血清VEGF、CA15-3、CA125和EGFR测定在乳腺癌诊断中的价值

近年的研究结果表明,多种生长因子及其受体之间的相互作用在恶心肿瘤的发生与发展中起着很关键的作用。血管内皮生长因子（VEGF）是肿瘤诱导血管生成过程中的一个主要调节因子,在实体瘤生长转移中起到关键作用。在许多表皮来源的肿瘤中同时存在表皮生长因子受体（EGFR）的高表达或异常表达,EGFR与肿瘤细胞的增殖、侵袭、转移、     

乳脂肪球表皮生长因子8与乳腺癌相关性研究进展

乳脂肪球表皮生长因子Ⅷ(MFG-E8)是一种亲脂性糖蛋白,作为分泌型多效蛋白广泛存在于多种组织和细胞中,参与细胞间及细胞与基质间的相互作用.大量研究表明MFG-E8通过促进肿瘤细胞的增殖、抑制凋亡、促进肿瘤血管生成等在乳腺癌的发生、侵袭和转移过程及预后中起重要作用.     

灵芝孢子油及灵芝提取物孢子油对乳腺癌血管生成调节因子的作用

目的探讨灵芝孢子油及灵芝提取物孢子油对人源高恶性乳腺癌血管生成调节因子的作用。方法不同剂量的灵芝孢子油、灵芝提取物孢子油分别刺激体外培养的人源高恶性乳腺癌细胞系MDA-MB-231细胞及MDA-MB-231细胞制作的荷廇小鼠,Western blotting检测表皮生长因子受体(EGFR)的蛋白表达变化,Real-time PCR检测肿瘤血管生成相关因子EGFR、血管内皮生长因子(VEGF)、基质金属蛋白酶(MMPs)、血小板反应素-1(TSP-1)、血小板衍生因子(PDGF)、成纤维细胞生长因子(FGF)转录水平的基因表达变化。结果灵芝孢子油、灵芝提取物孢子油均可在体内和体外抑制人源高恶性乳腺癌细胞MDA-MB-231的EGFR蛋白表达,且有剂量依赖性;均可在体内和体外抑制VEGF RNA表达,增强血管生成抑制因子TSP-1 RNA表达;灵芝提取物孢子油比灵芝孢子油的作用更为显著。结论灵芝孢子油、灵芝提取物孢子油均有抑制肿瘤血管生成因子表达和促进血管生成抑制因子表达的作用,其中灵芝提取物孢子油比灵芝孢子油的作用更为显著。     

Vasohibin-1在常见肿瘤发生发展中作用的研究进展

肿瘤的形成、生长和侵袭转移依赖于肿瘤血管的生成。抑制肿瘤血管形成是阻止肿瘤进展的重要途径。肿瘤血管的生长受多种促进因子(如血管内皮生长因子、碱性成纤维细胞生长因子、胸苷磷酸化酶等)和抑制因子(如血管抑素、内皮抑素、血管生成抑制蛋白等)的共同调节。Vasohibin-1(VASH-1)作为一种新型血管抑制因子,受VEGF诱导表达于内皮细胞,发挥负性调控作用。近年来越来越多的研究发现VASH-1在多种肿瘤组织中异常表达并发挥作用。该文旨在对VASH-1在一些常见肿瘤发生、发展中的作用及机制作一综述。     

Endoglin：肿瘤新生血管的标志物

Endoglin为细胞膜糖蛋白 ,能调节细胞对转化生长因子 β的反应 ,在血管生成的组织和肿瘤组织的血管内皮细胞中肿瘤组织边缘部分血管起源性内皮细胞高度表达。Endoglin的表达与某些肿瘤的预后密切相关 ,可能成为肿瘤的预后指标。应用免疫治疗、基因反义技术阻断肿瘤组织中尚未形成血管的内皮细胞合成Endoglin ,可抑制肿瘤组织微血管的生成 ,阻断肿瘤浸润转移途径 ,将在肿瘤治疗中显示出良好的前景。     

