血管抑素、bFGF与骨肉瘤血管形成

血管生成是微血管内皮细胞的一系列连续过程。生理性血管的生成对于胚胎发育、创伤愈合和月经周期是必需的，在时间性和空间性上都受到严密调控。而肿瘤血管生成则是持续性、不受控制和无序的。肿瘤的发生发展由血管生成因子和抗血管生成因子共同控制，因此探讨血管形成在肿瘤发生发展中的作用，不仅有助于防治骨肉瘤的研究，也有助于寻找骨肉瘤转移和侵袭的机制，并有利于开发特异性靶向于骨肉瘤血管组织的血管生成抑制剂。     

血清血管生成因子在骨肉瘤组织中的表达及其临床意义

目的：探讨血清血管形成相关因子在骨肉瘤组织中的表达，及其与临床病理和微血管密度(MVD)的关系。方法：免疫组化SP法检测80例骨肉瘤组织中VBGF、CD34和FⅧ-Rag等蛋白表达，并根据CD34和FⅧ-Rag免疫组化染色结果计数MVD。同时采用酶联免疫分析定量检测36例骨肉瘤患者血清中的血管生戍因子：血管内皮生成因子(vEGF)、碱性成纤维因子(hFGF)、转化生长因子(TGF-β1)以及内皮抑制素(edlostatin，ES)的表达。结果：1)术前血清VEGF(1706ng／dL)和ES(302．4ng／dL)水平明显高于正常对照组，是VEGF的升高与肿瘤的微血高管密度、患者早期复发及其组织高表达密切相关；2)血清VBGF水平(1706ng／dL)和ES(302．4ng／dL)水平呈正相关；3)术后、VEGF(490．0ng／dL)和ES(32．7ng／dL)水平明显下降，VEGF复发组较未复发组高，但差异无统计学意义，而复发组的ES水平明显低于未复发组。结论：术前血清、VEGF和术后ES水平能反映骨肉瘤血管生成特性，对骨肉瘤早期复发具有重要预测价值，可作为抗血管生成的重要靶标。     

CD34在胃癌中的表达及微血管密度的临床病理意义

目的　用CD3 4标记胃癌微血管内皮细胞 ,测定肿瘤微血管密度 (MVD) ,探讨其与胃癌各临床病理因素的关系。方法　采用免疫组织化学S P法检测 5 2例胃癌、10例癌旁组织和 16例正常胃黏膜组织CD3 4抗原的表达 ,对CD3 4单克隆抗体标记的血管计数MVD。结果　CD3 4染色胃癌微血管具有高度的特异性、敏感性及清晰的背景 ,易于计数。胃癌组织MVD明显高于正常胃黏膜组织(P <0 .0 1)和癌旁组织 (P <0 .0 5 ) ;MVD与肿瘤大小、浸润深度、是否发生远处器官转移、TNM分期明显相关 (P均 <0 .0 5 )。结论　CD3 4是良好的血管内皮细胞标记物 ;胃癌血管生成与肿瘤的生长、浸润、转移及疾病进展密切相关 ;MVD可作为判断胃癌生物学行为 ,预测胃癌发生发展的指标。     

血清血管生成因子在骨肉瘤组织中的表达及其临床意义

目的:探讨血清血管形成相关因子在骨肉瘤组织中的表达,及其与临床病理和微血管密度(MVD)的关系。方法:免疫组化SP法检测80例骨肉瘤组织中VEGF、CD34和FⅧRag等蛋白表达,并根据CD34和FⅧRag免疫组化染色结果计数MVD。同时采用酶联免疫分析定量检测36例骨肉瘤患者血清中的血管生成因子:血管内皮生成因子(VEGF)、碱性成纤维因子(bFGF)、转化生长因子(TGFβ1)以及内皮抑制素(edostatin,ES)的表达。结果:1)术前血清VEGF(1706ng/dL)和ES(302.4ng/dL)水平明显高于正常对照组,是VEGF的升高与肿瘤的微血高管密度、患者早期复发及其组织高表达密切相关;2)血清VEGF水平(1706ng/dL)和ES(302.4ng/dL)水平呈正相关;3)术后VEGF(490.0ng/dL)和ES(32.7ng/dL)水平明显下降,VEGF复发组较未复发组高,但差异无统计学意义,而复发组的ES水平明显低于未复发组。结论:术前血清VEGF和术后ES水平能反映骨肉瘤血管生成特性,对骨肉瘤早期复发具有重要预测价值,可作为抗血管生成的重要靶标。     

