limited value but may be important in the selection of high risk FIGO Stage I and borderline types. Data from this study indicate a possible role for VEGF as a serum tumor marker.     

血管内皮生长因子与多发性骨髓瘤

多发性骨髓瘤(MM)是目前仍缺乏根治手段的浆细胞肿瘤,与骨髓微环境异常密切相关.研究表明,血管内皮生长因子(VEGF)是肿瘤微环境中血管形成最重要的生长因子,直接参与MM的发病和进展.目前正在MM患者中开展VEGF相关途径的靶向治疗.     

Vascular response to irradiation in malignant gliomas

Summary The vascular response to irradiation was studied in peritumoral cortex and tumor areas in 9 autopsied cases of glioblastoma multiforme and in 10 biopsies of reoperated cases. The study was carried out by histological, immunohistochemical and electron microscope procedures. Hyaline thickening of the vessel walls with deformation and impoverishment of endothelial nuclei are the most striking features. Formation of large PAS-positive areas from the confluence of thickened vessel walls and development of a fibroblastic proliferation follow. Fibroblastic areas may entrap tumor glial cells. In PAS-positive areas a special population resembles myofibroblasts of tissue scars. Electron microscope reveals the production of collagen fibrils in and outside vessel walls. The presence of collagen III and IV is in line with the present interpretation of the mesodermic component.Presented in part at the 64th Annual Meeting of the American Association of Neuropathologists, Charleston, South Carolina, June 9–12, 1988.     

Cannabinoids inhibit the vascular endothelial growth factor pathway in gliomas

Cannabinoids inhibit tumor angiogenesis in mice, but the mechanism of their antiangiogenic action is still unknown. Because the vascular endothelial growth factor (VEGF) pathway plays a critical role in tumor angiogenesis, here we studied whether cannabinoids affect it. As a first approach, cDNA array analysis showed that cannabinoid administration to mice bearing s.c. gliomas lowered the expression of various VEGF pathway-related genes. The use of other methods (ELISA, Western blotting, and confocal microscopy) provided additional evidence that cannabinoids depressed the VEGF pathway by decreasing the production of VEGF and the activation of VEGF receptor (VEGFR)-2, the most prominent VEGF receptor, in cultured glioma cells and in mouse gliomas. Cannabinoid-induced inhibition of VEGF production and VEGFR-2 activation was abrogated both in vitro and in vivo by pharmacological blockade of ceramide biosynthesis. These changes in the VEGF pathway were paralleled by changes in tumor size. Moreover, intratumoral administration of the cannabinoid Delta9-tetrahydrocannabinol to two patients with glioblastoma multiforme (grade IV astrocytoma) decreased VEGF levels and VEGFR-2 activation in the tumors. Because blockade of the VEGF pathway constitutes one of the most promising antitumoral approaches currently available, the present findings provide a novel pharmacological target for cannabinoid-based therapies.     

Relationship between vascular endothelial growth factor expression and angiogenesis and cell proliferation of malignant gliomas in children

Thereismountingevidencethattumorangiogenesisisintimatelyrelatedtotumorgrowth,invasion,metastasisandprognosis.Tumorangiogenesisisregulatedbysomekindsofcytokinesintissues,suchasfibroblastgrowthfactor(FGF),transforminggrowthfactor(TGF),platelet-derivedgrowthfactor(PDGF)andvascularendothelialgrowthfactor(VEGF),amongwhich,VEGFisknowntobeparticularlyresponsiblefortheprocessofbraintumorangiogenesisVEGFinfluenceonbiologicalpropertiesofadultbraintumorhavebeenreportedinotherarticles.[1]Inthisstu…     

Vascular endothelial growth factor, platelet-derived endothelial cell growth factor and angiogenesis in non-small-cell lung cancer

