Prognostic Value of Vascular Endothelial Growth Factor and its Receptors Flt-1 and Flk-1 in Astrocytic Tumours

Summary  Background. Vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) is an important regulator of angiogenesis and vascular permeability.  Method. We examined immunohistochemically expressions of VEGF and its corresponding receptors Flt-1 and Flk-1 in a series of 50 astrocytic tumours, and correlated their expressions with the degree of angiogenesis, brain edema and prognosis.  Findings. There were significant relationships between VEGF, Flk-1 expressions and glioma malignancy grading, intratumoural vascularity and peritumoural brain edema, respectively. Patients with VEGF positive low grade astrocytoma and glioblastoma multiforme had a significantly shorter mean overall survival time than those with negative tumours (P=0.0010 and 0.0180, respectively). Flk-1 is also a significant prognostic factor within each tumour grade, which has a negative impact on overall survival. Additionally, overexpression of VEGF and Flk-1 were significantly associated with earlier recurrence in patients with low grade astrocytomas (P=0.0018 and 0.0240, respectively).  Interpretation. It is possible to subcategorize each grade of astrocytic tumours based on their VEGF and Flk-1 staining pattern, which may be crucial in predicting the biological behavior of tumours and thus provide useful information with regard to adequate treatment.     

低氧诱导因子1α及血管内皮生长因子在前列腺癌中的表达及意义

目的:观察低氧诱导因子1α(H IF-1α)及血管内皮生长因子(VEGF)在前列腺癌(PCa)中的表达及意义。方法:32例PCa患者,根据G leason评分,将≥7分者设为高G leason评分组(n=12),<7分者为低G leason评分组(n=20)。良性前列腺增生(BPH)16例,BPH伴高级别前列腺上皮内瘤(PIN)15例,正常前列腺组织(NP)12例。采用免疫组化染色CD34观察各组组织中微血管密度(MVD)及H IF-1α、VEGF的表达情况。结果:PCa、PIN中H IF-1α阳性表达率分别为62.5%、60.0%,较BPH(6.3%)及NP(0)高,差异有统计学意义(P<0.05)。PCa、PIN中VEGF阳性表达率分别为78.1%、73.3%,较BPH(18.7%)及NP(8.3%)高,差异亦有统计学意义(P<0.05)。PCa的MVD为66.9±18.0,明显高于BPH(28.3±6.9)及NP(15.3±2.9)(P<0.05)。高G leason评分组H IF-1α、VEGF阳性率及MVD值均高于低G leason评分组,差异均有显著性(P<0.05)。结论:H IF-1α及VEGF过表达是PCa形成的早期事件,与PCa密切相关。     

Vascular Endothelial Growth Factor C for Polycystic Kidney Diseases

Polycystic kidney diseases (PKD) are genetic disorders characterized by progressive epithelial cyst growth leading to destruction of normally functioning renal tissue. Current therapies have focused on the cyst epithelium, and little is known about how the blood and lymphatic microvasculature modulates cystogenesis. Hypomorphic Pkd1^nl/nl mice were examined, showing that cystogenesis was associated with a disorganized pericystic network of vessels expressing platelet/endothelial cell adhesion molecule 1 and vascular endothelial growth factor receptor 3 (VEGFR3). The major ligand for VEGFR3 is VEGFC, and there were lower levels of Vegfc mRNA within the kidneys during the early stages of cystogenesis in 7-day-old Pkd1^nl/nl mice. Seven-day-old mice were treated with exogenous VEGFC for 2 weeks on the premise that this would remodel both the VEGFR3⁺ pericystic vascular network and larger renal lymphatics that may also affect the severity of PKD. Treatment with VEGFC enhanced VEGFR3 phosphorylation in the kidney, normalized the pattern of the pericystic network of vessels, and widened the large lymphatics in Pkd1^nl/nl mice. These effects were associated with significant reductions in cystic disease, BUN and serum creatinine levels. Furthermore, VEGFC administration reduced M2 macrophage pericystic infiltrate, which has been implicated in the progression of PKD. VEGFC administration also improved cystic disease in Cys1^cpk/cpk mice, a model of autosomal recessive PKD, leading to a modest but significant increase in lifespan. Overall, this study highlights VEGFC as a potential new treatment for some aspects of PKD, with the possibility for synergy with current epithelially targeted approaches.     

