血管内皮生长因子对肝癌细胞侵袭能力和同质性粘附作用影响

目的　观察血管内皮细胞生长因子 (VascularEndothelialGrowthFactorVEGF)诱导肝癌HepG2 细胞转移及其对细胞同质性粘附作用的影响。方法　采用3 H -TdR掺入及鼠尾胶粘附试验测定VEGF对肝癌HepG2 细胞同质性粘附作用以及Bodyen -Chamber观察VEGF诱导肝癌细胞转移作用。 结果　 1ng/ml、5ng/mlVEGF诱导HepG2 细胞 6 0min、90min、12 0min3 H -TdR掺入实验 (dpm/min)分别为 175 8.6 7± 2 89.4 6、1380 .0 3± 32 8.5 5、2 6 5 7.4 3± 310 .31和 312 4 .3± 2 2 6 2 .14、2 2 4 5 .6±2 73.2 4、2 0 91.5 2± 2 13.84 ,10ng/mlVEGF诱导HepG2 细胞 6 0min、90min、12 0min ,3 H -TdR掺入实验 (dpm/min)分别为12 32 .32± 2 0 1.0 4、2 337.5± 333.0 4、2 2 36 .99± 2 37.0 7,显著低于对照组 6 0、90、12 0min的 2 184 .4 9± 336 .0 3、35 6 0± 2 5 5 .17、4 337.4± 377.35 ,(P <0 .0 5或 0 .0 1) ;用VEGF 1ng/ml、5ng/ml、10ng/ml培养肝癌细胞 2h ,下室浸润的肝癌细胞数分别为5 .75± 1.0 0、17.17± 2 .38、10 .33± 0 .88× 10 4/ml,分别高于对照组 1.5 8± 0 .38× 10 4/ml,(P <0 .0 5或 0 .0 1)。结论　VEGF可以促进肝癌HepG2 细胞转移 ,与VEGF降低肝癌细胞的同质性粘附作用有关。     

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.     

VEGF及其受体在多发性骨髓瘤中的表达及意义

背景与目的:骨髓新生血管形成在多发性骨髓瘤(multiple myeloma,MM)的发生、发展和预后中起着重要的作用,血管内皮生长因子(vascular endothelialgrowth factor,VEGF)在此过程中扮演了关键角色.本研究旨在研究VEGF及其受体在MM中的表达,分析其与MM发生、发展的关系.方法:采用RT-PCR的方法检测35例MM患者、16例非肿瘤患者(下称对照组)以及KM3细胞株中VEGF及其受体Flt-1和KDR的表达,并分析阳性率以及表达相对含量在MM患者和非肿瘤患者、MM不同分期间的差异.结果:VEGF和Flt-1基因在MM组的阳性率(62.9%和80.0%)显著高于对照组(18.8%和31.3%)(P＜0.01),VEGF在两组中的表达水平为0.41±0.19 vs.0.06±0.01(P＜0.05),Flt-1为0.60±0.33 vs.0.08±0.03(P＜0.01);VEGF基因在初治组和复发/难治MM组的阳性率为66.7%vs.60.9%(P＞0.05),Flt-1基因为83.3%vs.78.3%(P＞0.05);VEGF在Ⅱ期和Ⅲ期MM的阳性率为50%vs.73.7%(P＞0.05),Flt-1为81.3%vs.78.9%(P＞0.05);复发/难治MM组的VEGF和Flt-1基因的表达水平明显高于初治组(0.49±0.20 vs.0.28±0.04,P＜0.05;0.70±0.38 vs.0.41±0.06,P＜0.05),Ⅲ期MM患者VEGF和Flt-1基因的表达水平明显高于Ⅱ期患者(0.48±0.19 vs.0.28±0.09,P＜0.05;0.75±0.35 vs.0.41±0.21,P＜0.05).KDR仅在3例MM患者中检出,对照组未检出.结论:VEGF和Flt-1在MM中高表达,并与疾病进展相关.     