中期因子在不同分子分型的乳腺癌中的表达及其临床意义

探讨在5种不同分子分型的乳腺癌中中期因子在组织中的表达,并分析其临床意义。采用免疫组化法检测203例乳腺癌组织的中期因子表达量;采用CD105抗体标记微血管内皮细胞,计算微血管密度(MVD)。结果显示,中期因子与肿瘤的淋巴结转移、临床分期相关性密切。中期因子表达量高的样本具有较高的以CD105表征的微血管密度。与其他4种分子分型相比,中期因子和CD105在基底细胞样型的表达量最高,但是该差异不具有统计学意义。中期因子可以作为乳腺癌预后的标记物应用于临床诊断和治疗,与其他分子亚型的乳腺癌相比,基底细胞样型的乳腺癌可能并不具有独特的血管生成模式。     

P53蛋白和VEGF在肺癌组织中的表达及临床意义

近年来,肺癌的发病率和死亡率呈上升趋势。寻找肿瘤的早期诊断指标和正确估计其预后具有重要的临床意义。已有研究表明野生型P53蛋白可以抑制血管生成因子(如血管内皮生长因子VEGF)的表达,并通过旁观效应抑制肿瘤的生长和转移,而突变型P53则可以上调VEGF的表达,促进血管形成并促进肿瘤的     

基底细胞样型乳腺癌中HIF-1α、VEGF的表达及临床意义

目的 观察缺氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)、血管内皮生长因子(vascular endothelial growth factor,VEGF)在基底细胞样型乳腺癌(basal-like breast carcinomas,BLBCs)中的表达,探讨其与肿瘤侵袭转移的关系及两者之间的相关性.方法 采用免疫组化SP法检测HIF-1α、VEGF在45例BLBCs、25例非基底细胞样型乳腺癌(non-basal-like breast carcinomas,non-BLBCs)和10例正常乳腺组织中的表达.结果 HIF-1α、VEGF在BLBCs组织中的阳性率明显高于non-BLBCs和正常乳腺组织(P<0.05);BLBCs组织中HIF-1α的表达与肿瘤直径、pTNM分期及淋巴结转移均呈正相关关系(P<0.05);VEGF的表达与肿瘤pTNM分期及淋巴结转移相关(P<0.05),并且两者之间有相关性(P=0.028).结论 HIF-1α、VEGF在BLBCs组织中高表达,提示其可能是参与BLBCs病程进展的重要分子;HIF-1α、VEGF的表达与多项临床病理指标,尤其是淋巴结转移密切相关,提示其可作为预测BLBCs淋巴结转移及预后的指标.     

血管内皮生长因子和E26转录因子在乳腺癌中的表达及意义

目的 试图揭示血管内皮生长因子（VEGF）和E26转录因子（E26 transformation-specificl,ETS-1)在乳腺癌组织中的表达规律,探讨其在血管生成和肿瘤浸润转移中的作用机制。方法 应用原位杂交和免疫组织化学链霉素抗生物系－过氧化物酶复合物法（SP）法,检测48例乳腺癌组织中VEGF和ETS－1的mRNA和蛋白的表达。结果 乳腺癌细胞高表达VEGF mRNA和蛋白,阳性率分别为75％（36／48）,70．8％（34／48）,而血管内皮细胞几乎不表达;ETS－1既表达在乳腺癌细胞,也表达在血管内皮细胞。癌细胞中mRNA和蛋白表达阳性率分别为85．4％（41／48）,79．2％（38／48）;VEGF和ETS－1高表达组的血管密度明显高于低表达组（均P＜0．01）;VEGF和ETS－1的表达与组织学分级和淋巴结转移密切相关,并且高表达组的微血管密度明显高于低表达组（P＜0．01）。结论 VEGF和ETS－1可促进乳腺癌血管形成,同时也促进肿瘤的浸润和转移;检测VEGF和ETS－1的表达可做为乳腺癌恶性度,浸润转移等生物学行为的参考指标。     

uPA基因表达调控研究进展

uPA的高表达与肿瘤侵袭转移密切相关。研究表明在乳腺癌、肺癌、结肠癌等肿瘤组织中都有uPA的高表达。已经证实细胞内uPA蛋白合成增加主要由基因的转录水平引起 ,uPA基因启动子上含有AP1、NFκB、PEA3等增强子元件 ,可与相应转录因子结合增强uPA的基因转录 ,许多调节分子如细胞内cAMP、生长因子和佛波酯等都是通过核内转录因子起调节作用的。另外肿瘤细胞内外信号传导通路的某种改变也导致了uPA表达的增高 ,促进细胞浸润转移。     

