Relationship of hypoxia-inducible factor-1alpha expression and vascular endothelial growth factor in SKOV-3 ovarian cancer model

OBJECTIVE: To investigate the correlation of hypoxia-inducible factor (HIF)-1alpha and vascular endothelial growth factor (VEGF) or micro-vessel density (MVD). METHODS: The ovarian cancer cell line SKOV3 was transplanted into nude mice to form xenogeneic tumor. Mice were treated with rapamycin 4 mg/kg, sulindac 100 mg/(kg.d) and saline 200 microl respectively. Expression of HIF-1alpha and VEGF proteins and MVD were determined by immunohistochemistry. The mRNA of Glut1 and VEGF was studied by RT-PCR. RESULTS: The positive expression of HIF-1alpha and VEGF was moderate to strong, and MVD was high (31 +/- 8) in control group. In rapamycin treated group, the expression of HIF-1alpha was inhibited to weak positive or negative (P < 0.05), the VEGF protein and mRNA expression decreased (P < 0.05), MVD was also suppressed to a low level (13 +/- 5). There was a significant correlation between HIF-1alpha expression and VEGF expression (by Spearman's coefficient r = 0.8264, P < 0.01), and MVD (r = 0.4842, P < 0.05). CONCLUSIONS: HIF-1alpha protein can regulate VEGF protein and its mRNA expressions. It correlates with MVD in ovarian tumor tissue.     

Inhibition of hypoxia-inducible factor 1alpha expression and tumor growth in SKOV3 ovarian cancer model by sirolimus

OBJECTIVE: To investigate the inhibitory effect of the mammalian target of rapamycin (mTOR) inhibitor, sirolimus on expression of hypoxia-inducible factor (HIF)1alpha protein and growth of ovarian carcinoma in an athymic mouse xenogeneic transplant model of ovarian cancer. METHODS: Four groups of female nude mice were inoculated subcutaneously with SKOV3 cells. After inoculation, mice were treated with saline, rapamycin alone, paclitaxel alone and sirolimus + paclitaxel. In each tumor protein expressions of HIF-1alpha, bcl-2 and apoptosis were determined by immunohistochemistry and RT-PCR. RESULTS: In sirolimus and sirolimus + paclitaxel groups protein expression of HIF-1alpha was inhibited. Tumor burden in rapamycin alone, sirolimus + paclitaxel, and paclitaxel alone was reduced by 47.9% (P < 0.05), 51.0% (P < 0.05), and 31.8% (P > 0.05) respectively compared with controls. Cell apoptosis inder in sirolimus alone (36), sirolimus + paclitaxel (40), paclitaxel alone (22), increased compared with control (15), while expression of bcl-2 decreased compared with control. CONCLUSION: Sirolimus inhibited protein expression of HIF-1alpha, increased tumor apoptosis and decreased tumor growth.     

应用组织芯片技术研究卵巢癌组织中缺氧诱导因子1α与血管生成的关系

目的　探讨缺氧诱导因子 1α(hypoxiainduciblefactor 1α ,HIF 1α)在卵巢癌组织中的表达及其与血管生成的关系。方法　联合应用组织芯片和原位杂交、免疫组化技术 ,检测 2 95份卵巢上皮性肿瘤 (其中卵巢癌 2 38份、交界性卵巢肿瘤 19份、良性卵巢肿瘤 38份 )及 13份正常卵巢组织中HIF 1αmRNA和血管内皮生长因子 (VEGF)的表达情况 ,以CD3 4 单克隆抗体标记血管内皮细胞来检测微血管密度 (MVD)。结果　卵巢癌、交界性卵巢肿瘤和良性卵巢肿瘤、正常卵巢组织中HIF 1αmRNA的阳性表达率分别为 81 9%、4 2 1%、13 2 %和 0。交界性卵巢肿瘤和卵巢癌组织中HIF 1αmRNA的表达高于正常卵巢和良性卵巢肿瘤 ,卵巢癌高于交界性肿瘤 ,差异均有统计学意义 (P <0 0 1)。卵巢癌组织中HIF 1αmRNA的表达与手术病理分期和病理类型无关 (P >0 0 5 ) ,而与病理分级呈正相关 (r=0 2 4 6 ,P <0 0 1)。卵巢癌组织中HIF 1αmRNA表达与VEGF表达 (r =0 2 0 6 ,P =0 0 1)和MVD计数 (r =0 4 5 1,P <0 0 1)均呈显著正相关。结论　卵巢癌组织过度表达HIF 1αmRNA ,并通过诱导VEGF促进肿瘤的新生血管形成。     

