DLL4与血管生成的关系

血管生成是胚胎发育和肿瘤生长的重要因素.多项研究发现,参与Notch信号的Delta配体4(Delta-like ligand 4,DLL4)能抑制新生血管分支生成,促进新生血管的成熟.阻断DLL4可增加无功能性新生血管的数量,从而抑制肿瘤生长,这为肿瘤抗血管生成疗法提供了新的策略,使DLL4有可能成为肿瘤治疗的新靶点.     

肿瘤血管生成和抗血管生成治疗的研究进展

肿瘤组织中的新生血管是保证肿瘤持续生长所必需的,也是肿瘤转移的重要途径之一.针对促进肿瘤血管生成和血管生成抑制物制定新策略,采用合适手段与方法,抑制肿瘤内血管新生,消除或减少肿瘤内原有血管,可达到治愈肿瘤的目的.     

肿瘤治疗的新途径-抗肿瘤血管生成的生化和基因治疗

新生血管对于肿瘤的生长、浸润和转移有重要意义.体积超过1mm3～2mm3的肿瘤不仅需要新生血管维持营养供给和排泄代谢产物,还需要提供有利于转移的通道.新生血管形成包括内皮细胞的激活、增殖、迁移、血管基底膜的破坏、血管和血管网的形成,以及先前存在的血管网的连接等过程.抑制新生血管的生成可使肿瘤细胞进入休眠状态并诱导其凋亡.目前用抗血管生成来达到对肿瘤的治疗目的已不再是理论上的可能,而是一个渐趋成熟、实用的治疗方法.我们仅就此作一简要介绍.     

血管生成拟态的研究进展

1971年Folkman[1]提出了肿瘤生长依赖血管新生的假说,由此拉开了近代关于肿瘤血管生成研究的序幕。在深入的研究中发现,肿瘤直径达到1～2 mm后,若无新生血管生成来提供营养,则不能继续增长。因此,抑制肿瘤血管生成可望成为治疗肿瘤的新途径。     

胶质瘤血管新生及其调控机制

体内外研究表明实体性肿瘤的生长是依赖血管的,其直径一旦超过2 mm,若没有新生的血管供血则肿瘤的生长就会停止。胶质瘤是人体内血管化程度最高恶性的肿瘤之一。胶质瘤的血管发生与其他实体性肿瘤血管发生一样,由血管形成及血管新生两种方式构成：前者由内皮祖细胞或者血管母细胞形成新的血管;而后者是由组织中既存的成熟血管的内皮细胞发生增殖和游走形成小血管。血管新生是肿瘤血管生成的主要形式,胶质瘤血管新生的机制研究以及抑制其血管生成是胶质瘤治疗的一个新途径,成为近年来的研究热点,本文就胶质瘤血管新生及其调控机制作一综述。     

抗肿瘤血管生成研究的现状与有待解决的问题

 血管生成是指在原有组织血管结构基础上形成新血管结构的过程。1971年Folkman[1]提出了肿瘤血管依赖性生长的概念，并把肿瘤生长分为非血管期和血管期两个生长阶段。固体肿瘤在血管生成前，肿瘤体积一般不超过3 mm3。随着肿瘤细胞的不断增殖，肿瘤组织出现缺氧、代谢产物堆积、pH值改变等，这些因素刺激肿瘤细胞、周围间质细胞和淋巴细胞分泌各种促血管生长刺激因子，通过诱导血管基底膜降解和内皮细胞增殖，启动新生血管的生成。 肿瘤一旦血管化, 不仅生长速度加快，而且容易发生转移，说明血管生成对肿瘤的生长和转移都起到关键作用。因此,在过去30多年中，人们致力于对肿瘤血管生成机制的研究，并试图通过抑制和破坏肿瘤血管生成来建立一种治疗肿瘤的新方法。......     

