• 【胰岛素样生长因子I受体的抗体靶向通过抑制肿瘤增殖和血管生成来增强多发性骨髓瘤对化疗的抗肿瘤反应。】 复制标题 收藏 收藏
    DOI:10.1007/s00262-006-0196-9 复制DOI
    作者列表:Wu KD,Zhou L,Burtrum D,Ludwig DL,Moore MA
    BACKGROUND & AIMS: :Although many multiple myeloma (MM) patients initially respond to cytotoxic therapy, most eventually relapse. Novel therapeutic strategies employing a combination of chemotherapy with targeted biologics may significantly enhance the response of tumor cells to treatment. We tested a fully human anti-IGF-IR antibody (A12) against MM, and showed specific inhibition of IGF-I or serum-induced IGF-IR signaling in MM cells in vitro. The A12 as a single agent was demonstrated to exert modest to significant inhibition of tumor growth in vivo in various subcutaneous xenograft MM models. The A12 was also evaluated in a disseminated xenograft MM.1S NOD/SCID model as monotherapy or in combination with other drugs (bortezomib, melphalan) currently in clinical use. The tumor burden, as determined by luciferase bioimaging, was sharply decreased, and overall survival significantly prolonged when the therapies were combined. Immunohistochemical analysis demonstrated that the A12 treated tumors had significantly decreased vascularization compared to control tumors. Furthermore, most MM lines constitutively secreted significant quantities of VEGF, and this was enhanced following IGF-I treatment. Inhibition of IGF-IR by the A12 in vitro suppressed both constitutive and IGF-I-induced secretion of VEGF, indicating that a putative anti-angiogenic mechanism associated with the A12 treatment may contribute to its anti-tumor effect.
    背景与目标: : 尽管许多多发性骨髓瘤 (MM) 患者最初对细胞毒性治疗有反应,但大多数最终复发。采用化疗与靶向生物制剂相结合的新型治疗策略可能会显着增强肿瘤细胞对治疗的反应。我们测试了针对MM的全人抗igf-ir抗体 (A12),并在体外显示了对MM细胞中igf-i或血清诱导的igf-ir信号的特异性抑制。在各种皮下异种移植MM模型中,A12作为单一药物被证明对体内肿瘤生长具有适度至显着的抑制作用。还在播散性异种移植MM.1S NOD/SCID模型中评估了A12,作为单一疗法或与目前临床使用的其他药物 (硼替佐米,美法仑) 联合使用。通过荧光素酶生物成像确定的肿瘤负荷急剧降低,并且当联合治疗时,总生存期显着延长。免疫组织化学分析表明,与对照肿瘤相比,A12治疗的肿瘤血管形成明显减少。此外,大多数MM系组成型分泌了大量的VEGF,并且在igf-i治疗后这种情况得到了增强。体外A12抑制igf-ir抑制了组成型和igf-i诱导的VEGF分泌,表明与A12治疗相关的推定抗血管生成机制可能有助于其抗肿瘤作用。
  • 【Akt1对于皮肤伤口愈合过程中的血管成熟和血管生成是必需的。】 复制标题 收藏 收藏
    DOI:10.1007/s10456-008-9111-7 复制DOI
    作者列表:Somanath PR,Chen J,Byzova TV
    BACKGROUND & AIMS: :Previous in vivo and in vitro studies have shown that Akt1 serves as a crucial regulator of vascular maturation, extracellular matrix composition, and angiogenesis in tumors. Hence, we hypothesized that Akt1 may be necessary for other angiogenesis-dependent processes, including wound healing. Using Akt1 (-/-) and Akt2 (-/-) mice, we demonstrate that deficiency of Akt1, but not Akt2, results in impaired assembly of collagen in skin wounds and around the blood vessels. Wounds in Akt1 (-/-) mice, but not in Akt2 (-/-) mice, were characterized by reduced vascular area as well as impaired vascular maturation as evidenced by reduced smooth muscle cell recruitment. Expression level of a major angiogenic growth factor, VEGF, was significantly lower in wound tissues of Akt1 (-/-) mice as compared to WT. However, despite the impaired collagen assembly and reduced angiogenesis in Akt1 (-/-) wounds, no significant difference in migration of fibroblasts into the wound area was observed between WT and Akt1 (-/-) mice. Importantly, the dynamics of wound closure were similar between WT, Akt1 (-/-), and Akt2 (-/-) mice. Thus, it appears that although the lack of Akt1 impairs VEGF expression, wound angiogenesis, and subsequent maturation of vasculature, it has no effect on the wound closure. These findings may have clinical applications for the improvement of treatment procedures with reported history of wound healing complications.
