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The influence of Cox-2 and bioactive lipids on hematological cancers. Cox-2和生物活性脂质对血液学癌症的影响。
Pub Date : 2013-09-01 DOI: 10.2174/2211552802999140131105947
Sesquile Ramon, Collynn F Woeller, Richard P Phipps

Inflammation is implicated in the progression of multiple types of cancers including lung, colorectal, breast and hematological malignancies. Cyclooxygenases (Cox) -1 and -2 are important enzymes involved in the regulation of inflammation. Elevated Cox-2 expression is associated with a poor cancer prognosis. Hematological malignancies, which are among the top 10 most predominant cancers in the USA, express high levels of Cox-2. Current therapeutic approaches against hematological malignances are insufficient as many patients develop resistance or relapse. Therefore, targeting Cox-2 holds promise as a therapeutic approach to treat hematological malignancies. NSAIDs and Cox-2 selective inhibitors are anti-inflammatory drugs that decrease prostaglandin and thromboxane production while promoting the synthesis of specialized proresolving mediators. Here, we review the evidence regarding the applicability of NSAIDs, such as aspirin, as well as Cox-2 specific inhibitors, to treat hematological malignancies. Furthermore, we discuss how FDA-approved Cox inhibitors can be used as anti-cancer drugs alone or in combination with existing chemotherapeutic treatments.

炎症与多种类型癌症的进展有关,包括肺癌、结直肠癌、乳腺癌和血液系统恶性肿瘤。环氧合酶(Cox) -1和-2是参与炎症调节的重要酶。Cox-2表达升高与癌症预后不良相关。血液恶性肿瘤是美国十大最主要的癌症之一,它表达高水平的Cox-2。目前针对血液系统恶性肿瘤的治疗方法是不够的,因为许多患者出现耐药性或复发。因此,靶向Cox-2有望成为治疗血液系统恶性肿瘤的一种治疗方法。非甾体抗炎药和Cox-2选择性抑制剂是一种消炎药,可减少前列腺素和凝血素的产生,同时促进专门促生介质的合成。在这里,我们回顾了关于非甾体抗炎药(如阿司匹林)和Cox-2特异性抑制剂治疗血液恶性肿瘤的适用性的证据。此外,我们还讨论了fda批准的Cox抑制剂如何单独用作抗癌药物或与现有化疗药物联合使用。
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引用次数: 16
Exosomes Function in Pro- and Anti-Angiogenesis. 外泌体在促和抗血管生成中的作用。
Pub Date : 2013-01-01 DOI: 10.2174/22115528113020020001
Mara Fernandes Ribeiro, Hongyan Zhu, Ronald W Millard, Guo-Chang Fan

Exosomes, a group of small vesicles (30-100 nm), originate when the inward budding of the endosomal membrane forms multivesicular bodies (MVBs). Exosomes are released into the extracellular space when the MVBs fuse with the plasma membrane. Numerous studies have indicated that exosomes play critical roles in mediating cell-to-cell communication. Also, exosomes are believed to possess a powerful capacity in regulating cell survival/death, inflammation and tumor metastasis, depending on the particular array of molecules contained within a particular population of exosomes. This mini-review will summarize dual roles of exosomes derived from different types of cells (i.e. endothelial cells, tumor cells, platelets, bone-marrow stem cells, cardiomyocytes, myocardial progenitor cells and among others) in endothelial cell proliferation, migration and tube-like formation. In particular, this review will focus on the therapeutic potential of exosomes as a natural nano-particle for delivering pro-/anti-angiogenic factors (proteins, mRNAs and microRNAs) into endothelial cells.

外泌体是一组小泡(30-100 nm),当内体膜向内出芽形成多泡体(MVBs)时产生。当MVBs与质膜融合时,外泌体被释放到细胞外空间。大量研究表明外泌体在介导细胞间通讯中起着关键作用。此外,外泌体被认为在调节细胞存活/死亡、炎症和肿瘤转移方面具有强大的能力,这取决于特定外泌体群体中包含的特定分子阵列。本文将总结来自不同类型细胞(即内皮细胞、肿瘤细胞、血小板、骨髓干细胞、心肌细胞、心肌祖细胞等)的外泌体在内皮细胞增殖、迁移和管状细胞形成中的双重作用。特别地,本文将重点介绍外泌体作为一种天然纳米颗粒,将促/抗血管生成因子(蛋白质、mrna和microrna)输送到内皮细胞中的治疗潜力。
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引用次数: 135
Intracellular and Extracellular miRNAs in Regulation of Angiogenesis Signaling. 调节血管生成信号的细胞内和细胞外 miRNA。
Pub Date : 2012-12-01 DOI: 10.2174/2211552811201040299
Nnenna A Finn, Charles D Searles

