VEGF和VEGFR通路抑制剂在晚期胃癌治疗中的疗效

抗新生血管形成是目前胃癌治疗的重要研究方向,血管内皮生长因子(VEGF)及血管内皮生长因子受体(VEGFR)抑制剂是主要的研究热点.目前治疗晚期胃癌的VEGF及VEGFR通路抑制剂包括贝伐珠单抗、雷莫芦单抗、阿帕替尼、瑞戈非尼、索拉非尼等,这些药物为晚期胃癌的治疗提供了更多可能性.     

血管内皮生长因子与神经系统肿瘤的研究进展

血管内皮细胞生长因子 (vascularendothelialgrowthfactor,VEGF)是 1989年Ferrara等[1] 从培养的牛垂体滤泡星状细胞中纯化出来并首先命名的 ,对血管生长有强诱导作用 ,是目前所知唯一特异地作用于血管内皮细胞的一种生长因子 ,具有高度的血管渗透性 ,又名血管渗透因子 (vascularpermeabilityfactor,VPF) ,它是迄今发现的最强的血管渗透因子 ,比组胺作用强 5万倍[2 ] 。研究证实 ,VEGF在神经系统肿瘤生长及血管生成过程中发挥着关键作用 ,本文就VEGF/VEGFR的生物学特性及其在神经系统肿瘤中的表达、调控和相应抗VEGF/VEGFR治疗…     

血管内皮生长因子与神经系统肿瘤的研究进展

血管内皮细胞生长因子(vascular endothelial growth factor，vEGF)是1989年Ferrara等从培养的牛垂体滤泡星状细胞中纯化出来并首先命名的，对血管生长有强诱导作用，是目前所知唯一特异地作用于血管内皮细胞的一种生长因子，具有高度的血管渗透性，又名血管渗透因子(vascular perrneability factor，VPF)，它是迄今发现的最强的血管渗透因子，比组胺作用强5万倍。研究证实，VEGF在神经系统肿瘤生长及血管生成过程中发挥着关键作用，本文就VEGF／VEGFR的生物学特性及其在神经系统肿瘤中的表达、调控和相应抗VEGF／VEGFR治疗策略作一综述。     

VEGFs家族及其与胃癌关系的研究进展

目前发现血管内皮生长因子（vascular endothelial growth factors, VEGFs）家族包括7个成员：VEGFA，胎盘生长因子（placenta growth factor,PlGF)，VEGFB，VEGFC，VEGFD，VEGFE 和蛇毒VEGF(snake venom VEGF,svVEGF )；其同源受体有酪氨酸激酶受体VEGFR 1(Flt1)、VEGFR2(KDR)、VEGFR3(Flt4)等多种类型。其中，VEGFA与VEGFR1 和VEGF     

VEGF及其受体与胃癌的关系

VEGF是新生血管形成的主要促进因子,胃癌细胞的生长及转移与VEGF的产生及VEGFR的特异性激活密切相关.现综述近年来有关VEGF、VEGFR与胃癌关系,以及VEGF、VEGFR抑制剂在胃癌治疗中应用的研究进展.     

血管内皮生长因子及其受体与脑肿瘤的关系

新生血管形成是肿瘤生长的必要条件,而且也是肿瘤发生、发展、浸润、转移的重要原因之一。肿瘤血管形成是一个复杂过程,目前研究认为血管内皮生长因子(VEGF)及其受体在该过程中起着重要的作用。国内外学者研究VEGF及其受体已有多年,近几年主要集中在VEGF及受体的调节与作用机制、与脑肿瘤血管形成及瘤周水肿的关系和抗脑肿瘤治疗等方面。本文对近年来VEGF/VEGFR的研究成果以及与脑肿瘤相关的部分进行综述。     