胃癌病人血清中血管内皮生长因子与胃癌的血管生成

目的:检测胃癌患者术前血清中血管内皮生长因子(VEGF)浓度及胃癌组织中微血管密度(MVD),探讨血清中VEGF浓度与胃癌血管生成之间的关系。方法:应用酶联免疫技术(ELISA法)检测51例胃癌患者血清中VEGF浓度;应用抗人CD_(34)单克隆抗体进行免疫组织化学染色检测胃癌组织中MVD。结果:胃癌组织中MVD与血清中VEGF浓度呈显著性相关(r=0.938,P<0.01)。胃癌患者血清VEGF浓度与胃癌浸润深度(P<0.05)、淋巴结转移(P<0.01)、远处转移(P<0.01)、肿瘤分期(P<0.05)及肿瘤组织学分型(P<0.05)密切相关,与性别无关(P>0.05)。结论:胃癌的血管生成与血清中VEGF浓度密切相关,检测术前胃癌患者血清VEGF浓度可预测胃癌血管生成情况,可能有助于指导临床治疗。     

Bone marrow angiogenesis and progression in multiple myeloma: clinical significance and therapeutic approach

It is now well established that solid tumors depend on angiogenesis. Promoters and inhibitors of angiogenesis are in balance and antiangiogenic strategies aim at repressing the angiogenic process, thus retarding solid tumor progression. Recent data suggest the importance of angiogenesis in hematologic malignancies and several studies reveal an increased angiogenesis in active multiple myeloma. Angiogenesis seems to be a prominent feature of MM progression, and seems to be correlated with the prognosis and the resistance of MM to chemotherapy. Numerous cell populations and cytokines are involved in angiogenesis in multiple myeloma and antiangiogenic therapy with thalidomide is effective in patients with refractory or relapsed disease. The combination of thalidomide and of other immunomodulatory agents with other therapeutic regimens could lead to more effective management of patients with multiple myeloma.     

Norcantharidin anti-angiogenesis activity possibly through an endothelial cell pathway in human colorectal cancer

The present study was based on the unexpected discovery that norcantharidin exerted anti-angiogenesis activity when effects on growth of human colon cancer were studied. The aim was to further verify this finding and explore possible mechanisms using a tumor xenograft model in nude mice. We confirmed that norcantharidin (5 or 15 mg/kg) could inhibit angiogenesis of human colon cancer in vivo. In vitro, crossing river assay, cell adhesion assay and tube formation assay indicated that NCTD could reduce the migration, adhesion and vascular network tube formation ability of HUVECs. At the same time, the expression levels of VEGF and VEGFR-2 proteins which play important roles in angiogenesis were reduced as examined by western blotting analysis. Taken together, the results firstly showed NCTD could inhibit angiogenesis of human colon cancer in vivo, probably associated with effects on migration, adhesion and vascular network tube formation of HUVECs and expression levels of VEGF and VEGFR-2 proteins.     

Prognostic factors for overall survival in patients with metastatic colorectal carcinoma treated with vascular endothelial growth factor-targeting agents

Objective: Angiogenesis represents a key element in the pathogenesis of malignancy. There are no robust data on prognostic factors for overall survival (OS) in patients with metastatic colorectal cancer treated with vascular endothelial growth factor (VEGF)-targeted therapy. The present study was conducted to establish a prognostic model for patients using an oxaliplatin-based or irinotecan-based chemotherapy plus bevacizumab in metastatic colorectal cancer. Methods: Baseline characteristics and outcomes on 170 patients treated with FOLFIRI or XELOX plus anti-VEGF therapy-naïve metastatic colorectal cancer were collected from three Turkey cancer centers. Cox proportional hazards regression was used to identify independent prognostic factors for OS. Results: The median OS for the whole cohort was 19 months (95% CI, 14.3 to 23.6 months). Three of the seven adverse prognostic factors according to the Anatolian Society of Medical Oncology (ASMO) were independent predictors of short survival: serum lactate dehydrogenase (LDH) greater than the upper limit of normal (ULN; p<0.001); neutrophils greater than the ULN (p<0.0014); and progression free survival (PFS) less than 6 months (p =0.001). Conclusion: Serum LDH and neutrophil levels were the main prognostic factors in predicting survival, followed by PFS. This model validates incorporation of components of the ASMO model into patient care and clinical trials that use VEGF-targeting agents.     