    背景与目标: : 先前的体内和体外研究表明,Akt1是肿瘤中血管成熟,细胞外基质组成和血管生成的关键调节剂。因此,我们假设Akt1可能是其他血管生成依赖性过程 (包括伤口愈合) 所必需的。使用Akt1 (-/-) 和Akt2 (-/-) 小鼠,我们证明Akt1的缺乏而不是Akt2的缺乏会导致皮肤伤口和血管周围胶原蛋白的组装受损。Akt1 (-/-) 小鼠的伤口,但Akt2 (-/-) 小鼠的伤口的特征是血管面积减少以及血管成熟受损,平滑肌细胞募集减少证明了这一点。与WT相比,Akt1 (-/-) 小鼠伤口组织中主要血管生成生长因子VEGF的表达水平显着降低。然而,尽管在Akt1 (-/-) 伤口中胶原蛋白组装受损且血管生成减少,但在WT和Akt1 (-/-) 小鼠之间未观察到成纤维细胞向伤口区域迁移的显着差异。重要的是,WT,Akt1 (-/-) 和Akt2 (-/-) 小鼠之间的伤口闭合动力学相似。因此,尽管缺乏Akt1会损害VEGF的表达,伤口血管生成以及随后的脉管系统成熟,但它对伤口闭合没有影响。这些发现可能具有临床应用,可用于改善伤口愈合并发症史的治疗程序。
  • 【血管生成及其治疗机会。】 复制标题 收藏 收藏
    DOI:10.1155/2013/127170 复制DOI
    作者列表:Yoo SY,Kwon SM
    BACKGROUND & AIMS: :Angiogenesis plays critical roles in human physiology that range from reproduction and fetal growth to wound healing and tissue repair. The sophisticated multistep process is tightly regulated in a spatial and temporal manner by "on-off switch signals" between angiogenic factors, extracellular matrix components, and endothelial cells. Uncontrolled angiogenesis may lead to several angiogenic disorders, including vascular insufficiency (myocardial or critical limb ischemia) and vascular overgrowth (hemangiomas, vascularized tumors, and retinopathies). Thus, numerous therapeutic opportunities can be envisaged through the successful understanding and subsequent manipulation of angiogenesis. Here, we review the clinical implications of angiogenesis and discuss pro- and antiangiogenic agents that offer potential therapy for cancer and other angiogenic diseases.
    背景与目标: : 血管生成在人类生理中起着至关重要的作用,从生殖和胎儿生长到伤口愈合和组织修复。通过血管生成因子,细胞外基质成分和内皮细胞之间的 “开关信号”,以时空方式严格调节复杂的多步过程。不受控制的血管生成可能导致多种血管生成性疾病,包括血管功能不全 (心肌或严重肢体缺血) 和血管过度生长 (血管瘤,血管化肿瘤和视网膜病变)。因此,通过成功理解和随后操纵血管生成,可以设想许多治疗机会。在这里,我们回顾了血管生成的临床意义,并讨论了为癌症和其他血管生成疾病提供潜在治疗的促血管生成剂和抗血管生成剂。
  • 【山青石根提取物及其组成成分shisophloroglucin A在体外和体内高糖诱导的血管生成中减弱。】 复制标题 收藏 收藏
    DOI:10.3390/ijms20225542 复制DOI
    作者列表:Fernando KHN,Yang HW,Jiang Y,Jeon YJ,Ryu B
    BACKGROUND & AIMS: :Diabetes is associated with vascular complications, such as impaired wound healing and accelerated vascular growth. The different clinical manifestations, such as retinopathy and nephropathy, reveal the severity of enhanced vascular growth known as angiogenesis. This study was performed to evaluate the effects of an extract of Ishige okamurae (IO) and its constituent, Ishophloroglucin A (IPA) on high glucose-induced angiogenesis. A transgenic zebrafish (flk:EGFP) embryo model was used to evaluate vessel growth. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), gap closure, transwell, and Matrigel® assays were used to analyze the proliferation, migration, and capillary formation of EA.hy926 cells. Moreover, protein expression were determined using western blotting. IO extract and IPA suppressed vessel formation in the transgenic zebrafish (flk:EGFP) embryo. IPA attenuated cell proliferation, cell migration, and capillary-like structure formation in high glucose-treated human vascular endothelial cells. Further, IPA down regulated the expression of high glucose-induced vascular endothelial growth factor receptor 2 (VEGFR-2) and downstream signaling molecule cascade. Overall, the IO extract and IPA exhibited anti-angiogenic effects against high glucose-induced angiogenesis, suggesting their potential for use as therapeutic agents in diabetes-related angiogenesis.
