血管形成和抗血管形成在医学中的应用

肿瘤的生长与肿瘤血管形成密切相关,抑制肿瘤血管生成就能抑制肿瘤的生长、浸润和转移,抗肿瘤血管形成治疗近年来备受关注,导致了一种新的肿瘤治疗方法和一类新的抗肿瘤药物的出现.在闭塞性血管疾病中血管形成治疗也开始应用于临床.     

肿瘤血管形成机理研究进展

肿瘤血管形成是非常活跃的领域,新进展层出不穷。本文仅就近几年血管形成机理方面的进展进行综述。主要进展包括：内皮细胞表面整合素表达及其调节通路上新的分子机理;调节VEGF／VEGFR通路的新分子机理;内皮细胞表面其他分子活化与血管形成;细胞代谢产物及一些细胞因子、黏附分子通过非常规途径影响内皮细胞迁移;非甾醇类抗炎药物、磺胺药、血管紧张素转化酶抑制剂等老药也在血管形成中扮演新角色;淋巴细胞、浆细胞、单核细胞等也在血管形成过程中发挥特殊作用。     

血管形成的分子学基础

新血管的形成过程非常复杂 ,成人和胚胎的血管形成是二个不同的过程[1,2 ] 。研究成人的血管形成机制将深化对肿瘤生长、转移的认识 ,对肿瘤的防治具有重要的意义 [3 ] ;胚胎期血管形成的研究则能够使我们更深入的了解血管淋巴相关性疾病的发病机理 ,无疑对于它们的治疗亦具有重大的作用 [4～ 5] 。本文主要综述胚胎血管形成中的细胞、受体和配体之间的相互作用及其与血管瘤、淋巴管瘤的关系。1　新血管的形成过程　胚胎期的血管形成包括二个过程 ,即血管发生 (vasculogenesis)和血管生成 (angio-genesis)。胚胎期从中胚层分化而来的血管母…     

血管内皮生长因子及其受体与肿瘤

血管内皮生长因子 ( VEGF)是一种高度特异和高效的血管生成因子。它与两种特异的酪氨酸激酶受体 flt- 1和 KDR相结合产生作用 ,对于人的某些正常生理功能和某些病理过程如肿瘤的生长及转移起重要作用。以 VEGF及其受体为靶点的抗肿瘤血管形成治疗 ,可以达到预防和治疗肿瘤生长及转移的目的     

促血管生成素及其受体TEK在血管形成中的调节作用

促血管生成素（angiopoietins，ANGPT）及其受体TEK是新发现在机体的生理、病理性血管形成中发挥重要调节作用的信息途径。生理情况下，ANGPT1激活TEK受体，促进血管生成、维持血管完整稳定；ANGVF2则竞争性拮抗ANGPT1的作用，当血管内皮生长因子存在时，可促进血管重建，血管内皮生长因子缺乏时，则促进血管退化。肿瘤发生时，ANGPT及TEK受体在肿瘤组织中表达明显增高，特别是ANGPT2特异表达于肿瘤新生血管区，参与肿瘤血管新生的起始及延续过程。阻断ANGPT及TEK信号传导途径可抑制肿瘤生长，有望为肿瘤的临床治疗提供一种新途径。     

抗肿瘤血管生成主动免疫治疗研究进展

肿瘤血管生成在肿瘤生长、侵袭、转移中具有十分重要的作用。调控血管生成的因子很多,包括血管内皮细胞生长因子（VEGF）、成纤维细胞生长因子（FGF）、表皮细胞生长因子（EGF）等。近年来抗血管生成的肿瘤治疗已经取得较大进展,特别是抗肿瘤血管形成主动免疫治疗,已经成为抗肿瘤研究的热点。因而,以异种同源分子和非异种同源分子为疫苗的研究很有意义。     

DLL4／Notch信号传导途径调节肿瘤血管生成的研究进展

Folkman[1]于1971年提出的"肿瘤血管生成依赖学说"使人们对肿瘤生长与新生血管形成的关系有了较为深刻的认识,抗肿瘤新生血管形成成为肿瘤综合治疗的重要策略之一。其中,研究较多、也最有价值的是通过阻断血管内皮生长因子(vascular endothelial growth factor,VEGF)及其主要受体(VEGFR2)来     

肿瘤血管形成抑制物的研究

血管形成对于原发瘤的持续生长和继发瘤的形成、生长起到关键的作用。小于１～２ｍ的肿瘤主要通过弥散获取营养,若继续生长则需依赖新生毛细血管的形成来提供充足的血液,否则肿瘤组织将发生退化［１］。早在１９７１年,Ｆｏｌｋｍａｎ就首先提出了控制肿瘤生长的新途径—抗血管     