EGFL7基因沉默对裸鼠乳腺癌血管生成的影响

目的探讨类表皮生长因子域7（EGFL7）基因沉默对乳腺癌裸鼠模型瘤内血管生成的影响。方法构建EGFL7短发夹状RNA表达质粒并转染SGC-7901细胞（pshEGFL7组）,以空质粒转染为对照组。观察两组皮下种植瘤生长曲线及体积。免疫组织化学法检测抗-CD34、血管内皮生长因子（VEGF）、血小板反应蛋白（TSP1）表达;RT—PCR检测MMP-2和TIMP2表达。结果pshEGFL7组种植瘤体积为（1．86±0．65）cm^3,微血管密度（MVD）为20．84±6．38,分级为1～2级,对照组体积为（4．86±1．15）cm^3,MVD为39．48±9．01,分级为3～4级,两组种植瘤体积、MVD和分级的差异有统计学意义,P值均〈0．05。EGFL7组TSP1蛋白阳性表达,而VEGF蛋白为弱阳性或阴性表达,MMP-2mRNA表达下调,TIMP2mRNA表达上调,与对照组比较差异有统计学意义,P值均〈0．01。结论EGFL7基因沉默可降低乳腺痛种植瘤血管牛成．与调节MMP-2／TIMP2表汰和影响VEGF/TSP1平衡有关。     

Progress of EGFL6 in angiogenesis and tumor development

The epidermal growth factor (EGF) superfamily includes the protein 6 with an epidermal growth factor-like protein (EGFL6). EGFL6 has a signal peptide domain with an amino terminus and a MAM domain with a carboxy terminus. There are four whole EGF-like repeat regions and one partial EGF-like repeat region. Three of these regions include calcium-binding structures and an arg-gly-asp (RGD) integrin interaction motif. The epidermal growth factor-like (EGFL) and EGF domains have identical amino acid residues. Cell division, differentiation, mortality, cell adhesion, and migration are all affected by EGFL6. EGFL proteins are involved in a broad range of biological activities, making it important in tumor development and angiogenesis. We highlighted the latest development of EGFL6 research on tumor proliferation, invasion, and migration in this review.     

Pathological significance of vascular endothelial growth factor A isoform expression in human cancer

Vascular endothelial growth factor (VEGF) is a highly specific factor for vascular endothelial cells. Five VEGF-A isoforms (splice variants 121, 145, 165, 189 and 206) are generated as a result of alternative splicing from a single VEGF-A gene. These differ in their molecular weights and in biological properties such as their ability to bind to cell-surface heparan sulfate proteoglycans. Deregulated VEGF-A expression contributes to the development of solid tumors by promoting tumor angiogenesis. More specifically, VEGF-A189 expression is related to angiogenesis and prognosis in certain human solid tumors. VEGF-A189 expression is also related to the xenotransplantability of human cancers into immunodeficient mice in vivo. Consequently, inhibition of VEGF-A or VEGF-A189 signaling regulates the development and metastasis of a variety of tumors. This review focuses on recent studies of the mechanisms by which VEGF-A regulates angiogenesis in the cancer stroma and on our recent findings concerning the potential mechanisms of VEGF-A189 expression on tumor growth and metastasis.     

HOXB7 induces STAT3-mediated transformation and lung metastasis in immortalized mammary gland NMuMG cells

The homeobox family genes are often dysregulated in various cancer types. Particularly HOXB7 amplification and overexpression correlate with poor prognosis in various cancer such as gastric, pancreatic, and lung cancers. Moreover, HOXB7 is known to contribute to cancer progression by promoting epithelial to mesenchymal transition, anticancer drug resistance, and angiogenesis. In this study, we show that HOXB7 is coamplified with ERBB2 in a subset of breast cancer patients and HOXB7 expression correlates with poor prognosis in HER2-positive breast cancer patients. This clinical observation is supported by the following results—HOXB7 overexpression in an immortalized murine mammary gland epithelial cell line NMuMG induces cellular transformation in vitro, tumorigenesis, and lung metastasis through the activation of JAK-STAT signaling.     