    背景与目标: : 糖尿病与血管并发症有关,如伤口愈合受损和血管生长加速。不同的临床表现,如视网膜病变和肾病,揭示了血管生长增强的严重程度,即血管生成。进行这项研究是为了评估石原 (IO) 提取物及其成分Ishophloroglucin A (IPA) 对高糖诱导的血管生成的影响。使用转基因斑马鱼 (flk:EGFP) 胚胎模型评估血管生长。3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物 (MTT),间隙闭合,tranwell和Matrigel®测定用于分析EA.hy926细胞的增殖,迁移和毛细血管形成。此外,使用蛋白质印迹法测定蛋白质表达。IO提取物和IPA抑制了转基因斑马鱼 (flk:EGFP) 胚胎中的血管形成。IPA减弱了高糖处理的人血管内皮细胞的细胞增殖,细胞迁移和毛细血管样结构的形成。此外,IPA下调高糖诱导的血管内皮生长因子受体2 (VEGFR-2) 和下游信号分子级联的表达。总体而言,IO提取物和IPA对高糖诱导的血管生成表现出抗血管生成作用,表明它们有潜力用作糖尿病相关血管生成的治疗剂。
  • 【具有血管生成和Gibbs-Thomson关系的肿瘤生长的时延自由边界问题的定性分析。】 复制标题 收藏 收藏
    DOI:10.3934/mbe.2019372 复制DOI
    作者列表:Xu SH,Wu J
    BACKGROUND & AIMS: :In this paper we consider a time-delayed mathematical model describing tumor growth with angiogenesis and Gibbs-Thomson relation. In the model there are two unknown functions: One is $\sigma(r,t)$ which is the nutrient concentration at time $t$ and radius $r$, and the other one is $R(t)$ which is the outer tumor radius at time $t$. Since $R(t)$ is unknown and varies with time, this problem has a free boundary. Assume $\alpha(t)$ is the rate at which the tumor attracts blood vessels and the Gibbs-Thomson relation is considered for the concentration of nutrient at outer boundary of the tumor, so that on the outer boundary, the condition $$\dfrac{\partial \sigma}{\partial r}+\alpha(t)\left(\sigma-N(t)\right)=0,~~r=R(t)$$ holds, where $N(t)=\bar{\sigma}\left(1-\dfrac{\gamma}{R(t)}\right)H(R(t))$ is derived from Gibbs-Thomson relation. $H(\cdot)$ is smooth on $(0,\infty)$ satisfying $H(x)=0$ if $x\leq \gamma$, $H(x)=1$ if $x\geq 2\gamma$ and $0\leq H'(x)\leq 2/\gamma$ for all $x\geq 0$. In the case where $\alpha$ is a constant, the existence of steady-state solutions is discussed and the stability of the steady-state solutions is proved. In another case where $\alpha$ depends on time, we show that $R(t)$ will be also bounded if $\alpha(t)$ is bounded and some sufficient conditions for the disappearance of tumors are given.
    背景与目标:
  • 【类黄酮,饮食衍生的细胞增殖和体外血管生成抑制剂。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Fotsis T,Pepper MS,Aktas E,Breit S,Rasku S,Adlercreutz H,Wähälä K,Montesano R,Schweigerer L
    BACKGROUND & AIMS: :Consumption of a plant-based diet can prevent the development and progression of chronic diseases associated with extensive neovascularization, including solid malignant tumors. In previous studies, we have shown that the plant-derived isoflavonoid genistein is a potent inhibitor of cell proliferation and in vitro angiogenesis. In the present study, we report that certain structurally related flavonoids are more potent inhibitors than genistein. Indeed, 3-hydroxyflavone, 3',4'-dihydroxyflavone, 2',3'-dihydroxyflavone, fisetin, apigenin, and luteolin inhibited the proliferation of normal and tumor cells, as well as in vitro angiogenesis, at half-maximal concentrations in the low micromolar range. We have previously demonstrated that genistein concentrations in the urine of subjects consuming a plant-based diet is 30-fold higher than in subjects consuming a traditional Western diet. The wider distribution and the more abundant presence of flavonoids in the plant kingdom, together with the present results, suggest that flavonoids may contribute to the preventive effect of a plant-based diet on chronic diseases, including solid tumors.