上皮性卵巢癌血管内皮生长因子的表达与肿瘤内微血管密度的相关性研究

目的 :探讨上皮性卵巢癌组织中血管内皮生长因子 (VEGF)是否与肿瘤内微血管密度 (MVD)、淋巴转移等临床病理学因素存在相关性。方法 :以多克隆抗VEGF抗体和单克隆抗CD34抗体分别标记 4 5例FIGOⅠ～Ⅳ期上皮性卵巢癌术后标本的VEGF和MVD。用彩色图像病理分析系统测定VEGF的相对含量 ,MVD采用人工计数。分析VEGF与MVD、肿瘤期别、组织学类型、腹水量以及淋巴转移的关系。结果 :(1)VEGF的平均吸光度为 0 .178± 0 .14 9(中位数 0 .16 7)。MVD值平均为 72 .2 6± 5 8.5 2 /mm2 (中位数 6 8.4 7/mm2 ) ;(2 )VEGF表达水平与MVD之间存在显著相关性 (r =0 .92 6 ,P <0 .0 1) ;(3)盆腔淋巴转移(n =12 )VEGF平均吸光度 (0 .193± 0 .15 3)显著高于无盆腔淋巴转移组 (n =32 )的 0 .138± 0 .0 90 ,(P <0 .0 5 )。不同期别 ,组织学类型和腹水量之间的VEGF表达强度无显著差异(P >0 .0 5 )。结论 :VEGF表达与上皮性卵巢癌血管生成的增强密切相关     

Cytokines IL-1β, IL-2, IL-6, IL-8, MCP-1, GM-CSF and TNFα in patients with epithelial ovarian cancer and their relationship to treatment with paclitaxel

Abstract. Penson RT, Kronish K, Duan Z, Feller A, Stark P, Cook SE, Duska LR, Fuller AJ, Goodman AK, Nikrui N, MacNeill KM, Matulonis UA, Preffer FI, Seiden MV. Cytokines IL-1β, IL-2, IL-6, IL-8, MCP-1, GM-CSF and TNFα in patients with epithelial ovarian cancer and their relationship to treatment with paclitaxel.
In vitro work suggests that cytokines may be important modulators of the cytotoxic effects of paclitaxel and subsequent drug resistance. This has been investigated in vivo in patients with ovarian cancer by ELISA. There was consistently elevated expression of IL-6 and IL-8 but not MCP-1, IL-1β, IL-2, GM-CSF or TNFα. Peritoneal fluid concentrations of IL-6, IL-8 and MCP-1 were two to three logs greater than serum concentrations. Elevated concentrations of IL-6 correlated with a poor final outcome ( P = 0.039), and increased IL-6 and IL-8 correlated with a poor initial response to chemotherapy ( P = 0.041 and P = 0.041, respectively). There was a relatively clear pattern of change in all three cytokines. In serum, IL-6, IL-8 and MCP-1 decreased with the administration of steroids prior to paclitaxel, and increased in the 24 h after paclitaxel. Postoperative drainage fluid was relatively acellular, preventing flow-cytometric analysis of epithelial cells for apoptosis, but suggested activation of T cells by paclitaxel. IL-6 and IL-8 appear to be of prognostic importance in epithelial ovarian cancer. Treatment with paclitaxel is associated with an increase in expression of a limited number of cytokines in patients with ovarian cancer, notably IL-6, IL-8 and MCP-1.     

分化抑制因子Id-1与VEGF及MVD在宫颈癌变中的相关性分析

目的:研究分化抑制因子-1(Id-1)与血管内皮生长因子(VEGF)及微血管密度(MVD)在宫颈组织癌变中的相关性,探讨Id-1在宫颈癌血管形成中的机理。方法:采用免疫组化法检测50例宫颈癌石蜡标本中Id-1、VEGF及CD34的表达;用CD34标记肿瘤微血管,计算MVD。结果:宫颈癌组织中Id-1、VEGF及MVD均呈高表达,且均与临床FIGO分期进展具有相关性(P<0.05)。宫颈癌组织中三者的表达具有显著正相关性(P<0.01),Id-1与VEGF、Id-1与MVD的spearman相关系数(Ra)分别为0.43,0.48。结论:宫颈癌组织中Id-1与VEGF、MVD的表达具有正相关性,Id-1可能是通过促进肿瘤微血管生成的机制参与宫颈癌的发生。     