Silencing of CCR7 inhibits the growth,invasion and migration of prostate cancer cells induced by VEGFC

Early in prostate cancer development, tumor cells express vascular endothelial growth factor C (VEGF-C), a secreted molecule that is important in angiogenesis progression. CC-chemokine receptor 7 (CCR7), another protein involved in angiogenesis, is strongly expressed in most human cancers, where it activated promotes tumor growth as well as favoring tumor cell invasion and migration. The present study aimed to investigate the effect of down-regulating CCR7 expression on the growth of human prostate cancer cells stimulated by VEGFC. The CCR7-specific small interfering RNA (siRNA) plasmid vector was constructed and then transfected into prostate cancer cells. The expression of CCR7 mRNA and protein was detected by quantitative polymerase chain reaction and western blot analysis, respectively. Cell proliferation, apoptosis, cell cycle distribution and cell migration were assessed following knockdown of CCR7 by RNA interference (RNAi). Western blot analysis was used to identify differentially expressed angiogenesis- and cell cycle-associated proteins in cells with silenced CCR7. The expression levels of CCR7 in prostate cancer cells transfected with siRNA were decreased, leading to a significant inhibition of prostate cancer cell proliferation, migration and invasion induced by VEGFC. Western blot analysis revealed that silencing of CCR7 may inhibit vascular endothelial growth factor, matrix metalloproteinase (MMP)-2 and MMP-9 protein expression. In conclusion, the present study demonstrated that RNAi can effectively silence CCR7 gene expression and inhibit the growth of prostate cancer cells, which indicates that there is a potential of targeting CCR7 as a novel gene therapy approach for the treatment of prostate cancer.     

EGFL7 is a chemoattractant for endothelial cells and is up-regulated in angiogenesis and arterial injury

The endothelium of the adult vasculature is normally quiescent, with the exception of the vasculature of the female reproductive system. However, in response to appropriate stimuli (ie, wound healing, atherosclerosis, tumor growth and metastasis, arthritis) the vasculature becomes activated and grows new capillaries through angiogenesis. We have recently identified a novel endothelial-restricted gene, Egfl7, that encodes a 41-kd secreted protein (Fitch MJ, Campagnolo L, Kuhnert F, Stuhlmann H: Egfl7, a novel epidermal growth factor-domain gene expressed in endothelial cells. Dev Dyn 2004, 230:316-324). Egfl7 is expressed at high levels early during mouse embryonic development and is strictly associated with the vascular bed. In this study, we investigated Egfl7 expression in the quiescent adult vasculature, in the pregnant uterus, and in two different models of arterial injury, namely ballooning and ferric chloride injury. By RNA in situ hybridization, Egfl7 expression in the vasculature was found to be restricted to the endothelium of the capillaries and mature vessels. In the pregnant uterus, increased vascularization was accompanied by up-regulation of Egfl7. On arterial injury, Egfl7 expression was up-regulated in the regenerating endothelium, but not in the neointima. Importantly, the EGFL7 protein acted as a chemoattractant for embryonic endothelial cells and fibroblasts in a cell migration assay. Together, these results suggest that Egfl7 functions in the formation and maintenance of endothelial integrity and that its up-regulation may be a critical component in the reorganization of the vascular bed in response to angiogenic stimuli.     

In-vitro inhibitory effect of EGFL7-RNAi on endothelial angiogenesis in glioma

Objective: To investigate the role and mechanism of epidermal growth factor like domain 7 (EGFL7) in glioma angiogenesis by cell co-culture and RNA interference. Methods: NSCs-HUVECs co-culture system was established using Transwell culturing techniques. The interactions between glioma and endothelial cells were simulated in-vitro. Cellular expression of EGFL7 in NSCs and HUVEC was targeted and suppressed by lentiviral vector carrying siRNA. The effect of EGFL7 on angiogenesis in glioma in-vitro micro-environment was detected by endothelial cell proliferation, adhesion and tube formation assay. Results: Following EGFL7 gene silencing, expression of EGFL7 in HUVECs was reduced and cell adhesion capability was inhibited significantly. Endothelial cells failed to form a lumen-like structure after EGFL7 gene silencing, shown by the tube formation assay. Conclusion: By regulating endothelial cell adhesion, EGFL7 plays a key role in the regulation of glioma angiogenesis.     