    背景与目标: : 食用以植物为基础的饮食可以防止与广泛的新血管形成 (包括实体恶性肿瘤) 相关的慢性疾病的发展和进展。在先前的研究中,我们已经表明植物来源的异黄酮染料木素是细胞增殖和体外血管生成的有效抑制剂。在本研究中,我们报告某些结构相关的类黄酮比染料木黄酮更有效。实际上,3-羟基黄酮,3 ',4'-二羟基黄酮,2 ',3'-二羟基黄酮,fisetin,芹菜素和木犀草素抑制了正常细胞和肿瘤细胞的增殖,以及体外血管生成在低微摩尔范围内的最大浓度。我们以前已经证明,食用植物性饮食的受试者尿液中的染料木黄酮浓度比食用传统西方饮食的受试者高30倍。类黄酮在植物界的更广泛分布和更丰富的存在,以及目前的结果,表明类黄酮可能有助于植物性饮食对慢性疾病 (包括实体瘤) 的预防作用。
  • 【来自大戟的新的mirsinane型二萜。对VEGF诱导的血管生成具有抑制作用。】 复制标题 收藏 收藏
    DOI:10.1007/s11418-012-0686-3 复制DOI
    作者列表:Ghanadian SM,Ayatollahi AM,Afsharypuor S,Javanmard SH,Dana N
    BACKGROUND & AIMS: :Euphorbia microsciadia (Euphorbiaceae) is a perennial plant growing in Iran. Two new cyclomyrsinol esters, 3-O-propionyl-5, 10, 14-O-triacetyl-8-O-(2'-methyl-butanoyl)-cyclomyrsinol (1) and 3, 5, 10, 14, 15-O-pentaacetyl-8-O-isobutanoyl-cyclomyrsinol (2) were isolated from the methanolic extract of its dried aerial parts. The structures were elucidated based on (13)C- and (1)H-NMR as well as 2D-NMR, IR and different MS spectra. Anti-angiogenic activity was also evaluated on vascular endothelium growth factor (VEGF)-induced angiogenesis in cultured human umbilical vein endothelial cells in vitro by assessing capillary-like tube network formation.
    背景与目标: : 大戟科 (Euphorbiaceae) 是一种多年生植物,生长在伊朗。从其干燥的地上部分的甲醇提取物中分离出两种新的环氨酚酯,3-o-丙酰基-5,10,14-O-triacetyl-8-O-(2 '-甲基-丁酰基)-环氨酚 (1) 和3,5,10,14,15-O-pentaacetyl-8-O-isobutanoyl-cyclomyrsinol (2)。基于 (13)C-和 (1) h-nmr以及2D-NMR,IR和不同的MS光谱阐明了结构。还通过评估毛细血管样管网络的形成,评估了体外培养的人脐静脉内皮细胞中血管内皮生长因子 (VEGF) 诱导的血管生成的抗血管生成活性。
  • 【开发3D血管生成模型以研究肿瘤-内皮细胞相互作用和抗血管生成药物的作用。】 复制标题 收藏 收藏
    DOI:10.1038/s41598-017-03010-6 复制DOI
    作者列表:Amann A,Zwierzina M,Koeck S,Gamerith G,Pechriggl E,Huber JM,Lorenz E,Kelm JM,Hilbe W,Zwierzina H,Kern J
    BACKGROUND & AIMS: :The tumour microenvironment and tumour angiogenesis play a critical role in the development and therapy of many cancers, but in vitro models reflecting these circumstances are rare. In this study, we describe the development of a novel tri-culture model, using non-small cell lung cancer (NSCLC) cell lines (A549 and Colo699) in combination with a fibroblast cell line (SV 80) and two different endothelial cell lines in a hanging drop technology. Endothelial cells aggregated either in small colonies in Colo699 containing microtissues or in tube like structures mainly in the stromal compartment of microtissues containing A549. An up-regulation of hypoxia and vimentin, ASMA and a downregulation of E-cadherin were observed in co- and tri-cultures compared to monocultures. Furthermore, a morphological alteration of A549 tumour cells resembling "signet ring cells" was observed in tri-cultures. The secretion of proangiogenic growth factors like vascular endothelial growth factor (VEGF) was measured in supernatants. Inhibition of these proangiogenic factors by using antiangiogenic drugs (bevacizumab and nindetanib) led to a significant decrease in migration of endothelial cells into microtissues. We demonstrate that our method is a promising tool for the generation of multicellular tumour microtissues and reflects in vivo conditions closer than 2D cell culture.
    背景与目标: : 肿瘤微环境和肿瘤血管生成在许多癌症的发展和治疗中起着至关重要的作用,但是反映这些情况的体外模型很少。在这项研究中,我们描述了一种新的三培养模型的开发,使用非小细胞肺癌 (NSCLC) 细胞系 (A549和Colo699) 与成纤维细胞系 (SV 80) 和两种不同的内皮细胞系在悬挂式滴技术中。内皮细胞聚集在包含微组织的Colo699中的小菌落中,或主要在包含a549的微组织的基质区室中的管状结构中。与单培养相比,在共培养和三培养中观察到缺氧和波形蛋白,ASMA的上调以及E-cadherin的下调。此外,在三培养物中观察到类似于 “印戒细胞” 的A549肿瘤细胞的形态变化。在上清液中测量了促血管生成生长因子 (如血管内皮生长因子 (VEGF)) 的分泌。通过使用抗血管生成药物 (贝伐单抗和nindetanib) 抑制这些促血管生成因子导致内皮细胞向微组织的迁移显着减少。我们证明了我们的方法是产生多细胞肿瘤微组织的有前途的工具,并且反映了比2D细胞培养更接近的体内条件。
  • 【通过调节细胞氧化还原状态控制肿瘤血管生成和转移。】 复制标题 收藏 收藏
    DOI:10.1016/j.bbcan.2020.188352 复制DOI
    作者列表:Serrano JJ,Delgado B,Medina MÁ
    BACKGROUND & AIMS: :Redox reactions pervade all biology. The control of cellular redox state is essential for bioenergetics and for the proper functioning of many biological functions. This review traces a timeline of findings regarding the connections between redox and cancer. There is ample evidence of the involvement of cellular redox state on the different hallmarks of cancer. Evidence of the control of tumor angiogenesis and metastasis through modulation of cell redox state is reviewed and highlighted.
