In vivo neutralization of vascular endothelial growth factor (VEGF) vascular permeability factor (VPF) inhibits ovarian carcinoma-associated ascites formation and tumor growth

Vascular endothelial growth factor (VEGF)/ vascular permeability factor (VPF) is emerging as an important growth factor in a variety of tumor types. As a potent endothelial cell mitogen and vascular permeabilizing agent, VEGF/VPF has the unique functional capacity to mediate the component events of solid tumor neovascularization and ascites tumor growth. In the present series of investigations, our experimental hypothesis was that VEGF/VPF is a critical mediator of ovarian carcinoma-associated ascites formation and solid tumor growth. Athymic nude mice xenotransplanted with human ovarian carcinoma cell lines received either a preimmune rabbit serum or VEGF/VPF antiserum. Compared with the control group receiving the preimmune serum, the antiserum-treated animals displayed a 10- and 12-fold reduction in ascites accumulation and solid tumor growth, respectively. The administration of a neutralizing antiserum to VEGF/VPF conferred a modest survival advantage to animals harboring intraperitoneal tumors. These data demonstrate the significance of VEGF/VPF in the pathogenesis of ovarian carcinoma and suggest that interventions targeting this growth factor and/or its receptor may be of therapeutic value in the management of ovarian cancer.     

Neoangiogenesis and p53 protein in lung cancer: their prognostic role and their relation with vascular endothelial growth factor (VEGF) expression.

Following up-regulation of an angiogenesis inhibitor by the wild-type p53 protein proven recently, we have analysed on the one hand the prognostic impact of microvessel count (MC) and p53 protein overexpression in non-small-cell lung carcinoma (NSCLC) progression and, on the other hand, the inter-relation between the microvascular pattern and the p53 protein expression. Moreover, we assessed the expression of vascular endothelial growth factor (VEGF), one of the pivotal mediators of tumour angiogenesis, in order to investigate its relation to p53 protein expression and MC. Tumours from 73 patients resected for NSCLC between March 1991 and April 1992 (median follow-up 47 months, range 32-51 months) were analysed using an immunohistochemical method. In univariate analysis, MC and p53 accumulation were shown to affect metastatic nodal involvement, recurrence and death significantly. Multiple logistic regression analysis showed an important prognostic influence of MC and nodal status on overall (P = 0.0009; P = 0.01) and disease-free survival (P = 0.0001; P = 0.03). Interestingly, a strong statistical association was observed between p53 nuclear accumulation and MC (P = 0.0003). The same inter-relationship was found in non-squamous histotype (P = 0.002). When we analysed the concomitant influence of MC and p53 expression on overall survival, we were able to confirm a real predominant role of MC in comparison with p53. With regard to VEGF expression, p53-negative and lowly vascularized tumours showed a mean VEGF expression significantly lower than p53-positive and highly vascularized cancers (P = 0.02). These results underline the prognostic impact of MC and p53 protein accumulation in NSCLC and their reciprocal inter-relationship, supporting the hypothesis of a wild-type p53 regulation on the angiogenetic process through a VEGF up-regulation.     

Vascular permeability factor (VPF,VEGF) in tumor biology

Summary Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a multifunctional cytokine expressed and secreted at high levels by many tumor cells of animal and human origin. As secreted by tumor cells, VPF/VEGF is a 34–42 kDa heparin-binding, dimeric, disulfide-bonded glycoprotein that acts directly on endothelial cells (EC) by way of specific receptors to activate phospholipase C and induce [Ca²⁺]i transients. Two high affinity VPF/VEGF receptors, both tyrosine kinases, have thus far been described. VPF/VEGF is likely to have a number of important roles in tumor biology related, but not limited to, the process of tumor angiogenesis. As a potent permeability factor, VPF/VEGF promotes extravasation of plasma fibrinogen, leading to fibrin deposition which alters the tumor extracellular matrix. This matrix promotes the ingrowth of macrophages, fibroblasts, and endothelial cells. Moreover, VPF/VEGF is a selective endothelial cell (EC) growth factorin vitro, and it presumably stimulates EC proliferationin vivo. Furthermore, VPF/VEGF has been found in animal and human tumor effusions by immunoassay and by functional assays and very likely accounts for the induction of malignant ascites. In addition to its role in tumors, VPF/VEGF has recently been found to have a role in wound healing and its expression by activated macrophages suggests that it probably also participates in certain types of chronic inflammation. VPF/VEGF is expressed in normal development and in certain normal adult organs, notably kidney, heart, adrenal gland and lung. Its functions in normal adult tissues are under investigation.     