VEGF及其受体与胃癌的关系

VEGF是新生血管形成的主要促进因子，胃癌细胞的生长及转移与VEGF的产生及VEGFR的特异性激活密切相关：现综述近年来有关VEGF、VEGFR与胃癌关系，以及VEGF、VEGFR抑制剂存胃癌治疗中应用的研究进展。     

抗肿瘤新生血管治疗的新进展

血管新生是肿瘤生长、转移的重要条件。在导致肿瘤血管新生的因素中,血管内皮生长因子(vascular endothelialgrowth factor,VEGF)被认为是最重要的因素。抑制VEGF的信号转导有可能抑制血管新生,并进一步抑制肿瘤生长。目前有几种新的可能抑制VEGF信号转导的方法,其中包括基因水平上抑制VEGF及VEGF受体(VEGF receptor,VEGFR)的表达、中和血液循环中的VEGF或VEGFR,以及抑制VEGFR的酪氨酸激酶活性以达到抑制其下游的信号转导等。迄今为止,已报道多种针对VEGF抗血管新生的生物及化学制剂,部分已应用于临床,其他制剂正在进行动物试验或临床试验。本文对抑制VEGF信号转导在抗肿瘤治疗中的研究新进展做一综述。     

Lewis y高表达对人卵巢癌RMG-Ⅰ细胞裸鼠体内致瘤性及移植瘤VEGF和VEGFR表达的影响

目的:比较α1,2岩藻糖转移酶基因转染前后卵巢癌细胞株RMG-Ⅰ的裸鼠体内致瘤性及移植瘤组织血管内皮生长因子及其受体VEGFR1和VEGFR2表达的变化.方法:利用已建立的Lewis y抗原稳定高表达卵巢癌细胞株RMG-Ⅰ-H及转染前细胞株RMG-Ⅰ为细胞模型,将转染前后细胞株种植裸鼠皮下建立人卵巢癌裸鼠移植瘤模型,观察两组肿瘤生长情况.第5周处死动物,测量移植瘤重量,免疫组织化学方法检测肿瘤组织VEGF及VEGFR1、VEGFR2的表达.结果:转染组及未转染组裸鼠均有荷瘤形成,但转染组的成瘤时间(5.2±0.8 d)早于未转染组(8.8±1.3 d),且转染组的瘤重和体积与未转染组相比均明显增加(P＜0.05).转染组裸鼠移植瘤组织VEGF及VEGFR2表达量明显高于未转染组(P＜0.05).结论:Lewis y抗原高表达能增加卵巢癌RMG-Ⅰ细胞的体内致瘤性,上调裸鼠移植瘤VEGF及VEGFR2的表达.提示Lew-is y抗原能提高癌细胞的恶性程度,且该作用与VEGF及VEGFR2表达增高关系密切.     

VEGF及其受体与肝细胞癌血管生成和抗血管治疗研究进展

肝细胞癌(hepatocellular carcinoma,HCC)发生发展与肿瘤血管生成密切相关,而血管内皮生长因子(vascular endothelial growth factor,VEGF)及其受体能直接或间接参与肝癌血管生成,且具有很强的促进作用,在肝癌的发生、发展及预后中扮演着极其重要的角色。近年来,以VEGF及其受体为靶点的肿瘤抗血管治疗是HCC治疗研究的热点。本文复习近十年相关文献,对VEGF及其受体与HCC肿瘤血管生成和HCC抗血管治疗相关研究进展作简要综述。     