    背景与目标: : 氧化还原反应遍布所有生物学。细胞氧化还原状态的控制对于生物能学和许多生物功能的正常运行至关重要。这篇综述追溯了有关氧化还原与癌症之间联系的发现时间表。有充分的证据表明细胞氧化还原状态参与了癌症的不同特征。回顾并强调了通过调节细胞氧化还原状态控制肿瘤血管生成和转移的证据。
  • 【纳米库黄素通过下调斑马鱼中的hif1a/vegf-a信号来抑制血管生成。】 复制标题 收藏 收藏
    DOI:10.2174/1567202617666200207130039 复制DOI
    作者列表:Cao Z,He S,Peng Y,Liao X,Lu H
    BACKGROUND & AIMS: BACKGROUND:Curcumin has anti-inflammatory, antioxidant and anticancer properties. Despite the considerable evidence showing that curcumin is an efficacious and safe compound for multiple medicinal benefits, there are some demerits with respect to the therapeutic effectiveness of curcumin, namely, poor stability and solubility, and its role in angiogenesis in vivo is still not yet clear. More recently, the biodegradable polymer nanoparticles have been developed. This offers promise for the therapeutic effectiveness of curcumin by increasing its bioavailability, solubility and retention time. METHODS:Here, we compared the medicinal effectiveness of curcumin and nanocurcumin (NC), and found that nanocurcumin can inhibit angiogenesis more effectively than curcumin in zebrafish. Tests of proliferation and apoptosis showed no difference between nanocurcumin-treated and wildtype embryos. RESULTS:qPCR and in situ hybridization experiments indicated that the VEGF signaling pathway genes, vegfa, VEGF-C and flt4 were all down-regulated after nanocurcumin treatment, and vegfa over-expression rescued the vascular defective phenotype. Moreover, hif1a expression also decreased and hif1a over-expression also rescued the vascular defective phenotype but the Notch signaling pathway had no difference after nanocurcumin treatment. CONCLUSION:These results indicate that nano curcumin inhibits angiogenesis in zebrafish by downregulating hif1a/vegfa signaling pathway. Hence, our work reveals the key role of nanocurcumin in angiogenesis in vivo.
    背景与目标:
  • 【在氧诱导的视网膜病变大鼠模型中,布美他尼抑制血管生成。】 复制标题 收藏 收藏
    DOI:10.3390/ijms21030987 复制DOI
    作者列表:Guzel S,Cai CL,Ahmad T,Quan M,Valencia GB,Aranda JV,Beharry KD
    BACKGROUND & AIMS: :Aquaporins (AQPs) are involved in hypoxia-induced angiogenesis and retinal damage. Bumetanide is a diuretic agent, Na+/K+/Cl- cotransporter (NKCC1), and AQP 1-4 inhibitor. We tested the hypothesis that early postnatal treatment with bumetanide suppresses biomarkers of angiogenesis and decreases severe retinopathy oxygen-induced retinopathy (OIR). Neonatal rats were exposed at birth (P0) to either (1) room air (RA); (2) hyperoxia (50% O2); or (3) intermittent hypoxia (IH) consisting of 50% O2 with brief, clustered episodes of 12% O2 from P0 to postnatal day 14 (P14), during which they were treated intraperitoneally (IP) with bumetanide (0.1 mg/kg/day) or an equivalent volume of saline, on P0-P2. Pups were examined at P14 or allowed to recover in RA from P14-P21. Retinal angiogenesis, morphometry, pathology, AQPs, and angiogenesis biomarkers were determined at P14 and P21. Bumetanide reduced vascular abnormalities associated with severe OIR. This was associated with reductions in AQP-4 and VEGF. Bumetanide suppressed sVEGFR-1 in the serum and vitreous fluid, but levels were increased in the ocular tissues during recovery. Similar responses were noted for IGF-I. In this model, early systemic bumetanide administration reduces severe OIR, the benefits of which appear to be mediated via suppression of AQP-4 and VEGF. Further studies are needed to determine whether bumetanide at the right doses may be considered a potential pharmacologic agent to treat retinal neovascularization.