血管生成抑制因子与淋巴管生成抑制因子

应用血管或淋巴管生成抑制因子破坏或抑制肿瘤的血管和淋巴管的生成,从而有效地阻止肿瘤 的生长和转移,进而达到治疗肿瘤的目的,是近些年发展起来的肿瘤的抗血管和抗淋巴管生成疗法。该法使 肿瘤的血管和淋巴管系统成为一个崭新的、有希望的抗肿瘤的靶点。人们正致力于开发和研究安全、有效、经 济、实用的血管和淋巴管生成抑制药物,该类药物被称为肿瘤血管或淋巴管生成抑制剂。     

正常血管和肿瘤血管生成的调节机制研究进展

近 30年来在肿瘤领域研究的重大进展之一是确立了肿瘤血管生成 (ａｎｇｉｏｇｅｎｅｓｉｓ)在肿瘤发展中的重要地位与抗血管生成治疗肿瘤 (ａｎｔｉａｎｇｉｏｇｅｎｅｔｉｃｔｈｅｒａｐｙ)的意义[1 3 ] 。肿瘤的生长可分为无血管期 (ａｖａｓｃｕｌａｒｓｔａｇｅ)和血管期 (ｖａｓｃｕｌａｒｓｔａｇｅ) ,在无血管期由于肿瘤主要依靠周围组织的弥散来获取营养物质和排泄代谢产物 ,所以明显限制了其持续性的生长 ,肿瘤直径不超过 1～ 2ｍｍ ;而至血管期 ,肿瘤内出现新生毛细血管并获得进一步生长的能力 ,肿瘤从而迅速生长并可发生转移。…     

肿瘤血管生成抑制剂的研究进展

70年代初，Folkman提出肿瘤生长依赖于血管形成的概念。随之国内外大量研究证明肿瘤血管生成与肿瘤生长、侵袭和转移等特性密切相关，从而产生了肿瘤血管生成抑制疗法。因此，以肿瘤血管生成为靶点，开发肿瘤血管生成抑制剂（tumor angiogenesis inhibitor）在抗肿瘤治疗中已成为一个研究热点。目前大部分肿瘤血管抑制剂仍处于Ⅰ、期临床实验阶段，部分进入Ⅲ期临床实验，并取得较理想的疗效。本文对几类常用的肿瘤血管生成抑制剂作一介绍。     

VEGF/VEGFR信号转导通路在肝癌靶向治疗中的研究进展

肝细胞肝癌(Hepatocellular Carcinoma,HCC,简称肝癌)是典型的多血供恶性肿瘤,肝癌细胞的生长、转移、侵袭都依赖新生血管的形成.血管内皮细胞生长因子(Vascular endothelial growth factor,VEGF)及其受体(Vascular endothelial growth factor receptor,VEGFR)的信号转导通路的活化可刺激血管内皮细胞增殖、迁移、在肝癌血管生成并促进肿瘤生长和转移中发挥了重要作用. Folkman首先提出"肿瘤生长是血管依赖性的",并认为肿瘤血管新生是由肿瘤血管生长因子(Tumor angiogenesis factor,TAF)所引起的,从而提出了"抑制血管生成而抑制肿瘤生长的假说".     

氧环境对血管内皮生长因子、色素上皮衍生因子的影响及其与血管发育的关系

目的：研究视网膜发育过程中血管内皮生长因子(VEGF)和色素上皮衍生因子(PEDF)所起的调节作用及其机制。方法：C57BL/6J 小鼠从出生后7～12 d 饲养于75%氧环境,分别用抗 VEGF、抗 PEDF 和抗 CD31抗体作免疫组织化学标记视网膜切片。结果：持续处于高氧环境时,VEGF 表达处于低水平而 PEDF 快速上升,血管生长减缓。高氧处理5 d 后回到普通环境,VEGF 的表达迅速上升而 PEDF 却逐渐减少,出现了一过性的血管快速增长现象。结论：氧含量变化可调节 VEGF 和 PEDF 表达,参与视网膜血管发育。     

Up-regulation of vascular endothelial growth factor and down-regulation of pigment epithelium-derived factor messenger ribonucleic acid levels in leptin-exposed cultured retinal pericytes

Leptin, a circulating hormone secreted mainly from adipose tissues, is involved in the control of body weight. Recently, leptin was found to be an angiogenic factor and its vitreous levels were shown to be elevated in patients with angiogenic eye diseases such as proliferative diabetic retinopathy. However, the role of leptin in diabetic retinopathy is not fully understood. Since pericyte loss and dysfunction have been considered to be one of the characteristic changes of the early phases of diabetic retinopathy, we investigated the effects of leptin on the growth and function of bovine cultured retinal pericytes. Although it did not affect cell growth, leptin significantly up-regulated pericyte messenger ribonucleic acid levels of an endogenous angiogenic stimulator, vascular endothelial growth factor (VEGF). Leptin was also found to significantly inhibit gene expression of pigment epithelium-derived factor (PEDF), the most potent angiogenesis inhibitor in the mammalian eye, in pericytes. The present study suggests that leptin might elicit angiogenesis through VEGF induction as well as PEDF suppression in pericytes and could thus be involved in the development and progression of diabetic retinopathy, especially in obese insulin-resistant patients.     