Clinicopathologic study of vascular endothelial growth factor, thrombospondin-1, and microvessel density assessed by CD34 in patients with stage III ovarian carcinoma

Abstract.   Karavasilis V, Malamou-Mitsi V, Briasoulis E, Tsanou E, Kitsou E, Pavlidis N. Clinicopathologic study of vascular endothelial growth factor, thrombospondin-1, and microvessel density assessed by CD34 in patients with stage III ovarian carcinoma. Int J Gynecol Cancer 2006; 16(Suppl. 1): 241–246.
The aim of the study was to investigate angiogenesis in patients with advanced-stage ovarian carcinoma. We used paraffin-embedded tumor tissues from 33 patients diagnosed with FIGO III ovarian cancer who had optimal surgery and received platinum-based chemotherapy. The tissue expression of CD34, vascular endothelial growth factor (VEGF), and thrombospondin-1 (TSP-1) was assessed immunohistochemically. CD34 stained hot spot areas were used to evaluate tumor microvessel density (MVD). VEGF and TSP-1 were assessed by semiquantitative methods. The studied molecules were investigated for relationship with standard clinicopathologic parameters. MVD count was high: median value of 39, range 12–143 microvessels/mm². VEGF was present in all cases and stained strong in 91%. Stroma staining for TSP-1 was weak in 79% of the cases, strong in 6%, and absent in five (15%). We did not find correlations between the three studied markers and histologic type or tumor grade. MVD score did not relate to VEGF or TSP-1. We only observed a trend toward a longer survival in patients with tumors expressing high TSP-1 (60 vs. 36 months, P = 0.1). Proangiogenetic factor VEGF is highly expressed in advanced-stage ovarian carcinomas. The findings of this study may offer support for considering VEGF-targeted therapeutics in ovarian cancer treatment research.     

血管内皮生长因子及其受体在卵巢上皮性癌组织中的表达

目的研究血管内皮生长因子(VEGF)及其受体(FLT1、FLK1)mRNA在卵巢上皮性癌组织中的表达及与临床病理因素的相关性。方法采用逆转录聚合酶链反应技术检测70例卵巢上皮性癌及22例卵巢良性肿瘤病变组织标本中VEGFmRNA及其受体FLT1mRNA及FLK1mRNA的表达。结果在良、恶性卵巢组织中均检测到VEGF121mRNA、165mRNA的表达,在卵巢上皮性癌组织中表达水平分别为(0.452±0.134,0.301±0.096)高于良性卵巢肿瘤[0.195±0.066(P=0.000),0.204±0.059(P=0.001)];在卵巢上皮性癌组织中,VEGF121mRNA表达高于VEGF165mRNA(P=0.000),而在良性卵巢肿瘤组织中两者表达水平差异无显著性(P=0.667)。FLT1mRNA、FLK1mRNA在部分卵巢上皮性癌组织中表达,分别为38.6%(27/70)和25.7%(18/70),而在良性卵巢肿瘤组织中未见表达。卵巢癌组织中VEGF121、VEGF165、FLT1、FLK1之mRNA表达与患者年龄、肿瘤体积、淋巴结转移、肿瘤分期之间无明显相关性。结论VEGF121、165及其受体FLT1、FLK1在卵巢上皮性癌的血管生成中起重要作用。     