    背景与目标: : 水通道蛋白 (AQPs) 参与缺氧诱导的血管生成和视网膜损伤。布美他尼是一种利尿剂,Na/K/Cl-共转运蛋白 (NKCC1) 和AQP 1-4抑制剂。我们检验了以下假设: 布美他尼的早期产后治疗可抑制血管生成的生物标志物并减少严重的视网膜病变氧诱导的视网膜病变 (OIR)。新生大鼠在出生时 (P0) 暴露于 (1) 室内空气 (RA); (2) 高氧 (50% O2); 或 (3) 由50% O2组成的间歇性缺氧 (IH),从P0到出生后第14天 (P14) 短暂的12% O2聚集发作,在此期间,他们P0-P2用布美他尼 (0.1 mg/kg/天) 或等效体积的盐水腹膜内 (IP) 治疗。在P14检查幼崽或使其从P14-P21中恢复RA。在P14和p21测定视网膜血管生成,形态计量学,病理学,AQPs和血管生成生物标志物。布美他尼减少了与严重OIR相关的血管异常。这与AQP-4和VEGF的减少有关。布美他尼抑制了血清和玻璃体液中的sVEGFR-1,但在恢复过程中眼组织中的水平增加。Igf-i也有类似的反应。在该模型中,早期全身性布美他尼给药减少了严重的OIR,其益处似乎是通过抑制AQP-4和VEGF介导的。需要进一步的研究来确定正确剂量的布美他尼是否可以被认为是治疗视网膜新生血管的潜在药物。
  • 【血管生成素: 肿瘤血管生成中的一种平衡。】 复制标题 收藏 收藏
    DOI:10.1158/1541-7786.MCR-07-0072 复制DOI
    作者列表:Shim WS,Ho IA,Wong PE
    BACKGROUND & AIMS: :Angiopoietins (ANG-1 and ANG-2) and their TIE-2 receptor tyrosine kinase have wide-ranging effects on tumor malignancy that includes angiogenesis, inflammation, and vascular extravasation. These multifaceted pathways present a valuable opportunity in developing novel inhibition strategies for cancer treatment. However, the regulatory role of ANG-1 and ANG-2 in tumor angiogenesis remains controversial. There is a complex interplay between complementary yet conflicting roles of both the ANGs in shaping the outcome of angiogenesis. Embryonic vascular development suggests that ANG-1 is crucial in engaging interaction between endothelial and perivascular cells. However, recruitment of perivascular cells by ANG-1 has recently been implicated in its antiangiogenic effect on tumor growth. It is becoming clear that TIE-2 signaling may function in a paracrine and autocrine manner directly on tumor cells because the receptor has been increasingly found in tumor cells. In addition, alpha(5)beta(1) and alpha(v)beta(5) integrins were recently recognized as functional receptors for ANG-1 and ANG-2. Therefore, both the ligands may have wide-ranging functions in cellular activities that affect overall tumor development. Collectively, these TIE-2-dependent and TIE-2-independent activities may account for the conflicting findings of ANG-1 and ANG-2 in tumor angiogenesis. These uncertainties have impeded development of a clear strategy to target this important angiogenic pathway. A better understanding of the molecular basis of ANG-1 and ANG-2 activity in the pathophysiologic regulation of angiogenesis may set the stage for novel therapy targeting this pathway.
    背景与目标: : 血管生成素 (ANG-1和ANG-2) 及其TIE-2受体酪氨酸激酶对肿瘤恶性肿瘤具有广泛的作用,包括血管生成,炎症和血管外渗。这些多方面的途径为开发新的抑制癌症治疗策略提供了宝贵的机会。然而,ANG-1和ANG-2在肿瘤血管生成中的调节作用仍存在争议。在塑造血管生成结果中,两个ANGs的互补但相互矛盾的作用之间存在复杂的相互作用。胚胎血管发育表明,ANG-1在参与内皮细胞和血管周围细胞之间的相互作用中至关重要。然而,最近通过ANG-1募集血管周围细胞与其对肿瘤生长的抗血管生成作用有关。很明显,TIE-2信号传导可能直接在肿瘤细胞上以旁分泌和自分泌的方式起作用,因为该受体已在肿瘤细胞中越来越多地发现。此外,α (5) β (1) 和 α (v) β (5) 整联蛋白最近被认为是ANG-1和ANG-2的功能受体。因此,这两种配体在影响整体肿瘤发展的细胞活性中可能具有广泛的功能。总的来说,这些TIE-2依赖性和TIE-2依赖性活性可能解释了肿瘤血管生成中ANG-1和ANG-2的矛盾发现。这些不确定性阻碍了针对这一重要血管生成途径的明确策略的开发。更好地了解血管生成的病理生理调节中ANG-1和ANG-2活性的分子基础,可能为靶向该途径的新疗法奠定基础。
  • 【SP1/tgf-β1/SMAD2途径参与成骨过程中的血管生成。】 复制标题 收藏 收藏
    DOI:10.3892/mmr.2020.10965 复制DOI
    作者列表:Ding A,Bian YY,Zhang ZH