菩人丹超微粉对糖尿病大鼠视网膜血管内皮生长因子和色素上皮衍生因子表达的影响

目的 探讨菩人丹超微粉(PRD)对糖尿病大鼠视网膜血管内皮生长因子(VEGF)及色素上皮衍生因子(PEDF)表达的影响.方法 48只Wistar大鼠随机分为4组:正常对照组、糖尿病模型组、PRD组和导升明组,每组12只.糖尿病模型组、PRD组和导升明组大鼠均采用链脲佐菌素连续腹腔注射建立2型糖尿病大鼠模型.模型成功建立...     

Administration of Pigment Epithelium-Derived Factor Inhibits Airway Inflammation and Remodeling in Chronic OVA-Induced Mice via VEGF Suppression

Purpose

Pigment epithelium-derived factor (PEDF) is a recently discovered antiangiogenesis protein. PEDF possesses powerful anti-inflammatory, antioxidative, antiangiogenic, and antifibrosis properties. It has been reported that PEDF can regulate vascular endothelial growth factor (VEGF) expression. This study aimed to evaluate whether recombinant PEDF protein could attenuate allergic airway inflammation and airway remodeling via the negative regulation of VEGF using a murine model of chronic ovalbumin (OVA)-induced asthma and BEAS-2B human bronchial epithelial cells.

Methods

In an in vivo experiment, mice sensitized with OVA were chronically airway challenged with aerosolized 1% OVA solution for 8 weeks. Treated mice were given injections of recombinant PEDF protein (50 or 100 µg/kg body weight) via the tail vein. In an in vitro experiment, we investigated the effects of recombinant PEDF protein on VEGF release levels in BEAS-2B cells stimulated with IL-1β.

Results

Recombinant PEDF protein significantly inhibited eosinophilic airway inflammation, airway hyperresponsiveness, and airway remodeling, including goblet cell hyperplasia, subepithelial collagen deposition, and airway smooth muscle hypertrophy. In addition, recombinant PEDF protein suppressed the enhanced expression of VEGF protein in lung tissue and bronchoalveolar lavage fluid (BALF) in OVA-challenged chronically allergic mice. In the in vitro experiment, VEGF expression was increased after IL-1β stimulation. Pretreatment with 50 and 100 ng/mL of recombinant PEDF protein significantly attenuated the increase in VEGF release levels in a concentration-dependent manner in BEAS-2B cells stimulated by IL-1β.

Conclusions

These results suggest that recombinant PEDF protein may abolish the development of characteristic features of chronic allergic asthma via VEGF suppression, providing a potential treatment option for chronic airway inflammation diseases such as asthma.     

Angiogenic growth factor expression in benign and malignant vascular tumours

Angiosarcomas are rare malignant vascular tumours. Angiosarcoma expression of vascular endothelial growth factor (VEGF) has previously been reported, but angiosarcoma expression of other angiogenic growth factors has not been systematically studied. Non-VEGF angiogenic growth factors are a potential mechanism of resistance to VEGF-targeted therapy, but they also represent potential therapeutic targets.     

Overexpression of pigment epithelium-derived factor decreases angiogenesis and inhibits the growth of human malignant melanoma cells in vivo

Pigment epithelium-derived factor (PEDF) has recently been shown to be the most potent inhibitor of angiogenesis in the mammalian eye, and is involved in the pathogenesis of angiogenic eye disease such as proliferative diabetic retinopathy. However, a functional role for PEDF in tumor growth and angiogenesis remains to be determined. In this study, we have investigated both the in vitro and in vivo growth characteristics of human malignant melanoma G361 cell lines, stably transfected to overexpress human PEDF. Expression levels of PEDF proteins in melanoma cell lines G361 and A375 were comparable with that of human cultured melanocytes, whereas vascular endothelial growth factor levels in two tumor cell lines were much stronger than that in normal melanocytes. Overexpression of PEDF was found to significantly inhibit tumor growth and vessel formation in G361 nude mice xenografts. Furthermore, in vitro proliferation rates of G361 cells were decreased in PEDF-transfected cells. PEDF proteins showed dose-dependent induced growth retardation and apoptotic cell death in nontransfected G361 cells, which were completely prevented by treatment with antibodies against the Fas ligand. Our present study highlights two beneficial effects of PEDF treatment on melanoma growth and expansion; one is the suppression of tumor angiogenesis, and the other is induction of Fas ligand-dependent apoptosis in tumor cells. PEDF therefore might be a promising novel therapeutic agent for treatment of patients with melanoma.     