CD147在骨肉瘤中的表达及其临床意义

目的研究CD147在骨肉瘤中的表达情况,探讨其与临床病理及预后的关系。方法用S-P免疫组织化学染色法对76例骨肉瘤CD147蛋白的表达进行检测,并对其与骨肉瘤临床病理及预后的关系进行统计学分析。结果CD147在骨肉瘤中呈普遍阳性表达,对照组骨软骨瘤、骨瘤和正常骨基本不表达。CD147蛋白表达与Enneking分期和Price分级呈正相关,与软组织侵犯、WHO分型和预后相关。结论骨肉瘤CD147蛋白的表达与肿瘤恶性程度和侵袭性密切相关,对骨肉瘤诊断和预后评估具有重要价值。     

CD147在骨肉瘤中的表达及其临床意义

目的研究CD147在骨肉瘤中的表达情况,探讨其与临床病理及预后的关系。方法用S-P免疫组织化学染色法对76例骨肉瘤CD147蛋白的表达进行检测,并对其与骨肉瘤临床病理及预后的关系进行统计学分析。结果CD147在骨肉瘤中呈普遍阳性表达,对照组骨软骨瘤、骨瘤和正常骨基本不表达。CD147蛋白表达与Enneking分期和Price分级呈正相关,与软组织侵犯、WHO分型和预后相关。结论骨肉瘤CD147蛋白的表达与肿瘤恶性程度和侵袭性密切相关,对骨肉瘤诊断和预后评估具有重要价值。     

重组人血管内皮抑制素对裸鼠骨肉瘤的抑瘤作用

目的 研究Rh-Endostatin对人骨肉瘤细胞裸鼠移植瘤的抑瘤作用.方法 建立人骨肉瘤细胞OS-732皮下移植瘤裸鼠动物模型,分为4组,分别给予(a)生理盐水;(b、c、d) Rh-Endostatin低、中和高剂量,分别为2.5、5.0和10mg/kg;为腹腔注射给药,1次/天,4周后裸鼠全部处死,称量肿瘤重量计算抑瘤率,用药疗效.对肿瘤标本进行微血管密度计数和细胞凋亡指数检测.结果 Rh-Endostatin单药2.5、5和10mg/kg治疗抑瘤率分别为25.3%、34.1%和35.7%;微血管密度:所有治疗组与对照组比较,差异均具有统计学意义(P＜0.01).凋亡指数:治疗组与对照组比较,差异均具有统计学意义(P＜0.01).结论 Rh-Endostatin单药对骨肉瘤具有明显的抑瘤作用,抗血管生成治疗骨肉瘤具有潜在的临床应用价值,值得进一步临床试验评估其疗效.     

AQP1在骨肉瘤中的表达和意义

目的探讨骨肉瘤中AQP1的表达和临床意义。方法对39例骨肉瘤和22例骨良性疾病对照组标本采用免疫组化法观察AQP1的表达并用人工计数和自动图像分析两种方法检测其表达差别,同时行CD34抗体染色标记肿瘤微血管,计算所有标本MVD。结果①AQP1表达于肿瘤微血管和小血管内皮细胞及绝大多数骨肉瘤的肿瘤细胞,尤其见于骨肉瘤的肿瘤巨细胞上;②人工计数AQP1阳性细胞百分比（YP）、AQP1人工计数分级、自动图像分析所得平均光密度（MD）,均表明AQP1在骨肉瘤中高表达（P均〈0.01）;③骨肉瘤中AQP1的YP与MVD呈明显正相关（r=0.341,P〈0.05）。结论大多数骨肉瘤肿瘤细胞高表达AQP1的原因不明;AQP1在骨肉瘤生物学行为及肿瘤微血管生成中占有重要作用;提示AQP1有可能作为骨肉瘤治疗的新靶点。     