    BACKGROUND & AIMS: :The relationship between osteoblasts and angiogenesis is vital for bone regeneration, especially mandibular and maxillary bones. Transforming growth factor β1 (TGF‑β1) and vascular endothelial growth factor (VEGF) are closely related to angiogenesis; however, the regulatory mechanism between them remains unknown. The present study aimed to reveal this mechanism to provide novel insight for development of potential therapeutic opportunities. Western blotting and reverse transcription‑quantitative PCR was used to assess the protein and mRNA expression levels in MC3T3‑E1 preosteoblast cells and HUVECs, ELISAs were used to detect the expression levels of secreted VEGF, MTT assays were used to assess the viability of the cells, migratory ability was assessed using Transwell assays, angiogenesis assays were used to analyze the formation of blood vessels, and TGF‑β1 regulation was confirmed using a dual‑luciferase reporter assay. The overexpression of specificity protein 1 (SP1) or TGF‑β1 increased VEGF expression levels and secretion, and promoted angiogenesis of co‑cultured HUVECs. SP1 also promoted SMAD2 phosphorylation. These effects of SP1 were all reversed by the TGF‑β1 inhibitor. The VEGF inhibitor bevacizumab also reduced the SP1/TGF‑β1/SMAD2 pathway‑induced angiogenesis of preosteoblasts. In conclusion, it was demonstrated that SP1 promoted TGF‑β1 expression, activated the SMAD2 pathway and induced VEGF secretion, which may enhance angiogenic processes in preosteoblasts.
    背景与目标: : 成骨细胞与血管生成之间的关系对于骨再生至关重要,尤其是下颌骨和上颌骨。转化生长因子 β1 (tgf-β1) 和血管内皮生长因子 (VEGF) 与血管生成密切相关,但它们之间的调控机制尚不清楚。本研究旨在揭示这一机制,为潜在治疗机会的开发提供新的见解。Western blotting和逆转录-定量PCR用于评估MC3T3 ‑ E1前成骨细胞和HUVECs中的蛋白质和mRNA表达水平,ELISAs用于检测分泌的VEGF的表达水平,MTT测定用于评估细胞的活力,使用tranwell测定评估迁移能力,血管生成测定法用于分析血管的形成,并使用双荧光素酶报告测定法确认tgf-β1调节。特异性蛋白1 (SP1) 或tgf-β1的过表达增加了VEGF的表达水平和分泌,并促进了共培养的HUVECs的血管生成。SP1也促进了SMAD2磷酸化。SP1的这些作用都被tgf-β1抑制剂逆转。VEGF抑制剂贝伐单抗还减少了SP1/tgf-β1/SMAD2途径诱导的前成骨细胞血管生成。总之,已证明SP1促进tgf-β1表达,激活SMAD2途径并诱导VEGF分泌,这可能会增强成骨细胞的血管生成过程。
  • 【ETS-1的转录沉默可有效抑制胰腺癌的血管生成。】 复制标题 收藏 收藏
    DOI:10.1038/cgt.2008.65 复制DOI
    作者列表:Lefter LP,Dima S,Sunamura M,Furukawa T,Sato Y,Abe M,Chivu M,Popescu I,Horii A
    BACKGROUND & AIMS: :In this study, we addressed the hypothesis that transcriptional suppression of erythroblastosis virus E26 oncogene homolog 1 (ETS-1) is an efficient therapeutic approach to pancreatic adenocarcinoma by investigating the effect of ETS-1 suppression in human pancreatic cancer cells. We accomplished this by using an adenoviral vector encoding only the DNA-binding domain of wild-type ETS-1 (ETS-1 dominant negative, ETS-1-DN). ETS-1-DN decreases ETS-1-binding by competing for its binding to DNA. Adenoviral-mediated transfer of ETS-1-DN (adenoviral ETS-1-DN construct, AdETS-1-DN) into pancreatic tumor cell lines did not affect their proliferation rate in vitro but did significantly inhibit their in vivo growth in nude mice. Furthermore, to test the efficacy of ETS-1-DN in vivo, we injected the AdETS-1-DN into established human pancreatic adenocarcinomas grown in nude mice. This treatment significantly reduced tumor size as compared to saline injection, without any detectable side effects. Microvessel density in mouse xenografts displayed significantly lower values in tumors in which ETS-1 was downregulated. In addition, expression of the ETS-1-DN in the pancreatic cancer cells resulted in downregulation of urokinase-type plasminogen activator (u-PA) and metalloproteinase-1 (MMP-1) expression. Taken together, these data suggest that transcriptional inactivation of ETS-1 is able to significantly affect angiogenesis and growth of pancreatic cancer. This effect may be due in part to downregulation of MMP-1 and u-PA expression. Our results suggest that ETS-1-DN is a promising candidate for antiangiogenic gene therapy in pancreatic cancer.