血管内皮生长因子在支气管肺泡细胞癌中的表达及意义

目的　研究VEGF表达与支气管肺泡细胞癌临床病理特征之间的关系 ,探讨其在支气管肺泡细胞癌恶性生长中的意义。方法　应用免疫组织化学染色 ,检测 3 8例支气管肺泡细胞癌组织与正常肺组织标本中VEGF的表达水平及微血管密度 (MVD) ,并进行比较。结果　支气管肺泡细胞癌组织中VEGF阳性率 ( 73 .68%,2 8/ 3 8)和MVD( 63 .81± 19.2 6)均明显高于正常肺组织 ( 0及 18.44± 6.5 3 ) (P <0 .0 0 5 ,P <0 .0 0 1) ;VEGF表达水平、MVD分别与支气管肺泡细胞癌原发肿瘤大小 (P <0 .0 5 ,P <0 .0 5 )、淋巴结转移 (P<0 .0 2 5 ,P <0 .0 5 )及TNM分期 (P <0 .0 5 ,P <0 .0 5 )均有密切关系。与VEGF( -)者相比 ,VEGF( +)者支气管肺泡细胞癌组织中MVD显著增高 (P <0 .0 5 )。结论　VEGF表达与支气管肺泡细胞癌的临床病理特征密切相关 ,可能是促进支气管肺泡细胞癌恶性生长的重要因子。     

肝细胞生长因子及其受体在多发性骨髓瘤中的研究进展

肝细胞生长因子(HGF)是一个多功能的细胞因子,作用于细胞表面的跨膜受体c-Met发挥生物学作用.许多肿瘤的生长、侵袭和转移都与HGF-c-Met信号转导通路异常有关.HGF及其受体c-Met与多发性骨髓瘤(MM)的发生、转移、侵袭及预后关系密切.     

Marine compounds inhibit growth of multiple myeloma in vitro and in vivo

Purpose

The prognosis of patients with multiple myeloma (MM) is still dismal despite recent improvements achieved by introducing new therapeutic agents. However, there remains an urgent need for progress in myeloma drug development. We here show that novel marine-derived compounds can exert potent anti-myeloma activity.

Experimental Design

Nine marine-derived compounds were applied at low nM concentrations (0.1-100 nM) to MM cell lines (OPM-2, NCI-H929, U266, RPMI-8226), to primary human myeloma cells and to peripheral blood mononuclear cells. Apoptosis was determined by flow cytometry. In addition, eGFP-transgenic MM cell lines growing with mesenchymal cells from bone marrow were used to visualize tumors by fluorescence stereomicroscopy. Anti-myelomaactivities were studied in vitro in 3D spheroids and in vivo in myeloma xenografts on chicken embryos. Tumor size was analyzed by measuring GFP content with a GFP ELISA. Anti-angiogenic activities of compounds were tested in an in vivo gelatin sponge assay with conditioned media from primary bone marrow-derived endothelial cells.

Results

We identified a subset of marine compounds with strong anti-myeloma activity in vitro and in vivo. Moreover, some of the compounds inhibited myeloma-related angiogenesis in the in vivo gelatin sponge assay. They merit further drug development to improve treatment options for MM.     

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。     

Role of vascular endothelial growth factor inhibitors in the treatment of gynecologic malignancies

This article reviews the history and current status of vascular endothelial growth factor targeted therapy for the most common gynecologic malignancies - epithelial ovarian, endometrial and cervical cancers. The biologic rationale for targeting vascular endothelial growth factor (VEGF) for these disease sites is well-founded, and pre-clinical studies have supported the development of anti-VEGF agents. Their classification, known mechanisms of action, unique toxicities and clinical development are herein explored, the latter including issues related to study design, disease site and disease setting.     