环氧化酶2和血管内皮细胞生长因子在前列腺癌组织中的表达及意义

目的:探讨环氧化酶2(COX2)和血管内皮细胞生长因子(VEGF)在前列腺癌中的表达及临床意义。方法:采用免疫组化SP法检测40例前列腺癌和10例良性前列腺增生(BPH)组织中COX2和VEGF的表达。结果:前列腺癌组织中COX2和VEGF的阳性表达均明显高于BPH(P<0.01);COX2和VEGF在前列腺癌中的表达水平与其病理分级和临床分期均呈正相关(P均<0.05);前列腺癌中COX2表达水平和VEGF的表达水平相关(χ2=4.768,P=0.01)。结论:COX2可能诱导VEGF的表达而促进前列腺癌肿瘤血管的生成和侵袭转移。COX2和VEGF是检测前列腺癌的较好分子标志物,可望用于前列腺癌的辅助诊断和预后判断。     

胆管癌组织中VEGF和c-myc的表达及其意义

目的　探讨VEGF和c myc在胆管癌组织中的表达和二者之间的相关性及其在胆管癌发生、发展和转移中的作用。方法　应用免疫组化ABC法对 38例胆管癌组织和 2 0例正常胆管组织中VEGF和c myc的表达进行检测。结果　VEGF和c myc在胆管癌组织中的表达阳性率分别为 84 .2 % (32 /38)和 6 5 .8% (2 5 /38) ,明显高于正常胆管组织中的表达阳性率〔5 0 .0 % (10 /2 0 )和 2 0 .0 % (4/2 0 )〕 ,差异有统计学意义 (P<0 .0 5 ) ;VEGF与c myc的表达呈正相关 (r=0 .99,P<0 .0 1) ,二者的协同表达与胆管癌的淋巴结转移有关 ,而与肿瘤的分级无关。结论　VEGF可能在胆管癌形成、发展和转移中与c myc基因有协同作用 ,且与胆管癌的淋巴结转移有关。     

Angiogenesis and Brain Oedema in Intracranial Meningiomas: Influence of Vascular Endothelial Growth Factor

Summary The correlation between angiographic neovascularization, peritumoural brain oedema (PTBOe) and the expression of vascular endothelial growth factor (VEGF) , was analysed in 30 patients with intracranial meningiomas. Pre-operative angiograms were examined for the existence of either an exclusively dural tumour blush or an additionally pial tumour supply from cerebral arteries. Furthermore the presence of macroscopic tumour-neovascularization and dysplastic changes of tumour-draining cerebral veins was evaluated. VEGF expression was investigated on histological tissue samples, using immunohistochemical techniques. VEGF immunohistochemistry and neuroradiological evaluations were performed in double blind fashion. Tumour volume and the amount of oedema were calculated by computerized tomography (CT) or magnetic resonance imaging (MRI). The oedema-tumour volume ratio was defined as oedema index (OeI). Compared to VEGF-negative meningiomas, tumours with striking VEGF staining revealed a significant higher mean oedema index (OeI=4,2 vs. OeI=1,5; p<0.018), and a higher oedema incidence (91,7% vs. 44,4%; p<0.046). Equally, meningiomas with additionally tumour supply from cerebral arteries were associated with a significant higher mean OeI (OeI=4.1 vs. OeI=1.2; p<0.01) and oedema incidence (94,7% vs. 20,0%; p<0,0023) than meningiomas with exclusively tumour supply from dural arteries. All meningiomas with striking VEGF-expression were associated with vascular tumour supply from cerebral arteries, but VEGF-negative tumours only in 50% (p<0.029). These data suggest a link between VEGF-expression, arterial tumour supply and peritumoural brain oedema. The development of tumour supply from cerebral arteries may be important for formation of meningioma-related oedema. Therefore, VEGF may represent a potent mediator in the evolution of this type of vascularization in meningiomas.     