Angiogenesis, the process by which new blood vessels are formed, is a critical phenomenon that is activated during various stages of mammalian development. MicroRNAs (miRNAs), a class of short, single stranded, non-coding RNAs, are recognized as important regulators of angiogenesis, and the role of intracellular miRNAs in modulating angiogenesis signaling has been identified. The recent discovery of extracellular and circulating miRNAs has sparked new questions regarding their potential in modulating angiogenesis signaling not only within cells but also between cells. In this review, we discuss the characteristics of intracellular and extracellular miRNAs and decipher the potential functional roles for these molecules in regard to the angiogenic process. We summarize what is currently known about circulating miRNAs in distinct clinical populations and discuss evidence that implicates extracellular miRNAs as novel mediators of angiogenesis-associated intercellular signaling. Lastly, we offer a new perspective on the functional role of vesicle-encapsulated circulating miRNA in modulating angiogenesis signaling pathways.

血管生成是新血管形成的过程,是哺乳动物发育不同阶段激活的关键现象。微小RNA(miRNA)是一类短的单链非编码RNA,被认为是血管生成的重要调节因子,细胞内miRNA在调节血管生成信号中的作用已被确认。最近发现的细胞外和循环 miRNA 引发了新的问题,即它们不仅在细胞内,而且在细胞间调节血管生成信号的潜力。在这篇综述中,我们将讨论细胞内和细胞外 miRNA 的特点,并解读这些分子在血管生成过程中的潜在功能作用。我们总结了目前已知的不同临床人群中的循环 miRNA,并讨论了细胞外 miRNA 作为血管生成相关细胞间信号转导的新型介质的证据。最后,我们从一个新的角度探讨了囊泡包裹的循环 miRNA 在调节血管生成信号通路中的功能作用。
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引用次数: 0
Combining Bevacizumab with Radiation or Chemoradiation for Solid Tumors: A Review of the Scientific Rationale, and Clinical Trials. 贝伐单抗联合放疗或放化疗治疗实体肿瘤:科学依据和临床试验综述
Pub Date : 2012-09-01 DOI: 10.2174/2211552811201030169
Benjamin Schmidt, Hae-June Lee, Sandra Ryeom, Sam S Yoon

Radiation therapy or the combination of radiation and chemotherapy is an important component in the local control of many tumor types including glioblastoma, rectal cancer, and pancreatic cancer. The addition of anti-angiogenic agents to chemotherapy is now standard treatment for a variety of metastatic cancers including colorectal cancer and non-squamous cell lung cancer. Anti-angiogenic agents can increase the efficacy of radiation or chemoradiation for primary tumors through mechanisms such as vascular normalization and augmentation of endothelial cell injury. The most commonly used anti-angiogenic drug, bevacizumab, is a humanized monoclonal antibody that binds and neutralizes vascular endothelial growth factor A (VEGF-A). Dozens of preclinical studies nearly uniformly demonstrate that inhibition of VEGF-A or its receptors potentiates the effects of radiation therapy against solid tumors, and this potentiation is generally independent of the type or schedule of radiation and timing of VEGF-A inhibitor delivery. There are now several clinical trials combining bevacizumab with radiation or chemoradiation for the local control of various primary, recurrent, and metastatic tumors, and many of these early trials show encouraging results. Some added toxicities occur with the delivery of bevacizumab but common toxicities such as hypertension and proteinuria are generally easily managed while severe toxicities are rare. In the future, bevacizumab and other anti-angiogenic agents may become common additions to radiation and chemoradiation regimens for tumors that are difficult to locally control.