卵巢上皮癌细胞中VEGF和VEGFRs的表达与STATs的活化

目的　研究卵巢上皮癌细胞中血管内皮生长因子 (VEGF)、血管内皮生长因子受体(VEGFRs)的表达与血管内皮细胞内的信号转导和转录活化因子 (STATs)的活化及其相关性 ,并阐明VEGF对卵巢癌细胞的直接作用及机制。方法　选择 4 2例卵巢上皮性癌患者作为研究对象 ,2 9例卵巢良性肿瘤患者和 11例正常卵巢组织作为对照 ,用免疫组织化学LSAB法检测组织中VEGF、VEGFRs、STATs蛋白的表达 ,并进行半定量及相关性分析。结果　 (1)VEGF定位于胞浆 ,VEGFRs定位于胞浆和胞膜。VEGF在卵巢癌细胞呈高表达 ,VEGFRs在卵巢癌细胞及间质血管内皮细胞中均呈高表达 ,与良性及正常对照组差异有统计学意义 (P <0 .0 1)。 (2 )P STATs定位于胞浆和胞核。在卵巢癌细胞及血管内皮细胞中 ,P STAT3和P STAT5高表达 ,与两对照组相比 ,差异有统计学意义 (P <0 .0 1) ;P STAT1、P STAT6低表达 ,各组间差异无统计学意义。 (3)在血管内皮细胞中 ,VEGFR1的表达与P STAT5呈正相关 (r =0 .2 4 3) ,而VEGFR2与P STAT3呈正相关 (r =0 .30 8) ;在卵巢癌细胞中 ,VEGF、VEGFR1、VEGFR2与P STAT3、P STAT5之间均呈正相关 ,而与P STAT1、P STAT6无相关。结论VEGF可直接作用于卵巢上皮癌细胞 ,STATs可能参与了VEGF细胞内的信号传导。     

胃腺癌的血管内皮细胞生长因子和KDR受体的表达及其临床意义

目的：研究胃腺癌的血管内皮细胞生长因子（ｖａｓｃｕｌａｒ ｅｎｄｏｔｈｅｌｉａｌ ｃｅｌｌ ｇｒｏｗｔｈ　ｆａｃｔｏｒ, ＶＥＧＦ）及其受体 ＫＤＲ（ＶＥＧＦＲ）的表达,并探讨其临床意义。方法：应用免疫组织化学染色法检测ＶＥＧＦ／ＶＥＧＦＲ的表达,并分析其与６１例胃腺癌临床病理特征之间的关系。结果：胃腺癌组织ＶＥＧＦ／ＶＥＧＦＲ的阳性表达率分别为５５．９％和３９．３％;其中粘液腺癌和管状腺癌表达率较高（Ｐ＜０．０５,Ｐ＜０．０１）,ＶＥＧＦ／ＶＥＧＦＲ表达率分别为７１．４Ｔ／４２．８％和６１．９％／５２．４％;ＶＥＧＦ／ＶＥＧＦＲ的阳性表达与ＴＮＭ分期有显著差异（Ｐ＜０．０５,Ｐ＜０．０１）,阳性率为Ⅵ＞Ⅲ＞Ⅱ＞Ⅰ期,Ⅳ、Ⅲ、Ⅱ、Ⅰ期的表达率分别为 ８０．０％／５０．０％,６８．２％／４５．５％,４０．０％／３０．０％和３６．８％／３１． ６％;胃腺癌并转移患者,ＶＥＧＦ／ＶＥＧＦＲ的阳性表达分别为７６．２％和４７．６％,远高于无转移的４５．０％和３５．０％（Ｐ＜０．０５,Ｐ＜０．０１）;术后生存期小于１年的ＶＥＧＦ的表达率为６６．７％,明显高于术后生存期１年以上的５２．２％。结论：ＶＥＧＦ是胃腺癌血管生成的正向调     

血管内皮生长因子及其受体与白血病的关系

 血管内皮生长因子（vascular endothelial growth factor ,VEGF）是作用最强,特异性最高的血管新生调节因子,研究表明,白血病细胞不仅高表达VEGF,而且不同程度的表达VEGF受体,VEGF 与白血病的发生、发展相关,影响白血病的预后。研究VEGF 与白血病的关系,为白血病的抗血管增生治疗提供依据。     

Prognostic significance of the expression of vascular endothelial growth factors A,B, C,and D and their receptors R1, R2, and R3 in patients with nonsmall cell lung cancer

BACKGROUND:

Lung cancer is the leading cause of cancer death in the world. The objective of this study was to investigate the expression of vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) in patients with nonsmall cell lung cancer (NSCLC) and its correlation with the prognosis for patients with lung cancer.