Immunohistochemical evaluation of vascular endothelial growth factor (VEGF) in colorectal carcinoma

BACKGROUND: Vascular endothelial growth factor (VEGF) is one of the most important proangiogenic factors over-expressed in many human cancers and is usually associated with an unfavorable outcome. This work was planned to assess VEGF and microvessel density (MVD) in colorectal carcinoma (CRC) and to correlate them with the available clinicopathological parameters. MATERIAL AND METHODS: Ten normal colonic mucosa, 21 adenoma and 70 CRC cases were examined by immunohistochemical staining using anti-VEGF antibody. RESULTS: Eighty-one percent (81%) of adenoma and 78.6% of CRC cases showed VEGF immunoreactivity; however, the intensity of staining was significantly in favour of malignant cases (p=0.032). VEGF immunostaining in CRC was correlated with low grade (p=0.009), early stage either by Dukes' system (p=0.03) or TNM stage (p=0.03), negative nodal status (p=0.04) and high mast cell count (p=0.04). MVD assessed by Haematoxylin and Eosin staining was associated with dense inflammatory response (p=0.003) and high mast cell count (p=0.006). CONCLUSIONS: VEGF could be an early carcinogenic factor in CRC that declines with its progression. Inflammatory cells including mast cells could play a role in CRC angiogenesis.     

直肠癌中p53基因与血管内皮生长因子表达的关系

 目的　研究直肠癌中血管内皮生长因子 (VEGF)的表达与 p5 3基因之间的关系。 方法　采用免疫组化方法对 4 5例直肠癌标本中VEGF和 p5 3基因的表达进行检测。 结果　在直肠癌中VEGF的表达率为 6 6 .6 7% (30 / 45 ) ,p5 3的表达率为 5 1.11% (2 3/ 45 ) ;在VEGF表达较高的区域 ,p5 3的表达亦较强 ,二者之间具有相关性 (P <0 .0 5 ) ,且与直肠癌的淋巴结转移相关 (P <0 .0 5 )。结论　在直肠癌中 ,VEGF的表达与 p5 3基因的表达呈正相关 ,在直肠癌的转移中起重要作用     

Maspin expression in early oral tongue cancer and its relation to expression of mutant-type p53 and vascular endothelial growth factor (VEGF)

Even though oral tongue cancer is generally diagnosed at an early stage, the prognosis is poor due to frequent recurrence. Therefore, it is important to identify factors predictive of recurrence and to treat aggressively those patients with a high probability of recurrence. The relationship between angiogenesis and recurrence in tongue cancer has been widely investigated but no consensus has been reached. Mutant-type p53 and VEGF are known to be related to angiogenesis, and maspin is a potent angiogenic inhibitor but its role in tongue cancer has scarcely been examined. We observed the expression of maspin, mutant-type p53 and VEGF by immunohistochemistry in 33 patients with stages I and II oral tongue cancer. And the relationships between maspin, mutant-type p53, VEGF expression and recurrence were analyzed. Maspin and VEGF displayed a cytoplasmic staining pattern and mutant-type p53 a nuclear pattern. None of expression of maspin, mutant-type p53, and VEGF was significantly correlated with tumor recurrence (p=0.34, 0.56, and 0.33, respectively) and survival. Maspin expression was negatively correlated with both mutant-type p53 expression (p=0.02), and VEGF expression (p=0.01). There was no correlation between age, sex, clinical staging, and recurrence. In conclusion, the expression of maspin is not related to recurrence of early stage oral tongue cancer. It is inversely correlated with that of mutant-type p53 and of VEGF, suggesting that the maspin gene is a mutant-type p53 target in vivo and may contribute to regulate VEGF expression.     

食管癌组织中p53和VEGF的表达及其与肿瘤血管生成的关系

目的探讨p53、血管内皮生长因子 (vascular endothelial growth factor,VEGF)的表达和肿瘤内微血管密度 (microvessel density,MVD)测定在食管癌中的意义.方法采用免疫组化方法,检测 45例食管癌患者手术切除标本p53、VEGF的表达,并用CD34抗体标记肿瘤组织血管内皮细胞,计算MVD.结果 p53、VEGF总阳性表达率分别为73.3%(33/45)和62.2%(28/45),MVD平均为48±20.p53的表达与临床TNM分期和淋巴结转移相关,MVD和VEGF表达与食管癌的细胞分化程度、浸润深度和临床TNM分期密切相关.p53/VEGF表达均阳性组MVD高于p53/VEGF其一阳性组和p53/VEGF均阴性组,p53、VEGF表达与MVD密切相关,并存在交互作用.p53和VEGF表达符合率为84.4%(38/45),VEGF与p53的表达有相关性(P<0.001).结论 (1)p53、VEGF的表达以及MVD的测定可作为判断食管癌恶性潜能的重要生物学指标.(2)p53、VEGF的表达对肿瘤血管形成可能起重要作用,联合检测p53、VEGF的表达对了解肿瘤血管形成的机制有一定意义.     