大肠癌组织VEGF-C表达与血管生成和细胞增殖关系的研究

目的：研究大肠癌组织血管内皮生长因子C（VEGF—C）表达与肿瘤血管生成及肿瘤细胞增殖的关系。方法：采用SP免疫组织化学方法，检测81例大肠癌VEGF-C、CD34和Ki-67的表达，并分析VEGF-C与微血管密度（MVD）、Ki-67增殖指数（Ki-67PI）的相关性。结果：81例大肠癌中，VEGF-C表达阳性45例（55．56％）；VEGFC表达阳性的肿瘤其MVD和Ki-67PI高于VEGF-C者（P〈0.05）。VEGF-C表达与MVD、Ki-67PI呈正相关（P〈0.05）。有转移组（包括淋巴结转移和远处转移）的VEGF-C表达明显高于无转移组，表达随肿瘤分期的升高而增强。结论：VEGF-C通过诱导新生血管形成，促进肿瘤细胞的增殖生长，影响着大肠癌的浸润和转移。     

Prolactin Secreting Pituitary Adenomas: Analysis of 429 Surgically Treated Patients, Effect of Adjuvant Treatment Modalities and Review of the Literature

Summary ? Objective. We performed this retrospective analysis to determine the efficacy of surgery and radiotherapy over hormonal and volumetric control of prolactinomas, many of which had failed during dopa-agonist therapy. In the same analysis, the efficiency of topical bromocriptine application as a preliminary study was compared with standard treatment modalities.  Materials and Methods. Between 1982–1997, 429 prolactinoma patients who underwent surgery at Hacettepe University Neurosurgery Department and at Bayındır Medical Center were included in this study. All patients were classified according to Hardy's classification scheme and were further divided into `invasive' and `non-invasive' groups based on this radiological classification system. The mean follow-up time was 38.4 months. One hundred and thirty five patients had peroperative bromocriptine application into the sellar cavity¹ and these, either receiving radiotherapy (RT) or not, were analysed separately from the other 294 patients. In the early postoperative period, 104 of these patients were given conventional radiotherapy with median dose of 4500 cGy. We focused on the effects of surgery and radiotherapy over volumetric and hormonal tumour control on the basis of invasion characteristics and the early results of topical bromocriptine application in macroprolactinoma patients; and compared our results with the literature.  Results. Statistical analysis revealed that radiotherapy was not effective over hormonal and volumetric tumour control for prolactinomas. We did not observe any correlation to dural invasion of the sellar floor, recurrence, and the disease-free survival time. Topical bromocriptine application seemed to improve the volumetric control in 135 selected macroprolactinoma patients but not hormonal response compared with the standard treatment modalities.  Conclusion. Conventional radiotherapy is not as effective as expected for prolactinomas and should not be preferred considering its adverse effects. Tumoural infiltration of the sellar dura mater is not a prognostic criterion for recurrence expectation and, therefore, should not be a criterion for radiotherapy after surgery. After subtotal removal, postoperative dopa-agonist therapy should be considered even if the patient was intolerant or resistant to previous treatment since surgery seems to improve patients' drug tolerance and cooperation due probably to the lower dose requirement. The early results of topical bromocriptine application seem to improve volumetric tumour control but this should not be accepted as a judgement since we need to wait for later results and to expand the sample size for more reliable interpretation.     

血管内皮生长因子受体-3与胃癌临床病理因素的关系

目的　探讨血管内皮生长因子受体 3(VEGFR 3)与胃癌临床病理因素的关系。方法　应用免疫组织化学SP法测定胃癌及胃良性病变中VEGFR 3的表达 ,并以此来计数淋巴管密度。结果　淋巴管密度胃癌组为( 5 .80 0 0± 2 .3189)个 /× 2 0 0 ,胃良性病变组为 ( 2 .380 0± 0 .4 6 2 9)个 /× 2 0 0 (P =0 .0 0 0 ) ;有淋巴结转移者为 ( 6 .94 83± 1.5 831)个 /× 2 0 0 ,无淋巴结转移者为 ( 2 .772 7± 0 .4 2 89)个 /× 2 0 0 (P =0 .0 0 0 ) ;低分化组为( 7.6 818± 0 .982 9)个 /× 2 0 0 ,高 中分化组为 ( 3.5 0 0 0± 1.0 2 82 )个 /× 2 0 0 (P =0 .0 0 0 ) ;pTNM分期Ⅰ Ⅱ期为( 4 .2 917± 1.6 880 )个 /× 2 0 0 ,Ⅲ Ⅳ期组为 ( 8.0 6 2 5± 0 .75 94 )个 /× 2 0 0 (P =0 .0 0 0 )。结论　胃癌淋巴管密度与其 pTNM分期、分化程度及有无淋巴结转移相关     