VEGF特异siRNA对骨肉瘤细胞凋亡和仿血管发生的影响

目的：探讨VEGF特异siRNA在骨肉瘤细胞株（MG63）增殖、凋亡以及仿血管发生中的作用。方法：以pSilienc-er载体构建VEGF特异siRNA质粒pSilencer-VEGF siRNA,并转染骨肉瘤细胞MG63;将细胞分为pSilencer-VEGF siRNA质粒组（试验组）和空siRNA质粒组（对照组）,Western blotting在蛋白水平检测转染重组质粒后MG63细胞VEGF表达情况;MTT比色法、光镜、流式细胞仪结合Annexin V-FITC/PI染色和H-E染色观察质粒转染后骨肉瘤细胞增殖、凋亡和仿血管发生情况。结果：测序证实成功构建了针对VEGF的siRNA重组质粒。转染pSilencer-VEGF siRNA重组质粒后的试验组培养液中及骨肉瘤细胞内VEGF蛋白表达下降;转染后48、72、96h骨肉瘤细胞的增殖抑制率分别为41.67%、43.92%、35.32%,并发生了早期凋亡,凋亡率为28.27%。转染pSilencer-VEGF siRNA重组质粒的骨肉瘤细胞未见仿血管发生,转染空质粒的对照组骨肉瘤细胞则有仿血管发生。结论：RNA干扰VEGF基因能抑制骨肉瘤细胞增殖,促进骨肉瘤细胞早期凋亡,干扰骨肉瘤细胞仿血管发生,为临床基因治疗骨肉瘤提供了新的思路。     

趋化因子受体CCR7在NSCLC与转移淋巴结中的表达关系及意义

Objective  

The aim of this study was to explore the relationship between VEGF expression and vasculogenic mimicry of tumor in vitro.     

血管生成拟态研究进展

目的:总结肿瘤血管生成拟态(VM)的研究进展,并探讨肿瘤血管生成拟态形成机制。方法:应用PubMed和CNKI期刊全文数据库检索系统,以血管生成拟态为关键词,检索1999-01-01-2011-06-30相关文献,以三维培养模型中VM形态学、分子调节机制及抗肿瘤治疗研究为入选标准,分析文献45篇。结果:VM的生成机制比较复杂,其中VE-cad-herin/EphA2/PI3K/MMP是VM形成的关键通路,同时缺氧的微环境、cAMP和COX-2等对VM结构的形成也起一定的作用。结论:VM与肿瘤的侵袭转移潜能以及较差的临床预后有关,为抗肿瘤治疗提供了新的研究靶点。     

基质金属蛋白酶和肿瘤血管生成拟态的相关研究

血管生成拟态（vasculogenic mimicry,VM）是一种新的肿瘤细胞血液供应的方式。现有研究表明,基质金属蛋白酶（matrix metalloproteinase,MMPs）具有促进 VM 管道形成的作用。本文将对 MMPs 与血管生成拟态（vasculogenic mimicry,VM）的关系及其相关分子机制进行归纳,进一步探索两者之间的关系,从而为研究 VM 管道形成提供新的思路。     

结直肠腺癌血管生成拟态的形态学观察及其临床病理意义

目的:研究结直肠腺癌中是否存在血管生成拟态(vasculogenic mimicry,VM)及其临床病理意义。方法:收集156例结直肠腺癌组织学标本及其临床资料,利用CD34和PAS双重染色,观察是否存在VM,分析VM的形成与结直肠腺癌临床病理指标的关系。结果:156例结直肠腺癌中有31例存在VM,阳性率为19.87%,VM的形成与肿瘤大小无关,在低分化组、伴有血管及神经侵犯组、伴有淋巴结转移组,VM的阳性率比在中分化和高分化组、无血管及神经侵犯组、无淋巴结转移组高,差异有统计学意义（P＜0.05）。结论:结直肠腺癌中存在VM,VM形成与结直肠腺癌的侵袭性或远处转移相关。     