High circulating hepatocyte growth factor levels associate with epithelial to mesenchymal transition and poor outcome in small cell lung cancer patients

We have previously shown that Met activation through the hepatocyte growth factor (HGF) increases tumorogenesis, induces epithelial-to-mesenchymal transition (EMT) and chemoresistance in SCLC. We sought to evaluate circulating HGF levels in SCLC patients and assess correlation with outcome and EMT features in the tumor. Serum samples from patients with SCLC were prospectively obtained at diagnosis, response evaluation and progression. HGF serum (sHGF) was quantified by ELISA. EMT markers and p-Met/Met were assayed by immunohistochemistry in tumor samples. Clinical data were prospectively recorder. One-hundred twelve patients were included. High baseline levels of sHGF were associated with shorter overall survival (p=0.007) and remained independently associated with survival in the multivariate analysis (p=0.016). For stage IV patients, an increase of sHGF levels at response evaluation (p=0.042) and at progression (p=0.003) were associated with poor outcome. sHGF levels were associated (p<0.05) with a mesenchymal phenotype in the tumor. In conclusion, high sHGF at diagnosis and increases during the course of the disease predict for poor outcome in SCLC patients and associate with EMT in the tumor. These data provide novel evidence on a role of sHGF in the adverse clinical behavior of SCLC and support testing Met inhibitors in patients with high sHGF.     

基于Oncomine数据库及生物信息学方法分析肝细胞生长因子在多发性骨髓瘤中的表达及作用机制研究

目的:基于Oncomine数据库的基因信息,探讨肝细胞生长因子（HGF）在多发性骨髓瘤（MM）中的表达及作用机制。方法:收集Oncomine数据库中关于HGF研究的信息,对MM中HGF的表达水平变化进行分析。应用Genecards数据库收集与HGF基因相关的蛋白,并通过STRING软件绘制HGF相关蛋白网络图,应用DAVID在线工具分析蛋白功能富集的生理过程。通过DRUGSURV数据库及其在线工具分析HGF表达水平与MM患者生存间的关系,探讨其临床意义。结果:Oncomine数据库中共检索到445项不同肿瘤中关于HGF的研究;其中23项研究显示肿瘤组织与正常组织间HGF表达水平差异有统计学意义（ P<0.05）,包括肿瘤组织HGF表达增高10项,表达降低13项。Oncomine数据库中关于MM和正常组织HGF基因差异表达3项研究的4个数据集中,HGF在MM组织中的表达水平均高于正常组织（均 P<0.05）。通过Genecards数据库收集到SDC1、YWHAG、RAF1等25个与HGF相关的蛋白;蛋白功能富集分析显示,这些蛋白主要富集在过氧化氢介导的程序性细胞死亡的负调控、突触可塑性调节、死亡域受体对外源性凋亡信号通路的负调控等过程中,与PI3K-AKT及肿瘤相关通路有关。基于DRUGSURV数据库进行的生存分析显示,HGF高表达和低表达的MM患者总生存率差异无统计学意义（ P>0.05）。 结论:HGF基因可能通过PI3K-AKT通路调节MM细胞的凋亡,在MM的发生、发展中发挥作用。HGF可能是一个潜在的MM标志物,但其在预后判断中的价值需要进一步研究论证。     