The role of vascular endothelial growth factor (VEGF) in AIDS-related Kaposi's sarcoma

Kaposi's sarcoma (KS) is the most common neoplasm associated with human immunodeficiency virus-1 (HIV-1) infection. KS involves the skin and mucous membranes as well as other organs and can lead to tumor-associated edema and ulcerations. Despite therapy with highly active antiviral agents, most patients with HIV-1-related KS eventually develop disseminated disease. In the treatment of KS, a strong rationale exists for the use of agents that inhibit vascular endothelial growth factor (VEGF). Angiogenesis appears to be an important feature of this disease, and recent experimental studies have demonstrated the role of VEGF and its receptors in the pathogenesis of KS. Thus, therapeutic agents that target the VEGF pathway may be an effective strategy in reducing the tumor growth and edema associated with KS. Phase I study results with SU5416, a synthetic low molecular-weight inhibitor of the VEGF-Flk-1/KDR receptor tyrosine kinase, demonstrate that this agent is well tolerated. Preliminary results show that in a majority of patients with autoimmune deficiency syndrome (AIDS)-related disease, SU5416 clearly has biological activity (it flattens, shrinks, or dissolves lesions and reduces or resolves edema) or stabilizes the disease. Angiogenesis inhibition with SU5416 is a promising therapeutic approach in treating patients with KS, and further clinical evaluation is currently under way.     

The role of vascular endothelial growth factor (VEGF) in oral dysplasia and oral squamous cell carcinoma

A better understanding of oral cancer pathogenesis is essential to improving patient prognosis and treatment modalities. Research has shown a significant increase in vascularity during the transition from normal oral mucosa, through differing degrees of dysplasia, to invasive carcinoma. A close association between tumour angiogenesis and tumour progression to late oral squamous cell carcinoma has also been reported. Vascular endothelial growth factor (VEGF) acts to induce endothelial proliferation, migration and specialisation in new and developing vascular beds. VEGF is also a promoter of angiogenesis in many tumour types, and has therefore been subject to numerous studies in oral dysplasia and squamous cell carcinomas. The contribution of VEGF to the development of oral dysplasia and invasive carcinomas is currently disputed due to conflicting results within the literature. More research is required before VEGF technology can be used to improve the diagnosis, prognosis and treatment of sufferers.     

Prognostic significance of the expression of vascular endothelial growth factor (VEGF) and VEGF-C in gastric carcinoma

BACKGROUND AND OBJECTIVES: Angiogenic factors play a major role in tumor growth and metastasis. The purpose of this study was to clarify the prognostic significance of the expression of vascular endothelial growth factor (VEGF) and VEGF-C in gastric carcinoma. METHODS: Formalin-fixed and paraffin embedded sections of tumor tissue were obtained from 76 patients who underwent curative gastrectomy for gastric carcinoma. Immunohistochemical staining for VEGF and VEGF-C was performed. RESULTS: VEGF and VEGF-C were positively expressed in 39 and 45% of the patients, respectively. No correlation existed between VEGF and VEGF-C expressions. VEGF expression was significantly correlated with venous invasion. VEGF-C expression was significantly correlated with lymphatic and venous invasion. Patients with positive staining for VEGF showed a significantly lower survival rate than VEGF negative patients. After subdivision, according to the combination of VEGF and VEGF-C expression, VEGF-C expression had a significant unfavorable impact on prognosis among patients with negative staining for VEGF. The expression of VEGF and/or VEGF-C was independent prognostic determinant by the multivariate survival analysis. CONCLUSIONS: The positive expression for VEGF and/or VEGF-C was an important prognostic determinant after curative gastrectomy for gastric carcinoma. VEGF-C may stimulate the tumor progression in the absence of VEGF.     

Serum vascular endothelial growth factor (VEGF) levels correlate with tumor VEGF and p53 overexpression in endocrine positive primary breast cancer

Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, associated with unfavorable clinical characteristics in breast cancer. The aim of this study was to evaluate different angiogenic markers in endocrine-positive breast cancer patients. The authors analyzed serum and tumor samples from 71 patients with endocrine-positive operable primary breast cancer to determine the expression and the possible relationship between circulating serum VEGF levels, tumor VEGF expression, microvessel density (MVD), and other immunohistochemical parameters. Basal VEGF serum levels were significantly higher in breast cancer patients than in healthy controls. A significant correlation was observed between basal VEGF serum concentrations, microvessel density (p = 0.01) and p53 status (p = 0.004). Intratumoral VEGF expression was significantly associated with neoplastic embolization (p = 0.041) and circulating VEGF levels (p = 0.047). The results confirm that in primary endocrine-positive breast cancer serum VEGF levels are elevated and show a positive relationship with tumor VEGF and p53 overexpression.     