    背景与目标: : 在这项研究中,我们通过研究ETS-1抑制在人胰腺癌细胞中的作用,解决了促红细胞生成素病毒26癌基因同源物1 (ETS-1) 的转录抑制是胰腺癌的有效治疗方法的假说。我们通过使用仅编码野生型ETS-1 (ETS-1显性阴性,ETS-1-DN) 的DNA结合域的腺病毒载体来实现这一点。ETS-1-DN通过竞争其与DNA的结合来降低ETS-1-binding。腺病毒介导的ETS-1-DN (腺病毒ETS-1-DN构建体,AdETS-1-DN) 转移到胰腺肿瘤细胞系中不会影响其体外增殖速率,但会显着抑制其在裸鼠体内的生长。此外,为了在体内测试ETS-1-DN的功效,我们将AdETS-1-DN注射到在裸鼠中生长的已建立的人胰腺腺癌中。与注射盐水相比,这种治疗方法可显着减少肿瘤大小,没有任何可检测的副作用。小鼠异种移植物中的微血管密度在ETS-1被下调的肿瘤中显示出明显较低的值。此外,胰腺癌细胞中ETS-1-DN的表达导致尿激酶型纤溶酶原激活剂 (u-PA) 和metalloproteinase-1 (MMP-1) 表达的下调。综合起来,这些数据表明ETS-1的转录失活能够显著影响胰腺癌的血管生成和生长。这种作用可能部分归因于MMP-1和u-PA表达的下调。我们的结果表明,ETS-1-DN是胰腺癌抗血管生成基因治疗的有希望的候选者。
  • 【分泌卷曲相关蛋白2,一种通过血管生成诱导心肌缺血保护的新机制。】 复制标题 收藏 收藏
    DOI:10.1007/s00395-020-0808-0 复制DOI
    作者列表:Vatner DE,Oydanich M,Zhang J,Babici D,Vatner SF
    BACKGROUND & AIMS: :Our hypothesis is that Secreted Frizzled-Related Protein 2 (sFPR2) is an important mechanism mediating ischemic cardioprotection, since it is the most upregulated gene in the third window of ischemic preconditioning. One week after permanent coronary artery occlusion (CAO), sFRP2 TG mice exhibited a 49% higher LV ejection fraction and a 36% reduction in infarct size, p < 0.05, and reduced fibrosis in both adjacent and remote zones, along with an increase in collagen type III and a decrease in the collagen type I/III ratio compared with WTL. The ischemic cardioprotection was associated with increased angiogenesis and arteriogenesis, reflected by increased capillary and arteriolar proliferation in the ischemic zone, thereby preserving blood flow after CAO. The angiogenesis and arteriogenesis were mediated by cross talk between myocytes and endothelial cells. The mechanism for cardioprotection and angiogenesis/arteriogenesis did not involve a traditional vascular growth hormone, e.g., VEGF or FGF, but rather cTGF, and ATF6 through the stress signaling pathway. The ATF6 inhibitor, AEBSF, blocked the upregulation of cTGF and both the angiogenesis and arteriogenesis, resulting in abolition of the reduced infarct size and protection of cardiac function in the sFRP2 TG mouse following permanent CAO. sFRP2 is a novel mechanism to induce angiogenesis/arteriogenesis, mediated through the endoplasmatic reticulum (ER) stress signaling pathway, ATF6 and cTGF, which protects the heart from myocardial ischemia.
    背景与目标: : 我们的假设是,分泌的卷曲相关蛋白2 (sFPR2) 是介导缺血性心脏保护的重要机制,因为它是缺血预处理第三窗口中上调最多的基因。永久性冠状动脉闭塞 (CAO) 一周后,sFRP2 TG小鼠表现出49% 较高的左室射血分数,梗死面积36% 减少,p  <  0.05,邻近和偏远地区的纤维化减少,与WTL相比,随着III型胶原的增加和I/III型胶原比例的降低。缺血心脏保护与血管生成和动脉生成增加有关,这反映在缺血区域的毛细血管和小动脉增殖增加,从而保留了CAO后的血流。血管生成和动脉生成是由心肌细胞和内皮细胞之间的串扰介导的。心脏保护和血管生成/动脉生成的机制不涉及传统的血管生长激素,例如VEGF或FGF,而是cTGF和ATF6通过应激信号通路。ATF6抑制剂AEBSF阻止了cTGF的上调以及血管生成和动脉生成,从而消除了永久性CAO后sFRP2 TG小鼠的梗死面积减少并保护了心脏功能。sFRP2是一种通过内质网 (ER) 应激信号通路ATF6和cTGF介导的诱导血管生成/动脉生成的新机制,可保护心脏免受心肌缺血的侵害。

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