血管生成拟态在子宫内膜癌组织中的表达及意义

目的：探讨血管生成拟态（v asculogenic mimicry,VM）在子宫内膜癌中的表达及其与临床病理特征和预后的关系。方法：收集解放军白求恩国际和平医院2005年1 月至2014年6 月术后随访资料完整的子宫内膜癌标本267 例,采用CD31/PAS双重染色鉴定VM结构,分为VM阳性组与VM阴性组,免疫组织化学SP法检测CD133 的表达。结果：267 例子宫内膜癌患者中65例（24.3%）存在VM。VM的形成与子宫内膜癌FIGO分期（χ2= 9.987 ,P = 0.002）,组织学分级（χ2= 11.795 ,P = 0.001）,肌层浸润深度（χ2= 5.499,P = 0.019）,脉管内有无癌栓（χ2= 22.599,P < 0.001）及淋巴结有无转移（χ2= 7.848,P = 0.005）密切相关。Kaplan-Mei er法生存分析发现VM阳性组生存时间（中位生存时间为51个月）明显低于VM阴性组（中位生存时间为100 个月）,二者比较差异具有统计学意义（χ2= 70.973,P < 0.001）。 CD133 在VM阳性组的表达率为75.4%（49/ 65）,较VM阴性组58.9%（119/ 202）高,二者比较差异具有统计学意义（χ2= 5.720,P = 0.017）。 结论：VM与子宫内膜癌的发生、发展及恶性度密切相关,是影响患者预后的重要指标,CD133 表达阳性的肿瘤干细胞可能参与子宫内膜癌VM的形成。     

胶质瘤血管生成拟态的研究进展

血管生成拟态（vasculogenic mimicry,VM）是血管依赖性实体肿瘤中一种无内皮细胞的“血管样”结构,是肿瘤在高度侵袭过程中的一种特殊的供血模式。VM广泛存在于多种人体恶性肿瘤中,与肿瘤的进展、转移、侵袭和复发密切相关。本文将就胶质瘤血管生成拟态的发生机制、信号通路途径以及分子调控机制等作一综述,并探讨目前研究中面临的问题,旨在为胶质瘤的基因治疗的新切入点提供理论依据。     

The effect of hepatocellular carcinoma-associated fibroblasts on hepatoma vasculogenic mimicry

Vasculogenic Mimicry (VM) is the main source of blood supply in the early stage of tumor growth. Carcinoma-associated fibroblasts (CAFs) are one of the most important host cells in the tumor microenvironment. Some studies have found that CAFs can promote tumor angiogenesis, but there are few reports on the relationship between CAFs and VM. Tissue samples were collected from 60 cases of hepatocellular carcinoma (HCC) and 10 persons with normal liver function. The relationship between VM expression and clinicopathologic features was analyzed. Furthermore, the relationship between VM expression and vimentin or α-SMA expression was analyzed. Primary culture of hepatocellular CAFs and the collection of conditioned media were carried out. The effects of hepatocellular CAF conditioned medium on the formation of VM and the levels of VM-related proteins and genes in MHCC-97H cells were studied. The positive rate of VM was 35.0% in HCC tissues. There was no VM expression in normal liver tissues. VM expression was related to tumor diameter, Edmondson grade, clinical stage, and liver cirrhosis. The expression of vimentin and α-SMA in VM-positive patients was higher than in VM-negative patients. Different concentrations of hepatocellular CAF conditioned medium could promote the formation of VM and increase the expression of VM-related genes and proteins (MMP2 and EphA2) in MHCC-97H cells. The results show that there was a significant correlation between VM formation and the expression of vimentin or α-SMA in HCC tissues. The conditioned medium of hepatocellular CAFs may promote VM formation and the expression of VM-related genes and proteins (MMP2 and EphA2) in hepatoma cell line MHCC-97H.     