胃癌组织NOS和VEGF表达与癌细胞增殖相关性的研究

目的:研究人胃癌组织血管内皮生长因子(VEGF)、诱导型一氧化氮合酶(iNOS)、内皮型一氧化氮合酶(eNOS)的表达与癌细胞增殖的相关性。方法:应用免疫组化方法检测34例胃癌手术切除标本VEGF、iNOS、eNOS和增殖细胞核抗原(PCNA)的分布及表达。结果:①31例胃癌组织表达VEGF,25例(73.5%)表达iNOS,28例(82.4%)表达eNOS;②VEGF与iNOS的表达具有明显相关性,VEGF与eNOS的表达无明显相关性;③表达VEGF的胃癌PCNA标记指数(PLI)明显高于不表达VEGF的胃癌,表达iNOS的胃癌PLI明显高于不表达iNOS的胃癌,表达eNOS的胃癌PLI与不表达eNOS的胃癌无显著性差异(P<0.05)。结论:①VEGF与iNOS的表达具有明显相关性,说明iNOS在VEGF的生成和发挥作用过程中起重要作用;②PLI随着VEGF和iNOS表达的增加而增加,说明二者对胃癌细胞增殖具有促进作用。     

姜黄素对雄激素非依赖性前列腺癌细胞PC-3及血管内皮生长因子的影响

目的：研究姜黄素对雄激素非依赖性前列腺癌细胞株PC-3细胞体外作用及其对血管内皮生长因子（VEGF）表达的影响，探讨其抗肿瘤的作用机制。方法：分别用0、6．25、12．5、25、50μmol／L浓度的姜黄素作用于PC-3细胞，12、24、36、48、72、96h后台盼蓝拒染法、四甲基偶氮唑蓝（MTT）法检测细胞生长活性；24h后流式细胞仪测定细胞周期及凋亡的变化，透射电镜观察细胞超微结构变化；半定量RT-PCR法检测PC-3细胞内VEGF mRNA的表达；ELISA检测细胞上清液中VEGF浓度。结果：姜黄素能显著抑制PC-3细胞的增殖，呈剂量与时间依赖性，不同浓度姜黄素组之间及不同时间组之间差异均有统计学意义（P〈0．01）。不同浓度姜黄素诱导PC-3细胞出现剂量依赖性G2／M期阻滞（P〈0．01），且各浓度组凋亡细胞比例均显著高于空白对照组（P〈0．01），差异有统计学意义；姜黄素作用24h后PC-3细胞出现凋亡的形态学改变；PC-3细胞内VEGF mRNA的表达和细胞上清液中VEGF呈剂量依赖性降低。结论：姜黄素能显著抑制体外PC-3细胞的生长，并促进其G2／M期阻滞和凋亡，VEGF mRNA及蛋白的表达也明显降低，可能是其抑制肿瘤和血管生长的机制之一。     

姜黄素对雄激素非依赖性前列腺癌细胞PC-3及血管内皮生长因子的影响

目的:研究姜黄素对雄激素非依赖性前列腺癌细胞株PC-3细胞体外作用及其对血管内皮生长因子(VEGF)表达的影响,探讨其抗肿瘤的作用机制。方法:分别用0、6.25、12.5、25、50μmol/L浓度的姜黄素作用于PC-3细胞,12、24、36、48、72、96h后台盼蓝拒染法、四甲基偶氮唑蓝(MTT)法检测细胞生长活性;24h后流式细胞仪测定细胞周期及凋亡的变化,透射电镜观察细胞超微结构变化;半定量RT-PCR法检测PC-3细胞内VEGFmRNA的表达;ELISA检测细胞上清液中VEGF浓度。结果:姜黄素能显著抑制PC-3细胞的增殖,呈剂量与时间依赖性,不同浓度姜黄素组之间及不同时间组之间差异均有统计学意义(P<0.01)。不同浓度姜黄素诱导PC-3细胞出现剂量依赖性G2/M期阻滞(P<0.01),且各浓度组凋亡细胞比例均显著高于空白对照组(P<0.01),差异有统计学意义;姜黄素作用24h后PC-3细胞出现凋亡的形态学改变;PC-3细胞内VEGF mRNA的表达和细胞上清液中VEGF呈剂量依赖性降低。结论:姜黄素能显著抑制体外PC-3细胞的生长,并促进其G2/M期阻滞和凋亡,VEGFmRNA及蛋白的表达也明显降低,可能是其抑制肿瘤和血管生长的机制之一。     