METHODS:

The expression status of VEGFs and VEGFRs was examined in 48 nonconsecutive specimens of primary lung cancer by immunohistochemistry. Correlations between the expression of VEGFs and VEGFRs and clinicopathologic parameters were analyzed.

RESULTS:

Nineteen of 48 samples (39.6%) were moderately/highly immunoreactive for VEGF‐A, 6 samples (12.5%) were reactive for VEGF‐B, 14 samples (29.2%) were reactive for VEGF‐C, 11 samples (22.9%) were reactive for VEGF‐D, 20 samples (41.7%) were reactive for VEGFR1, 26 samples (54.2%) were reactive for VEGFR2, 20 samples (41.7%) were reactive for VEGFR3, and 19 samples (39.6%) were reactive for nuclear expression of VEGFR3. Patients with moderate/high VEGF‐C, VEGFR1, and VEGFR2 expression had worse survival, whereas patients with moderate/high VEGF‐D and nuclear VEGFR3 expression had better survival. After adjusting according to tumor stage, VEGF‐B and VEGF‐D expression had a significant correlation with worse survival in patients with stage I and II disease. Patients with stage III and IV disease who had VEGFR1 and VEGFR2 expression had worse survival, whereas the expression of VEGF‐D was correlated significantly with better survival. Finally, stage, VEGF‐D expression, and VEGFR1 expression were significantly independent prognostic predictors.

CONCLUSIONS:

The results of the current study indicated that the over‐expression of VEGFs and VEGFRs plays an important role in the survival of patients with NSCLC. The inclusion of angiogenic factors in the standard pathologic study of lung cancer may improve the clinical evaluation of patients with NSCLC. Cancer 2009. © 2009 American Cancer Society.     

血管内皮生长因子及其受体与肝癌治疗的研究进展

 肿瘤转移和复发是癌症患者死亡的重要因素，转移和复发是由于肿瘤新血管形成，提供了氧和其他营养成分。血管内皮生长因子（VEGF）通过与其受体的相互作用促进新血管的形成，为肿瘤细胞转移复发提供基础。综述了VEGF及其受体在肝癌新血管和治疗中的最新研究，并对其进行展望，为进一步研究提供有益的帮助。     

Avastin阻断VEGF促横纹肌肉瘤细胞株RH4增殖的作用

背景与目的：血管内皮生长因子（vascular endothelial growth factor,VEGF）及其通路的研究是目前研究的热点之一,但其在横纹肌肉瘤中的研究鲜有报道．其作用机制尚不完全清楚。本研究通过检测横纹肌肉瘤细胞株RH4中VEGF及其受体的表达情况,以了解VEGF在横纹肌肉瘤中的作用及机制,并研究Avastin阻断VEGF促细胞增殖的作用。方法：使用RT-PCR方法检测RH4细胞株中VEGF、VEGFR1、2、3mRNA的表达：使用ELISA方法检测培养液上清中VEGF的分泌水平;使用Western blot方法检测VEGFR1蛋白的表达水平;使用直接计数的方法检测VEGF、Avastin对RH4细胞增殖的影响。结果：RT-PCR和ELISA结果显示在RH4细胞中存在VEGF的表达和分泌;在RH4细胞中仅有VEGFR1表达,VEGFR2和VEGFR3均为阴性：Western blot的结果进一步证实了VEGFR1在RH4中的表达。VEGF可直接促进RH4细胞的增殖,在0～100ng／ml的区间其促进增殖的作用随着浓度的增加而增加。10～40μg／ml Avastin可以阻断VEGF的促增殖作用。结论：在横纹肌肉瘤细胞RH4中VEGF可以通过自分泌的方式作用于自身,并通过VEGFR1促进肿瘤细胞的增殖,Avastin可以阻断VEGF的促增殖作用。     

Vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in the blood serum, tumor and renal parenchyma of patients with renal cell carcinoma

Serum, tumor and renal parenchyma levels of VEGF and VEGFR2 were compared in patients with renal carcinoma (RC) with reference to basic clinicomorphological characteristics of the disease. VEGF and VEGFR2 were estimated in 37 RC patients and 57 healthy controls (serum levels only). VEGF and VEGFR2 were detected in all the samples. Their concentrations in the serum were the same in the patients and controls. The tumor tissue contained more VEGF than renal parenchyma. In unfavorable clinicomorphological features the tumor contained higher content of VEGF, higher VEGF/VEGFR2, lower VEGFR2. Thus, angiogenic factors studied closely correlate with clinicomorphological characteristics of renal carcinoma: primary tumor size, stage of the disease, tumor differentiation, tumor pseudocapsule invasion.     

Lenvatinib in combination with golvatinib overcomes hepatocyte growth factor pathway‐induced resistance to vascular endothelial growth factor receptor inhibitor

Vascular endothelial growth factor receptor (VEGFR) inhibitors are approved for the treatment of several tumor types; however, some tumors show intrinsic resistance to VEGFR inhibitors, and some patients develop acquired resistance to these inhibitors. Therefore, a strategy to overcome VEGFR inhibitor resistance is urgently required. Recent reports suggest that activation of the hepatocyte growth factor (HGF) pathway through its cognate receptor, Met, contributes to VEGFR inhibitor resistance. Here, we explored the effect of the HGF/Met signaling pathway and its inhibitors on resistance to lenvatinib, a VEGFR inhibitor. In in vitro experiments, addition of VEGF plus HGF enhanced cell growth and tube formation of HUVECs when compared with stimulation by either factor alone. Lenvatinib potently inhibited the growth of HUVECs induced by VEGF alone, but cells induced by VEGF plus HGF showed lenvatinib resistance. This HGF‐induced resistance was cancelled when the Met inhibitor, golvatinib, was added with lenvatinib. Conditioned medium from tumor cells producing high amounts of HGF also conferred resistance to inhibition by lenvatinib. In s.c. xenograft models based on various tumor cell lines with high HGF expression, treatment with lenvatinib alone showed weak antitumor effects, but treatment with lenvatinib plus golvatinib showed synergistic antitumor effects, accompanied by decreased tumor vessel density. These results suggest that HGF from tumor cells confers resistance to tumor endothelial cells against VEGFR inhibitors, and that combination therapy using VEGFR inhibitors with Met inhibitors may be effective for overcoming resistance to VEGFR inhibitors. Further evaluation in clinical trials is warranted.     

Everolimus (RAD001) in the Treatment of Advanced Renal Cell Carcinoma: A Review

Historically, there have been few treatment options for patients with advanced renal cell carcinoma (RCC) besides immunotherapy with interleukin‐2 and interferon (IFN)‐α. Targeted therapies have improved clinical outcomes over the past several years. These include the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors sunitinib and sorafenib, which inhibit angiogenic signaling in endothelial cells and vascular pericytes predominantly through VEGFR and platelet‐derived growth factor receptor β. Also included is the anti‐VEGF monoclonal antibody bevacizumab used in combination with IFN‐α. These agents mediate their antitumor effects by interfering with the VEGF signaling pathway, thereby inhibiting angiogenesis and causing tumor shrinkage. However, ultimately, most patients develop resistance and experience disease progression during VEGF/VEGFR‐targeted therapy, and until the recent approval of the mammalian target of rapamycin (mTOR) inhibitor everolimus (RAD001), there were no agents available with proven activity in this setting. This review describes the clinical development of everolimus in advanced RCC and the rationale for the use of mTOR inhibitors after failure of VEGF/VEGFR inhibitors.