肿瘤血管生成拟态在结肠癌中的研究进展

血管生成拟态（vasculogenic mimicry,VM）是近年来发现的一种与经典的肿瘤血管生成途径完全不同、不依赖机体内皮细胞的全新肿瘤微循环模式,与肿瘤生长、侵袭、转移及患者预后密切相关。VM可能是一个潜在的肿瘤治疗新靶点,但其形成的分子机制尚未完全清楚。本文就近年来VM在结肠癌中发现、可能分子机制及其对治疗的影响作一综述,探讨当前研究中存在的问题,展望未来的发展方向。     

Tissue Microarray Study of Vasculogenic Mimicry in Bi-directional Differentiated Malignant Tumors

Objective To determine if vasculogenic mimicry (VM) exists in bi-directional differentiated malignant tumors. Methods The blood supply models for bi-directional differentiated tumors were studied with immunohistochemical and PAS double-staining techniques. New sections were made from 158 paraffin-embedded bi-directional malignant-tumor samples, including melanoma (high malignancy n= 30, low malignancy n=30); synoviosarcoma(SS) (high malignancy n=26, low malignancy n=13); acinarrhabdomyosarcoma(AR) (high malignancy n=16, low malignancy n=13); malignant mesothelioma (MM) (n=26), and epithelioid sarcoma (ES)(n=4). Tissue microarrays were made. The representative points in the paraffin sections were labeled and two tissue microarrays were made, one included 60 cases of melanoma, and the other included the other tumors. Immunohistochemical staining of the platelet-endothelial cell adhesive molecule(CD31 antigen) and periodic acid Schiff(PAS) staining were conducted. The areas were calculated of vessel-like channels consisting of CD31 antigen-positive tumor cells and of PAS positive materials. The VM was studied using the data obtained. Results Some of these bi-directional tumor cells secreted PAS-positive materials and CD31 positive materials. The walls of the VM consisted of PAS-positive materials lined with CD31 negative tumor cells with red blood cells inside the channel, whereas the walls of the epithelium-dependent vessels were comprised of CD31 positive materials. The positive areas of CD31 were significantly less than that of PAS (P<0.01 ). The number of cases with VM in highly malignant tumors was greater than that found in the lowly malignant tumors. Conclusions Bi-directional differentiated malignant tumor cells have the ability to auto-transform and might interact with the extracellular matrix to form a vessel channel system which mimics blood vessels for transporting blood. That process is called VM. Results in this study show that bi-directional differentiated tumors develop a nutritional supply by VM to satisfy the demand for the rapid growth, and thus acquire higher invasive ability and malignancy. This work was supported by National Nature Science Foundation (30070378).     

Verteporfin suppresses cell survival,angiogenesis and vasculogenic mimicry of pancreatic ductal adenocarcinoma via disrupting the YAP‐TEAD complex

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies. The Yes‐associated protein‐1 (YAP) plays a critical role in cell proliferation, apoptosis and angiogenesis. Verteporfin is a photosensitizer used in photodynamic therapy and also a small molecular inhibitor of the Hippo‐YAP pathway. However, little is known about whether verteporfin could inhibit YAP activity in PDAC cells. Our present results showed that verteporfin suppressed the proliferation of human PDAC PANC‐1 and SW1990 cells by arresting cells at the G1 phase, and inducing apoptosis in dose‐ and time‐dependent manners. Verteporfin also inhibited the tumor growth on the PDAC xenograft model. Treatment with verteporfin led to downregulation of cyclinD1 and cyclinE1, modulation of Bcl‐2 family proteins and activation of PARP. In addition, verteporfin exhibited an inhibitory effect on angiogenesis and vasculogenic mimicry via suppressing Ang2, MMP2, VE‐cadherin, and α‐SMA expression in vitro and in vivo. Mechanism studies demonstrated that verteporfin impaired YAP and TEAD interaction to suppress the expression of targeted genes. Our results provide a foundation for repurposing verteporfin as a promising anti‐tumor drug in the treatment of pancreatic cancer by targeting the Hippo pathway.