HIF-1α、VEGF及MVD在子痫前期不同发病类型胎盘的表达

目的:探讨缺氧诱导因子1α(HIF-1α)、靶基因血管内皮生长因子(VEGF)及微血管密度(MVD)在子痫前期患者胎盘组织的表达及与胎盘血管病变的关系。方法:用链酶菌抗生物素蛋白-过氧化物酶连接(SP)法检测早发型,晚发型重度子痫前期患者和正常妊娠妇女(对照组)胎盘组织中HIF-1α、VEGF的表达,并计数胎盘微血管密度(MVD)值,并进行相关性分析。结果:(1)子痫前期患者胎盘组织中HIF-1α阳性表达率明显高于正常对照组,差异有统计学意义(P<0.05),早发型、晚发型子痫前期组HIF-1α与正常对照组的差异有统计学意义(P<0.05),早发型组HIF-1α阳性表达率高于晚发型组,两者差异有统计学意义(P<0.05);(2)子痫前期患者胎盘组织中VEGF阳性表达率低于正常对照组,两者差异有统计学意义(P<0.05),而早发型组VEGF阳性表达率低于晚发型组,差异亦有统计学意义(P<0.05);(3)正常对照组,晚发型子痫前期组,早发型子痫前期组MVD计数依次递减,子痫前期组与正常对照组比较有统计学差异(P<0.05),早发型组与晚发型组比较有统计学差异(P<0.05);(4)子痫前期组和正常对照组胎盘中HIF-1α表达与VEGF及MVD值的变化呈显著负相关(r=-0.562,P<0.05;r=-0.622,P<0.05),VEGF及MVD值的变化则呈显著正相关(r=0.718,P<0.05)。结论:HIF-1α在子痫前期患者胎盘组织中表达升高,通过下调靶基因VEGF,引起VEGF降低,影响胎盘血管重铸,参与子痫前期的发生和发展。     

VEGF、MMP2、MVD与卵巢癌临床病理关系的研究

目的 :研究卵巢癌中VEGF、MMP2的表达和MVD与临床病理参数和预后的关系并探讨其临床价值。方法 :采用免疫组化技术检测 5 3例卵巢癌和 10例卵巢交界性肿瘤中VEGF、MMP2的表达水平 ,用CD34标记新生血管内皮细胞 ,在显微镜下观察血管密度。结果 :卵巢癌中MVD与年龄呈正相关 (P =0 .0 16 ) ,粘液性囊腺癌中MVD高于其它组织学类型 (P <0 .0 1)。卵巢癌中VEGF的表达与FIGO手术分期呈正相关 (P =0 .0 0 1) ,VEGF表达还与腹水量呈正相关 (P =0 .0 0 2 )。MVD与VEGF、MMP2表达呈正相关 (P值分别为 0 .0 2 1和 0 .0 31) ,VEGF表达与MMP2表达呈正相关 (P =0 .0 0 2 )。VEGF、MMP2强阳性表达和MVD较高 (≥ 10 /HP)的患者预后差 (P值分别为 0 .0 2 6 ,0 .0 36和 0 .0 38)。结论 :VEGF是重要的血管生成因子 ,MMP2不仅在肿瘤的浸润和转移中意义重大 ,而且在肿瘤的血管生成中发挥作用。卵巢癌的FIGO手术分期、MVD及VEGF、MMP2表达与预后相关 ,特别是MMP2在肿瘤的浸润、转移和血管生成中有双重作用 ,既有助于判断患者对传统治疗的敏感性 ,而且对开发针对肿瘤的生物特异性治疗具有启发作用。     

血管抑素基因治疗人卵巢癌裸鼠皮下移植瘤的实验研究

目的:研究血管抑素(Angiostatin)基因转染治疗人卵巢癌裸鼠皮下移植瘤的作用及其相关机理。方法:使用人卵巢癌细胞株SKOV3建立人卵巢癌裸鼠皮下移植瘤模型。随机将荷瘤裸鼠分为基因治疗组、空质粒组和空白对照组,分别于瘤体注射Angiosta-tin/PCDNA3、空质粒PCDNA3和无菌生理盐水,质粒用脂质体DOTAP介导转染细胞。观察各组动物的肿瘤生长曲线,检测各组肿瘤Angiostatin、VEGF的表达和微血管密度(MVD),利用TUNEL染色法行原位细胞凋亡分析,计算细胞凋亡指数(AI)。结果:基因治疗组裸鼠的肿瘤生长在早期受到明显抑制,大约1周后生长速度有所加快,肿瘤组织中Angiostatin蛋白局部高表达,VEGF的表达高于空质粒组和空白对照组,AI(4.21±0.49)高于空质粒组和空白对照组,MVD(19.3±3.2)低于空质粒组。结论:Angiostatin基因可以通过抑制血管生成而在一定程度上抑制肿瘤生长,其作用的发挥是独立于VEGF的。     

Early missed abortion is associated with villous angiogenesis via the HIF-1α/VEGF signaling pathway

Purpose

To analyze the effects of the hypoxia-inducible factor 1-alpha (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway on villous angiogenesis in early missed abortion.