血管内皮细胞生长因子在食管癌中的表达及意义

目的 探讨食管癌血管内皮细胞生长因子（VEGF）表达及其与肿瘤血管新生和病理学特点的关系。方法 对40例手术切除的原发性食管癌标本进行免疫组织化学染色,确定其VEGF的表达及微血管密度。结果 40例食管癌患者中27例VEGF蛋白表达阳性,阳性率为67．5％,微血管密度在食管癌VEGF表达阴性、弱阳性和强阳性者间比较差别具有显著性意义（P＜0．05）,有淋巴结转移者VEGF表达阳性率较无淋巴结转移者明显增高（P＜0．01）。结论 食管癌VEGF表达水平与肿瘤血管新生强度、淋巴结转移有密切关系。     

环氧化酶-2和血管内皮生长因子在胰腺癌组织中的表达及其相关性研究

目的　探讨环氧化酶 2 (COX 2 )和血管内皮生长因子 (VEGF)在胰腺癌组织中的表达及与其生物学行为的相关性。方法　采用免疫组织化学Envision法对 5 1例胰腺导管癌组织中COX 2和VEGF的表达进行检测。结果　该 5 1例胰腺导管癌组织中COX 2和VEGF的表达阳性率分别为 74.5 %和 68.6% ,而二者在 11例癌旁胰腺组织中均未见阳性表达 ;COX 2和VEGF的表达阳性率在临床Ⅲ～Ⅳ期明显高于临床Ⅰ～Ⅱ期 ,淋巴结转移阳性组明显高于淋巴结转移阴性组 ,其差异均有显著性意义 (P<0 .0 5 ) ;COX 2和VEGF的表达与胰腺癌的组织学分级、患者的性别、年龄以及肿瘤的大小和部位无关 (P>0 .0 5 ) ;COX 2的表达与VEGF的表达呈正相关 (r =0 .411,P<0 .0 1)。结论　COX 2和VEGF可能在胰腺癌的发生、发展过程中起着关键性作用 ,二者在血管生成过程中密切相关 ,可能为胰腺癌的治疗提供新的靶点 ,值得深入探讨。     

Vascular Endothelial Growth Factor: An Essential Component of Angiogenesis and Fracture Healing

Fractures require adequate stability and blood supply to heal. The vascular supply to long bones is compromised in a fracture, and the ability to heal hinges on the ability of new blood vessels to proliferate from surrounding vessels in a process known as angiogenesis. This process is largely driven by the growth factor, vascular endothelial growth factor (VEGF), whose levels are increased locally and systemically during fracture healing. VEGF is involved in many steps throughout the fracture healing cascade, from initially being concentrated in fracture hematoma, to the promotion of bone turnover during the final remodeling phase. This article reviews the current literature surrounding the role of VEGF and other growth factors in reestablishing vascular supply to fractured bone, as well as medications and surgical techniques that may inhibit this process.     