色素上皮衍生因子和血管内皮生长因子在糖尿病大鼠肾脏的不平衡表达

目的检测色素上皮衍生因子（PEDF）和血管内皮生长因子（VEGF）在糖尿病大鼠肾脏的表达，探讨其在糖尿病肾病（DN）发生发展中的作用。方法40只雄性Wistar大鼠随机分为：正常对照组（NC）、糖尿病模型组（DM）。4、8周末，检测血糖、糖化血红蛋白、肾重指数、尿白蛋白排泄率，免疫组织化学法检测肾脏PEDF、VEGF的表达。结果4、8周末，DM组大鼠肾脏PEDF的表达较NC组明显减少（P〈0．01）；VEGF的表达较NC组明显增多（P〈0．01）；肾脏PEDF的表达与VEGF明显负相关（r=-0．823，P〈0．01）。结论PEDF和VEGF在肾脏的不平衡表达可能参与了DN的发病。     

Effect of tamoxifen on serum IL-18, vascular endothelial growth factor and nitric oxide activities in breast carcinoma patients

Vascular endothelial growth factor (VEGF) is a multi-functional cytokine that has been suggested to be a major angiogenic factor in breast cancer. Nitric oxide (NO) is a potent biological molecule that participates in the multi-step process of carcinogenesis. Interleukin (IL)-18 has been shown to have potent anti-tumour effects. In this study, we investigated the effect of tamoxifen therapy on serum VEGF, NO and IL-18 activity in breast cancer patients. Serum levels of VEGF, nitrate + nitrite and IL-18 were measured in 34 postmenopausal breast cancer patients before and 3 months after the tamoxifen therapy. Both serum VEGF and IL-18 levels decreased after tamoxifen therapy (P = 0.051, P < 0.05, respectively). Serum VEGF levels increased in patients with endometrial thickness, while patients without endometrial thickness had a significant reduction in serum VEGF levels after therapy (P < 0.05). Serum nitrate + nitrite levels increased after the therapy, but this was not statistically significant (P > 0.05). A decrease in serum VEGF levels with tamoxifen therapy may be a reflection of reduced angiogenic activity in patients without endometrial thickness. The negative effect of tamoxifen therapy on IL-18, which is known to have a potent antitumour activity, may be related to the decreased tumour growth by induction of NO and reduction of VEGF activity as a feedback mechanism.     

Therapeutic potential of bone marrow-derived mesenchymal stem cells producing pigment epithelium-derived factor in lung carcinoma

Specific and efficient gene delivery to target cells and the subsequent expression of the RNA and protein is crucial to the success of gene-based therapy for cancer. Mesenchymal stem cells (MSCs) represent novel and efficient tools for delivery of therapeutic agents to tumor cells. In this study, we evaluated the potential of bone marrow-derived mesenchymal stem cells, genetically modified to express pigment epithelium-derived factor (PEDF) for the treatment of Lewis lung carcinoma (LLC). MSCs derived from murine bone marrow were efficiently engineered to express human PEDF by adenoviral transduction, and the expression and bioactivity of the transgenic protein from engineered MSCs were confirmed in vitro. Animal experiments showed that the systemic administration of MSCs treated with PEDF dramatically reduced the growth of LLC tumors and significantly prolonged survival. Immunohistochemistry analysis of the tumors from MSC-PEDF-treated animals indicated an increase in apoptosis and a decrease in microvessel density. ELISA showed that the group of MSCs treated with PEDF had relatively higher expression levels of PEDF in tumor tissue and lower levels in serum compared with the free Ad-PEDF group. These results suggest that MSCs have potential use as effective delivery of vehicles for therapeutic genes in the treatment of LLC.