High microvessel density, an indirect measure of angiogenesis, has been shown to correlate with increased tumour size, lymph node involvement and poor prognosis in non-small-cell lung cancer (NSCLC). Tumour cell vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) expression correlate with angiogenesis and a poor outcome in this disease. In a retrospective study VEGF and PD-ECGF expression and microvessel density were evaluated immunohistochemically in surgically resected specimens (T1-3, N0-2) from 223 patients with operable NSCLC using the VG1, P-GF.44C and JC70 monoclonal antibodies respectively. High VEGF immunoreactivity was seen in 104 (46.6%) and PD-ECGF in 72 (32.3%) cases and both were associated with high vascular grade tumours (P= 0.009 and P= 0.05 respectively). Linear regression analysis revealed a weak positive correlation between VEGF and PD-ECGF expression in cancer cells (r= 0.21; P = 0.002). Co-expression of VEGF and PD-ECGF was not associated with a higher microvessel density than VEGF or PD-ECGF only expressing tumours. Furthermore a proportion of high vascular grade tumours expressed neither growth factor. Univariate analysis revealed tumour size, nodal status, microvessel density and VEGF and PD-ECGF expression as significant prognostic factors. Tumour size (P < 0.02) and microvessel density (P < 0.04) remained significant on multivariate analysis. In conclusion, VEGF and PD-ECGF are important angiogenic growth factors and have prognostic significance in NSCLC. Furthermore the study underlines the prognostic significance of microvessel density in operable NSCLC.     

Expression of vascular endothelial growth factor and p53 protein in association with neovascularization in human malignant gliomas

We examined the expression of vascular endothelial growth factor (VEGF) protein, p53 protein, and the MIB-1 index in 43 patients with malignant gliomas in relation to tumor vascularization by an immunohistochemical method. Factor VIII-related antibody was employed for the evaluation of the vascularity and endothelial proliferation. Of the 42 cases of malignant gliomas, 36 (86%) demonstrated immunoreactivity for VEGF in their tumor cells, whereas 22 (52%) had VEGF in their endothelial cells. There was a tendency for the vascularity to be correlated with the immunoreactivity for VEGF (coefficient, 0.340). In addition, a marked increase in endothelial proliferation was evident in cases showing moderate to strong positivity for VEGF as compared with the others. Immunoreactivity for VEGF was found mostly in the malignant gliomas without p53 overexpression and/or with p53 overexpression. However, statistical analysis revealed a correlation between the grade of p53 overexpression and the grade of VEGF expression (coefficient, 0.507), but not between the VEGF and MIB-1 index in our series. There was a tendency for the MIB-1 indices to increase in correlation with increasing vascularity.     

Vascular endothelial growth factor expression is independent of hypoxia in human malignant glioma spheroids and tumours

We recently showed that severe hypoxia was not universally present adjacent to necrosis in human glioma xenografts and spheroids established from the M059K, M006, M006X, M006XLo and M010b cell lines. Using these glioma models, we wished to test whether oxygen serves as a regulator of cellular VEGF expression in situ. In situ hybridization (ISH) and immunohistochemistry (IHC) were used to detect vascular endothelial growth factor (VEGF) mRNA and protein expression in sections of glioma xenografts and spheroids in which hypoxic regions and regions with well-oxygenated necrosis were identified on contiguous sections by use of the hypoxia-specific marker, 3H-misonidazole. Independent validation of the presence of radiobiologically hypoxic cells in M006 xenografts was undertaken using the comet assay. Northern blotting analyses of monolayer cells demonstrated significant up-regulation of VEGF mRNA in the M006X line at oxygen concentrations of 6% and below. ISH analysis of VEGF mRNA showed unexpectedly strong staining for VEGF mRNA across the entire viable rim of M006X and M006XLo glioma spheroids. Similarly, in virtually all xenograft tumours of the M059K, M006 and M010b lines, VEGF ISH showed similar staining across all regions of healthy cells up to the border of necrosis. Only in one M006X tumour was there a suggestion of increased VEGF expression in cells adjacent to necrosis. IHC for VEGF showed good concordance with the ISH results. IHC analysis of the VEGF receptor flt-1 showed strong tumour cell staining in M006XLo glioma cells. In human glioma spheroids and xenograft tumours, regions of severe hypoxia do not correspond to areas of up-regulated VEGF expression; in fact, VEGF expression is quite uniform. Furthermore, this and our previous study demonstrate that levels of VEGF expression vary among sublines (M006, M006X and M006XLo) derived from a single human glioma specimen.