Methods

Immunohistochemical assays were performed to detect the expression of micro-vessel density (MVD), HIF-1α, and VEGF in villous tissue samples from 30 missed abortions and 30 elective abortions in early pregnancy. We further analyzed the correlation between HIF-1α/VEGF and MVD. HTR8/SVneo cells were cultured under hypoxic (1%) or normoxic (20%) conditions, tube formation was investigated, and protein and mRNA level of HIF-1α/VEGF were determined using western blot and qRT-PCR. Finally, HIF-1α was knocked down with siRNA introduced into HTR8/SVneo cell line under hypoxia, and HIF-1α/VEGF expression and HTR8/SVneo tube formation were investigated.

Results

The expression of HIF-1α, VEGF, and MVD was lower in the missed abortion than in the elective abortion group. Correlational analysis showed that the expression of HIF-1α and VEGF was positively correlated with MVD in both groups. The levels of HIF-1α/VEGF mRNA and protein in HTR8/SVneo cells were significantly enhanced under hypoxia. HIF-1α knockdown with siRNA inhibited HIF-1α/VEGF mRNA and protein levels of HTR8/SVneo cells induced by hypoxia. Tube formation of HTR8/SVneo cells was significantly enhanced in hypoxic culture and was inhibited by HIF-1α knockdown with siRNA.

Conclusions

Our results reveal a novel role for HIF-1α/VEGF in regulating villous angiogenesis in early pregnancy and suggest that it may be a novel biomarker for missed abortion.

     

Effects of the hypoxia-inducible factor-1 inhibitor echinomycin on vascular endothelial growth factor production and apoptosis in human ectopic endometriotic stromal cells

Recent evidence points to a possible role for hypoxia-inducible factor (HIF)-1 in the pathogenesis and development of endometriosis. The objectives of this study were to investigate the critical role of HIF-1 in endometriosis and the effect of the HIF-1 inhibitor echinomycin on human ectopic endometriotic stromal cells (eESCs). Ectopic endometriotic tissues were obtained from 20 patients, who received an operation for ovarian endometriomas. We examined vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) production, HIF-1 expression, cell proliferation and apoptosis of eESCs. Cobalt chloride (CoCl₂) significantly induced expression of HIF-1α protein and VEGF production in a time-dependent manner in eESCs, but reduced SDF-1 production. VEGF production was significantly suppressed by treatment of 100?nM echinomycin without causing cell toxicity, but 0.1–10?nM echinomycin or 100?nM progestin had no significant effect. SDF-1 production was not affected by echinomycin treatment at any dose. Echinomycin inhibited cell proliferation and induced apoptotic cell death of the eESCs, and significantly inhibited expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL. Echinomycin inhibits VEGF production and induces apoptosis of eESCs by suppression of Bcl-2 and Bcl-xL. These findings suggest the unique therapeutic potential for echinomycin as an inhibitor of HIF-1 activation for endometriosis treatment.     

Vascular endothelial growth factor (VEGF): can we use it as prognostic factor in endometrial cancer?

AIM: The aim of the study was to investigate if VEGF levels reflect the severity of endometrial cancer and the clinic relationship between microvasal density (MVD) and concentration of VEGF in tumor. METHODS: The study was conducted on 22 patients affected by endometrial cancer who were submitted to total abdominal radical hysterectomy plus bilateral salpingo-ophorectomy. VEGF (pg/mL) and MVD values were measured on histologic specimens of endometrial cancer obtained during the surgical treatment. The means and standard deviations of estimated values were calculated and a statistical comparison was effected by student t test for not coupled data. Pearson correlation test was used to analyze the eventual correlation among VEGF and MVD values in overall patients. RESULTS: We have documented that VEGF expression and MVD change according to FIGO stage, lympho-vascular infiltration and lymph node involvement. Pearson correlation test shows a good linear positive correlation in overall patients between VEGF and MVD values. CONCLUSIONS: Results obtained show a possible use of VEGF as prognostic factor in endometrial cancer. Confirmation of these data may permit both to identify high-risk patients, who must be treated with a more aggressive treatment, and to use an angiogenic therapy in endometrial cancer.     