磁共振弥散加权成像评估前列腺癌血管生成及血管内皮生长因子表达的价值研究

目的:通过对前列腺癌(PCa)磁共振弥散加权成像(DWI)特征与血管生成的相关分析,探讨磁共振DWI及表观弥散系数(ADC)评价PCa血管生成及血管内皮生长因子(VEGF)表达的价值。方法:磁共振DWI检查使用Siemens Sonata 1.5 T高场强超导磁共振成像仪和腹部相控阵线圈,采用平面回波成像(echo planar imaging,EPI)技术对共38例资料完整的PCa患者行DWI检查,另外还选取了33例经病理证实的良性前列腺增生(BPH)患者和15例男性健康志愿者,测量癌组织、BPH及正常前列腺外周带(NPZ)的ADC值。所有PCa标本均行微血管密度(MVD)和VEGF的免疫组化染色。结果:PCa、BPH和NPZ ADC值分别为(49.32±12.68)×10-5mm2/s、(86.73±26.75)×10-5mm2/s、(126.25±27.21)×10-5mm2/s,PCa的ADC值小于BPH和NPZ的ADC值(P<0.05)。PCa MVD和VEGF表达水平高于BPH,差别具有统计学意义(P<0.05);PCa的ADC值与MVD存在负相关性(r=-0.510,P<0.05),VEGF与MVD表达存在正相关关系(r=0.481,P<0.05)。VEGF阳性和阴性组的ADC值为(47.27±9.55)×10-5mm2/s和(55.06±11.6)×10-5mm2/s,差异有统计学意义(P<0.05)。结论:ADC值能反映前列腺癌血管生成水平高低,DWI有助于对前列腺癌生物学特性进行评估。     

Expression of CD44, Vascular Endothelial Growth Factor, and Proliferating Cell Nuclear Antigen in Severe Venous Invasional Colorectal Cancer and Its Relationship to Liver Metastasis

(Received for publication on Jan. 5, 1999; accepted on Nov. 11, 1999)     

Immunohistochemical Analysis of Vascular Endothelial Growth Factor and Hepatocyte Growth Factor,and Their Receptors,in Transplanted Islets in Rats

Purpose. Our previous studies showed that transplanted islets increasingly express a marker of neovascularization, platelet endothelial cell adhesion molecule-1 (PECAM-1), as well as vascular endothelial growth factor (VEGF). Hepatocyte growth factor (HGF) is another stimulator of neovascularization. In this study, we examined the expression of these growth factors and their receptors; fetal liver kinase-1 (Flk-1) for VEGF and c-Met for HGF, to acertain whether VEGF and HGF play a role in the neovascularization of transplanted islets. Methods. Islets were isolated from male Lewis rats by collagenase digestion and the discontinuous dextran gradient method, then transplanted into the bilateral subnephrocapsular space. The kidneys were excised 1–28 days after transplantation, then fixed in formaldehyde and embedded in paraffin. Serial slices were immunostained for VEGF, HGF, Flk-1, or c-Met, respectively. Results. Islets in the normal pancreas were positively stained for VEGF, HGF, and c-Met; however, Flk-1 was only stained at the periphery of the islets. In the transplanted islets, staining for VEGF, HGF, and c-Met was positive, but Flk-1 was not stained. Moreover, staining for HGF and c-Met became stronger in the transplanted islets with time. Conclusion. These results suggest that HGF, rather than VEGF, may play a role in the neovascularization of transplanted islets.     

Elevated Serum Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor Levels in Patients with Thymic Epithelial Neoplasms

Neovascularization, an essential event for the growth of solid tumors, is regulated by a number of angiogenic factors, among which vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), are considered to exert potent angiogenic activity. In this study, we investigated whether serum VEGF and bFGF levels could be predictors of the development and extension of thymic epithelial neoplasms. The subjects of this study were 37 patients with thymoma, 6 with thymic carcinoma, and 23 healthy volunteers. Serum samples were collected before clinical treatment. Serum VEGF levels were significantly (P < 0.05) elevated in the patients with thymic carcinoma (1 080 ± 1 185 pg/ml) compared with those in the healthy volunteers (407 ± 589 pg/ml). Serum bFGF levels were also significantly (P < 0.05) elevated in the patients with thymic carcinoma (2 740 ± 631 pg/ml) compared with those in the healthy volunteers (1 728 ± 1 192 pg/ml). However, the serum VEGF and bFGF levels did not significantly differ between the patients with thymoma and the healthy volunteers. Serum VEGF and bFGF levels did not significantly differ according to the stage and pathological subtype of thymoma. Moreover, there was no correlation between the serum levels of VEGF and those of bFGF. Thus, while serum VEGF and bFGF levels may serve as markers for thymic epithelial tumors, it is unlikely that circulating VEGF and bFGF could be used as markers for assessing the progression of thymoma tumors. Received: November 10, 2000 / Accepted: May 15, 2001