血管内皮生长因子在子宫颈癌组织中的表达及意义

目的　探讨血管内皮生长因子 (VEGF ,VEGFmRNA)在子宫颈癌组织中的表达及意义。方法　采用免疫组织化学技术SP法及原位杂交方法检测 33例宫颈癌 ,其中鳞癌 2 0例 ,腺癌 13例及 10例正常宫颈组织中VEGF及VEGFmRNA的表达情况。结果　宫颈癌组织切片中VEGF及VEGFmRNA皆有活跃表达。正常宫颈组织中VEGFmRNA呈阴性表达 ,VEGF蛋白可见弱阳性表达 ,两组比较差异有显著性 (P <0 .0 5 ) ;宫颈癌组织切片中的VEGFmRNA的表达与宫颈癌病理类型比较差异有显著性 (P <0 .0 5 ) ;而与宫颈癌临床分期及病理分化程度比较差异无显著性 (P >0 .0 5 )。结论　VEGF及VEGFmRNA的阳性表达在子宫颈癌的发生 ,发展中可能有着重要的意义。VEGF的检测对判断宫颈癌的病理类型有一定的临床价值。     

VEGF硫代反义寡核苷酸抑制U937细胞VEGF的表达

Objective： To study the effect of VEGF antisense oligodeoxynucleotide （VEGF ASODN） on VEGF expression in acute monocyte leukemic cell line U937 in vitro. Methods： U937 cells were incubated with VEGF ASODN （final concentration as follows： 10, 20 and 30 μmol/L respectively） or scrambled sequence, compared with negative control. The expression of VEGF mRNA was measured by semi-quantitative RT-PCR, VEGF protein was measured by Western blot. Results： VEGF ASODN obviously inhibited expression of VEGF mRNA in U937 cell, compared with scrambled sequence and negative control （P〈0.05）. And the inhibition effect was most remarkable after 24 h, which is related with the dose of VEGF ASODN （P〈0.05）. Scrambled sequence groups had no significant difference compared with negative control groups （P〉0.05）. VEGF ASODN obviously inhibited expression of VEGF protein, compared with scrambled sequence and negative control （P〈0.05）. Conclusion： The expressions of VEGF at mRNA and protein levels in leukemic cell line U937 are down-regulated after being treated with VEGF ASODN.     

胰腺癌组织中VEGF的表达与血管计数的关系

目的　研究血管内皮生长因子（ＶＥＧＦ）在胰腺癌组织血管形成中的作用。方法采用免疫组织化学 ＡＢＣ法研究了３３的胰腺癌标本中 ＶＥＧＦ的表达及分布,并研究了ＶＥＧＦ的表达强度与肿瘤血管计数的关系。结果（１）２２例（６６．７％）强表达ＶＥＧＦ, ８例（２４．２％）表达呈中等强度,３例（９．１％）呈弱阳性。ＶＥＧＦ在癌细胞呈胞浆内染色,肿瘤间质血管内皮细胞及瘤周正常组织中也可见 ＶＥＧＦ着色。（２）ＶＥＧＦ中等强度以上染色的病例中７例（２３．３％）血管计数不足 ２０个,弱阳性的标本中 １例计数达 １５个。（３）ＶＥＧＦ表达强度与肿瘤血管计数存在显著相关性（Ｐ＜０．０５）。结论ＶＥＧＦ在胰腺病组织血管形成过程中起重要作用,可以作为肿瘤血管抑制治疗的靶因子。     

Vascular endothelial growth factor (VEGF) expression in plasmacytoma

Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis. Although the role and importance of angiogenic factors such as VEGF have been established in various solid tumors, this has not been widely evaluated in hemopoietic neoplasias. In this trial, VEGF was studied in plasmacytoma and VEGF expression was compared with histopathologic grade. Forty-seven samples have taken from cases with plasmacytoma (Pm) (33 bones and 14 soft tissue plasmacytomas) were used as study material. Pm was the initial presentation in all cases, and bone marrow (BM) involvement was detected in 19 cases with systemic evaluation. Twenty-seven of the cases were male (age range was between 19 and 81 years). Histopathologically 27 cases had mature and 20 cases had immature morphology. Immunohistochemical analysis was used to detect VEGF expression and this was scored according to the percentage of the VEGF stained cells. VEGF expression was detected in 32 cases and in eight cases this expression was strong. In 11 cases expression was moderate and 13 cases showed mild expression. When we compared VEGF expression with pathologic grade, 17 of 20 immature samples showed VEGF expression while 15 of 27 mature samples showed VEGF expression. There was a statistically significant association between immature morphology and VEGF expression (p < 0.0264). Additionally all the samples, except one, with strong VEGF expression showed immature morphology. In conclusion two thirds of the cases with Pm showed VEGF expression and this was associated with immature morphology. Increased expression of VEGF was seen in plasmacytomas, and additional studies are needed to determine whether this translates to increased microvasculature or increased risk of progression to myeloma.