卵巢癌临床和生物学预测因子研究

目的 :研究影响卵巢癌患者预后的临床和生物学因素。方法 :回顾分析卵巢癌患者 88例的临床资料 ,并检测肿瘤组织上皮中血管内皮生长因子 (VEGF)和胸苷磷酸化酶 (TP)的表达及肿瘤间质内微血管密度 (MVD) ,应用Cox比例风险模型评估临床因素包括年龄、临床分期、组织学类型、细胞分化级别、术后残余癌灶及生物学因子 :VEGF、TP、MVD与总生存期 (OS)和无进展生存期 (PFS)之间的相关性。结果 :(1)患者的年龄、临床分期和术后癌灶大小显著影响其生存期的长短 ;(2 )Cox模型未发现VEGF、TP和MVD与OS和PFS之间的相关性 ;(3)低分化 (G3、G4 )肿瘤细胞中VEGF的表达显著高于高分化(G1、G2 )者。结论 :(1)年龄、临床分期和术后残余癌灶是三个独立的临床预测因子 ,表明早期诊断和适宜治疗极为重要 ;对老年患者应密切监护 ;(2 )低分化肿瘤细胞比高分化肿瘤细胞具有更恶的基因型和表现型 ,更易诱导间质内微血管生成 ,促进肿瘤的复发、转移和快速生长 ,提示抗微血管生成治疗肿瘤的可行性     

VEGF、P53在卵巢上皮性肿瘤的表达及其与血管生成关系的研究

目的探讨VEGF、P53在卵巢上皮性肿瘤中的表达及其与血管生成的关系,旨在了解卵巢上皮性肿瘤血管生成活性及其调节机制,为卵巢癌的治疗提出新的思路.方法采用免疫组化LSAB法分析74例卵巢上皮性肿瘤微血管密度(MVD)、血管内皮生长因子(VEGF)和P53蛋白的表达状况及三者间的关系.结果MVD在腺瘤、交界瘤、卵巢癌中的数值依次升高,各组间差异均有显著性(P＜0.001,P＜0.05);MVD在卵巢癌中粘液性明显高于浆液性和子宫内膜样(P＜0.05,P＜0.05);VEGF在卵巢癌中的表达率明显高于腺瘤及交界瘤(P＜0.05).P53蛋白仅出现于卵巢癌组织,表达率50%,卵巢癌P53蛋白阳性组MVD高于P53阴性组(P＜0.05);等级相关分析显示卵巢上皮性肿瘤VEGF的表达强度与MVD呈正相关(r=0.762,P＜0.001);P53、VEGF间也存在正相关关系(ra=0.762,P＜0.01).结论血管生成活性的不同,有助于卵巢良、恶性肿瘤的鉴别;VEGF是卵巢上皮性肿瘤重要的促血管生成因子,且可能与卵巢癌腹水形成有关;P53突变可促进卵巢上皮性癌的血管生成,且在一定程度上可上调VEGF表达.     

Prognostic significance of vascular endothelial growth factor expression in ovarian cancer patients: a long-term follow-up

Abstract.   Rudlowski C, Pickart A-K, Fuhljahn C, Friepoertner T, Schlehe B, Biesterfeld S, Schroeder W. Prognostic significance of vascular endothelial growth factor VEGF expression in ovarian cancer patients: a long-term follow-up. Int J Gynecol Cancer 2006; 16(Suppl. 1): 183–189.
The purpose of the study was to determine vascular endothelial growth factor (VEGF) concentrations in ascites from ovarian cancer and to correlate these data with VEGF expression in ovarian tumors, serum VEGF concentrations, and clinicopathologic characteristics. Ascites, serum, and tumor tissue from 65 ovarian carcinomas and eight borderline tumors were collected. VEGF concentration in peritoneal fluids and sera was determined using enzyme immunoassay. VEGF tumor expression was evaluated immunohistochemically. Significantly higher VEGF concentrations were found in ascites from malignant tumors (median, 2575 pg mL⁻¹) compared with borderline tumors (median 181.9 pg mL⁻¹) and benign peritoneal fluid (184.5 pg mL⁻¹). Both VEGF ascites concentration and tumor expression correlated with advanced tumor stages and ascites volume. Elevated VEGF ascites levels were negatively correlated to patient survival. No differences between VEGF serum levels could be observed between ovarian cancer patients and patients with benign cysts. This study showed for the first time the clinical significance of elevated VEGF ascites level in ovarian carcinomas. VEGF is expressed by ovarian tumor cells and locally released in the malignant peritoneal fluid but is not increased in the serum of preoperative ovarian cancer patients. The enhanced VEGF level support novel therapeutic perspectives by VEGF inhibition.