Notch信号途径在血管形成和内皮细胞中的作用

Notch信号途径除了可以直接调控免疫细胞的发生和功能外,还可以通过血管内皮细胞影响免疫应答。血管形成(angiogenesis)是成年个体血管生长最重要的方式,不仅参与组织的发育与再生,还参与多种疾病如肿瘤的发生和进展。血管形成最主要的调控信号是血管内皮生长因子及其受体组成的信号途径。近年来的研究表明,进化上高度保守的Notch信号途径也是血管形成的重要调控信号途径。Notch信号途径可参与血管形成中的多个步骤,如顶端细胞的分化、内皮细胞的增殖、成熟血管结构的形成等。此外,Notch信号途径还参与血管形成相关疾病的发生和进展。尤为引人注目的是,近来发现Notch信号途径是肿瘤新生血管的重要调控信号,提示深入揭示Notch信号在血管形成中的作用和机制极有可能为开发新生血管靶向治疗提供靶点。     

苦参素对小鼠移植性S180肉瘤血管形成的抑制作用

目的 :苦参素注射液是氧化苦参碱水溶液制剂 ,为纯生物碱类药物 ,氧化苦参碱含量达 98%以上 ,为纯中药制剂。研究表明 :苦参及其主要成分 -氧化苦参碱均具有明显的抗肿瘤活性 ,但是否具有抗肿瘤血管生成的作用 ,目前鲜见报道。我们对氧化苦参碱进行了研究 ,以探讨苦参素注射液对肿瘤血管形成是否具有抑制作用。方法 :小鼠肉瘤S180瘤株 ,腹腔传代接种。待腹水生长旺盛时 ,抽出腹水 ,细胞计数 ,调整细胞浓度为 2× 10 10 个细胞 /L ,在小鼠腋下皮下注射S180肉瘤细胞 ,每只接种0 2mL ,以建立小鼠皮下肿瘤模型。 4 8只小鼠于接种当天随机分为…     

Mechanisms of neovascularization and resistance to anti-angiogenic therapies in glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most malignant brain tumor and highly resistant to intensive combination therapies. GBM is one of the most vascularized tumors and vascular endothelial growth factor (VEGF) produced by tumor cells is a major factor regulating angiogenesis. Successful results of preclinical studies of anti-angiogenic therapies using xenograft mouse models of human GBM cell lines encouraged clinical studies of anti-angiogenic drugs, such as bevacizumab (Avastin), an anti-VEGF antibody. However, these clinical studies have shown that most patients become resistant to anti-VEGF therapy after an initial response. Recent studies have revealed some resistance mechanisms against anti-VEGF therapies involved in several types of cancer. In this review, we address mechanisms of angiogenesis, including unique features in GBMs, and resistance to anti-VEGF therapies frequently observed in GBM. Enhanced invasiveness is one such resistance mechanism and recent works report the contribution of activated MET signaling induced by inhibition of VEGF signaling. On the other hand, tumor cell-originated neovascularization including tumor-derived endothelial cell-induced angiogenesis and vasculogenic mimicry has been suggested to be involved in the resistance to anti-VEGF therapy. Therefore, these mechanisms should be targeted in addition to anti-angiogenic therapies to achieve better results for patients with GBM.     

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。     

HE4在妇科盆腔恶性肿瘤中表达的意义研究进展

目的:探讨人附睾蛋白4(HE4)在妇科盆腔恶性肿瘤中的表达及临床意义.方法:查阅国内外相关文献,综合分析在妇科盆腔恶性肿瘤中,HE4的表达情况.结果:HE4在多种妇科盆腔恶性肿瘤中高表达,与众多肿瘤的发生发展密切相关.结论:作为新的妇科盆腔恶性肿瘤的标志物,HE4有着广阔的临床应用前景,其价值有待进一步深入研究.     

Cancer immunotherapy of targeting angiogenesis

Tumor growth and metastasis are angiogenesis-dependent. Anti-angiogenic therapy may be a useful approach to cancer therapy. This review discussed tumor angiogenesis and immunotherapy of targeting tumor angiogenesis from two main aspects: (1) active vaccination to induce effective anti-angiogenesis immunity; (2) passive immunotherapy with anti-pro-angiogenic molecules relevant antibody. Evidence from the recent years suggested that anti-angiogenic therapy should be one of the most promising approaches to cancer therapy.     