乳腺癌患者血管内皮生长因子水平与外周血各成分的相关性

目的寻求血管内皮生长因子（VEGF）的最佳检测方法并探讨VEGF水平与血小板、白细胞数量之间的关系。方法采集42例乳腺癌患者（乳腺癌组）及20例健康志愿者（对照组）外周静脉血,用VEGF单克隆抗体ELISA法分别测定血清、血浆、P—APRVEGF水平,经酶标仪半定量,同时血细胞分析仪计数血小板、白细胞数量。结果血清VEGF水平与血小板数量呈正相关（r=0．424,P=0．063）,血清VEGF水平与白细胞数量呈正相关（r=0．443,P=0．050）。P—APR中的VEGF含量在局限性乳腺癌组与对照组间的差异有统计学意义（P=0．007）。结论外周血VEGF水平与血小板、白细胞呈线性相关,血小板、白细胞在外周血中可分泌VEGF;相对血清、血浆,P—APR是外周血中VEGF检测的最佳成分。     

Role of hepatocyte growth factor and its receptorc-met in multiple myeloma

Multiple myeloma is characterised by the clonal expansion of malignant plasma cells. Recently, we reported that a new cytokine, hepatocyte growth factor (HGF), and its receptorc-met are related to this disease. Here we review the observations that associate HGF with myeloma. Malignant plasma cells produce HGF and express the receptorc-met. Many patients have elevated HGF levels, which is unfavourable both in terms of survival and response to treatment. Possible biological roles of HGF in this disease are discussed, with special focus on bone homeostasis and its binding to heparan sulphate proteoglycans.     

恶性心包积液中血管内皮生长因子分泌水平的研究

目的：通过检测良、恶性心包积液中血管内皮生长因子（VEGF）的水平,探讨VEGF在恶性心包积液生成中的作用。方法：用EIA法检测22例恶性心包积液与16例非恶性心包积液及血清中VEGF水平,比较良、恶性心包积液中VEGF水平差异;并观察丝裂霉素心包腔内化疗后VEGF水平改变。结果：恶性心包积液中VEGF水平明显高于非恶性心包积液;肺癌与乳腺癌导致心包积液VEGF水平无明显差异;心包腔内化疗只可暂时降低VEGF水平。结论：恶性心包积液的VEGF明显增高,VEGF与恶性心包积液的发生、发展相关。     

A Phase I Open-Label Clinical Trial Evaluating the Therapeutic Vaccine hVEGF26–104/RFASE in Patients with Advanced Solid Malignancies

Lessons Learned

• The novel therapeutic vaccine hVEGF_26–104/RFASE was found to be safe and well tolerated in patients with cancer.
• hVEGF_26–104/RFASE failed to induce seroconversion against native hVEGF₁₆₅ and, accordingly, neither a decrease in circulating vascular endothelial growth factor (VEGF) levels nor clinical benefit was observed.
• Remarkably, hVEGF_26–104/RFASE induced VEGF₁₆₅-neutralizing antibodies in a nonhuman primate model. The absence of seroconversion in human calls for caution in the interpretation of efficacy of human vaccines in nonhuman primates.

     

多发性骨髓瘤骨病的诊断与治疗新进展

 约90 %的多发性骨髓瘤（MM）患者存在骨损害。常规X线检查只有在30 %的骨小梁缺失后才能发现溶骨性损害,对于初诊MM患者的分期,常规X线检查仍是"金标准"。在发现小的溶骨性病变方面CT扫描比常规X线检查更敏感,但对怀疑有椎体压迫的患者应行磁共振成像（MRI）或CT扫描。同位素骨扫描常常低估MM患者骨损害的程度。MM骨病的治疗包括双磷酸盐、新的靶向治疗、外科手术、放射治疗等治疗措施。     

多发性骨髓瘤骨病的机制研究及治疗进展

多发性骨髓瘤是血液内科较常见的恶性疾病,其以恶性浆细胞在骨髓中过度增殖和积累为特征,产生大量单克隆免疫球蛋白及其片段,导致终末器官的损害.其中约80％的患者合并有多发性骨髓瘤骨病(MBD),从而严重影响了患者的生活质量及疾病预后.研究发现成骨细胞受抑、破骨细胞激活为其主要发病原因,而多种细胞因子及通路影响了这一机制的发生.本文就MBD发生、发展的最新因素及治疗做一综述.