乳腺癌组织Livin和PTEN表达与肿瘤血管生成的相关性

目的:研究乳腺癌组织中凋亡抑制蛋白Livin和抑癌基因PTEN的表达与微血管密度(MVD)的关系,探讨乳腺癌血管生成的影响机制。方法:应用免疫组化Elivision法检测90例乳腺癌和30例乳腺纤维腺瘤组织中Livin、PTEN、VEGF的表达和CD34标记的MVD值,分析Livin和PTEN表达与乳腺癌血管生成及侵袭转移的关系。结果:在90例乳腺癌中Livin、PTEN和VEGF表达阳性率分别为54.4%、48.9%和61.1%,MVD为(30.81±11.29)个/HPF,与良性对照组比较均有显著差异(P<0.01);Livin阳性表达与乳腺癌肿瘤大小、临床分期、MVD值及VEGF表达呈正相关(P<0.05),与年龄、病理分级、淋巴结转移未见显著相关(P>0.05);PTEN表达与乳腺癌淋巴结转移、临床分期和MVD呈负相关(P<0.05),与VEGF表达、年龄、肿瘤大小、病理分级未见显著相关(P>0.05)。结论:Livin和PTEN在乳腺癌的血管生成及发生发展过程中分别起促进和抑制作用,Livin的促血管生成作用可能与其上调VEGF的表达有关。     

肝素酶和碱性成纤维细胞生长因子与非小细胞肺癌转移和预后的关系

目的 探讨肝素酶(heparanase)和碱性成纤维细胞生长因子(bFGF)在人非小细胞肺癌(NSCLC)组织中表达的临床意义及其与肺癌转移和预后的关系。方法 采用免疫组织化学、原位杂交和Western blot方法,检测115例人NSCLC石蜡切片和45例新鲜肺癌及对应癌旁正常组织中肝素酶和bFGF的表达情况。采用χ^2检验、t检验、生存曲线和Cox比例风险回归等方法分析肝素酶和bFGF分别表达及共表达的意义。结果 免疫组织化学染色证实肝素酶(91／115)和bFGF(89／115)主要表达在癌细胞质和(或)细胞膜中,在正常肺泡上皮和支气管上皮中则呈阴性表达。Western blot也证实肝素酶在肺癌中的表达明显增高(P=0．041)。统计分析结果显示：肝素酶和bFGF的表达具有明显的一致性(P：0．0001),二者单独表达和共表达均与肺癌的分期、血管侵袭、淋巴结转移、微血管密度和预后有关,其中,二者共表达时与分期和微血管密度的相关性更显著;另外,bFGF还与肺癌的分化程度有关。多因素分析结果显示,肺癌的分化程度、血管浸润、淋巴结转移和bFGF的表达可以作为判断肺癌预后的危险因素,但肝素酶不是影响预后的独立因素。结论 肝素酶和bFGF均与肺癌的转移、血管生成和预后密切相关。     

Targeting COX-2 and EP4 to control tumor growth, angiogenesis, lymphangiogenesis and metastasis to the lungs and lymph nodes in a breast cancer model

We reported that cyclo-oxygenase (COX)-2 expression in human breast cancer stimulated cancer cell migration and invasiveness, production of vascular endothelial growth factor (VEGF)-C and lymphangiogenesis in situ, largely from endogenous PGE2-mediated stimulation of prostaglandin E (EP)1 and EP4 receptors, presenting them as candidate therapeutic targets against lymphatic metastasis. As human breast cancer xenografts in immuno-compromised mice have limitations for preclinical testing, we developed a syngeneic murine breast cancer model of spontaneous lymphatic metastasis mimicking human and applied it for mechanistic and therapeutic studies. We tested the roles of COX-2 and EP receptors in VEGF-C and -D production by a highly metastatic COX-2 expressing murine breast cancer cell line C3L5. These cells expressed all EP receptors and produced VEGF-C and -D, both inhibited with COX-2 inhibitors or EP4 (but not EP1, EP2 or EP3) antagonists. C3H/HeJ mice, when implanted SC in both inguinal regions with C3L5 cells suspended in growth factor-reduced Matrigel, exhibited rapid tumor growth, tumor-associated angiogenesis and lymphangiogenesis (respectively measured with CD31 and LYVE-1 immunostaining), metastasis to the inguinal and axillary lymph nodes and the lungs. Chronic oral administration of COX-1/COX-2 inhibitor indomethacin, COX-2 inhibitor celecoxib and an EP4 antagonist ONO-AE3-208, but not an EP1 antagonist ONO-8713 at nontoxic doses markedly reduced tumor growth, lymphangiogenesis, angiogenesis, and metastasis to lymph nodes and lungs. Residual tumors in responding mice revealed reduced VEGF-C and -D proteins, AkT phosphorylation and increased apoptotic/proliferative cell ratios consistent with blockade of EP4 signaling. We suggest that EP4 antagonists deserve clinical testing for chemo-intervention of lymphatic metastasis in human breast cancer.