Dynamic fluorescence imaging for multiparametric measurement of tumor vasculature

Angiogenesis is essential for tumor growth and a promising target for cancer therapy. Blood vessel monitoring is an indispensable tool for evaluation and development of anti-angiogenic drugs. Here, we report a new noninvasive in vivo imaging tool, named dynamic fluorescence imaging (DyFI), for the simultaneous measurement of multiple vascular parameters including vascular density, perfusion rate, and permeability using spatiotemporal profiles of indocyanine green. Using DyFI in a tumor xenograft model, we quantitatively measured multiple vascular parameters in tumors and normal tissues with high spatial resolution. The multimodality of this method allowed us to find negative spatial correlations between perfusion and permeability. Moreover, DyFI was effective for revealing the early effects of an anti-angiogenic drug. We suggest that DyFI could be a useful tool for the preclinical development of anti-angiogenic drugs.     

Gynecologic complications of cyclic estrogen progestin therapy

We evaluated the long-term gynecologic risks of postmenopausal estrogen therapy in conjunction with cyclic, monthly progestin (progestin-estrogen replacement therapy, or PERT). Our medical record review showed that incidence of abnormal vaginal bleeding necessitating gynecologic procedures for evaluation was significantly higher (RR, 3.1; 95% CI, 2.1–4.5), as was the rate of endometrial biopsy (RR, 3.4; 95% CI, 2.3–5.1), among women receiving PERT than among women not receiving hormone therapy. We also identified a non-significant trend toward a higher rate of dilation and curettage (RR, 1.5; CI, 0.7-3.3) among women receiving PERT. However, rates of endometrial hyperplasia and hysterectomy were similarly low in both groups. PERT apparently protects women against these serious gynecologic consequences previously seen in women taking unopposed estrogen.     

Dynamics of tumor growth and combination of anti-angiogenic and cytotoxic therapies

Tumors cannot grow beyond a certain size (about 1-2 mm in diameter) through simple diffusion of oxygen and other essential nutrients into the tumor. Angiogenesis, the formation of blood vessels from pre-existing vessels, is a crucial and observed step, through which a tumor obtains its own blood supply. Thus, strategies that interfere with the development of this tumor vasculature, known as anti-angiogenic therapy, represent a novel approach to controlling tumor growth. Several pre-clinical studies have suggested that currently available angiogenesis inhibitors are unlikely to yield significant sustained improvements in tumor control on their own, but rather will need to be used in combination with conventional treatments to achieve maximal benefit. Optimal sequencing of anti-angiogenic treatment and radiotherapy or chemotherapy is essential to the success of these combined treatment strategies. Hence, a major challenge to mathematical modeling and computer simulations is to find appropriate dosages, schedules and sequencing of combination therapies to control or eliminate tumor growth. Here, we present a mathematical model that incorporates tumor cells and the vascular network, as well as their interplay. We can then include the effects of two different treatments, conventional cytotoxic therapy and anti-angiogenic therapy. The results are compared with available experimental and clinical data.     

Suppression of angiogenic activity of sera from diabetic patients with non-proliferative retinopathy by compounds of herbal origin and sulindac sulfone

Angiogenesis, the process of new blood vessel formation, is the key event in the mechanism of several pathological processes including diabetic retinopathy. The physiological control of angiogenesis depends on the balance between stimulatory and inhibitory factors. Therefore, a number of anti-angiogenic approaches has been developed, many of them based on the inhibition of the functional activity of pro-angiogenic factors. The aim of the present study was to compare the anti-angiogenic effectiveness of sulindac sulfone and some herbal compounds in the serum-induced angiogenesis test performed in Balb/c mice. Pooled sera from 35 patients with diabetes type 2 and retinopathy were used as pro-angiogenic stimuli. The strongest inhibitory effect was observed for the sulindac sulfone and ursolic acid in the highest concentration of 200 micro g/ml, as well as for the low-dosage concomitant treatment with 2 micro g/ml of epigallocatechin gallate (EGCG, green tea flavanol), ursolic acid (plant-derived triterpenoid), sulindac sulfone and convalamaroside (steroidal saponin). Combination treatment was significantly more effective than monotherapy with medium (20 micro g/ml) or lowest doses of tested compounds. The present study is the first to demonstrate the potent anti-angiogenic effect of the combination therapy comprising of plant-derived extracts and sulindac sulfone, as tested in the in vivo angiogenesis experimental model with sera of non-proliferative diabetic retinopathy patients used as the pro-angiogenic stimuli. We think that it might be the first step toward application of some of these compounds, in the future, in preventive anti-angiogenic therapy of these patients, as well, as in the treatment of later, proliferative stage of this disease.