放射治疗或放化疗联合治疗是局部控制许多肿瘤类型的重要组成部分,包括胶质母细胞瘤、直肠癌和胰腺癌。在化疗中加入抗血管生成药物现在是包括结直肠癌和非鳞状细胞肺癌在内的各种转移性癌症的标准治疗方法。抗血管生成药物可以通过血管正常化和内皮细胞损伤的增强等机制增加放射或放化疗对原发性肿瘤的疗效。最常用的抗血管生成药物贝伐单抗是一种人源化单克隆抗体,可结合并中和血管内皮生长因子a (VEGF-A)。数十项临床前研究几乎一致表明,VEGF-A或其受体的抑制可以增强放射治疗对实体肿瘤的作用,并且这种增强作用通常与辐射的类型或时间表以及VEGF-A抑制剂递送的时间无关。目前有几项临床试验将贝伐单抗与放疗或放化疗相结合,用于局部控制各种原发性、复发性和转移性肿瘤,其中许多早期试验显示出令人鼓舞的结果。贝伐单抗给药过程中会出现一些额外的毒性,但常见的毒性如高血压和蛋白尿通常很容易控制,而严重的毒性很少见。在未来,贝伐单抗和其他抗血管生成药物可能成为难以局部控制肿瘤的放射和放化疗方案的常见补充。
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引用次数: 20
Vascular Mimicry: Concepts and Implications for Anti-Angiogenic Therapy. 血管模拟:抗血管生成治疗的概念和意义。
Pub Date : 2012-06-01 DOI: 10.2174/2211552811201020133
James M Dunleavey, Andrew C Dudley

As in normal tissues, solid tumors depend on vascular networks to supply blood, oxygen, and nutrients. Tumor blood vessels are formed by common processes of neovascularization for example endothelial sprouting. However, some tumors have alternative and unexpected mechanisms of neovascularization at their disposal. In a process termed "vascular mimicry," tumors create their own, tumor cell-lined channels for fluid transport independent of typical modes of angiogenesis. These tumor cell-lined conduits may express endothelial-selective markers and anti-coagulant factors which allow for anastamosis with host endothelium. In this review, we explore the current status of vascular mimicry research, highlighting recent evidence which strengthens the hypothesis for this unusual ability of tumor cells. Furthermore, we address the theoretical possibility that vascular mimicry provides a mechanism whereby tumors could escape anti-angiogenic therapies.

和正常组织一样,实体瘤依靠血管网络提供血液、氧气和营养。肿瘤血管是通过常见的新生血管过程形成的,例如内皮发芽。然而,一些肿瘤具有可选择的和意想不到的新血管形成机制。在一个被称为“血管模仿”的过程中,肿瘤创造了它们自己的、与肿瘤细胞相连的通道,用于流体运输,独立于典型的血管生成模式。这些肿瘤细胞系导管可能表达内皮选择性标记物和抗凝血因子,从而允许与宿主内皮细胞吻合。在这篇综述中,我们探讨了血管拟态研究的现状,重点介绍了最近的证据,这些证据加强了肿瘤细胞这种不寻常能力的假设。此外,我们提出了理论上的可能性,即血管模拟提供了一种机制,使肿瘤可以逃避抗血管生成治疗。
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引用次数: 48
HGF Airway Over-expression Leads to Enhanced Pulmonary Vascularization without Induction of VEGF. HGF气道过表达导致肺血管化增强而不诱导VEGF。
Pub Date : 2012-02-01 Epub Date: 2012-03-28 DOI: 10.2174/2211552811201010052
Cassandra Henry, Ariel Lopez-Chavez, Laura P Stabile, Jill M Siegfried

The hepatocyte growth factor (HGF)/c-Met signaling pathway mediates angiogenesis. We have previously reported that airway expression of a human HGF transgene (HGF TG) produced mice that were more susceptible to lung tumorigenesis induced by 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK). Here we show untreated HGF TG mice display enhanced vascularization (40 wks) and enhanced lymph vessel formation (20 wks) in the lungs compared to wild-type (WT) littermates, as ascertained by microvessel density. We profiled mRNA expression from HGF TG and WT mice for genes involved in angiogenesis. We consistently found significant decreases in expression of the VEGF family of angiogenic genes, including Vegfa, Vegfb, Vegfc, and Vegfd / Figf. Decreases were confirmed in whole lung protein extracts by immunoblot. Similar patterns of down-regulation were observed at 10, 20, and 40 wks of age. Vandetanib, an inhibitor of VEGFR2 and VEGFR3, did not prevent the increase in microvessel density observed in HGF TG mice. Reduction in VEGF pathway genes was also detected in lung tumors derived from NNK-treated HGF TG mice. HGF TG lung tumors also showed increased expression of five Cxcl family genes including Cxcl1 and Cxcl2 (murine forms of IL8). These results suggest increased vascularization produced by airway over-expression of HGF occurs through direct activation of c-Met on endothelial cells, rather than induction of VEGF pathways. Elevated HGF may also increase expression of inflammatory mediators that contribute to lung tumor progression.

肝细胞生长因子(HGF)/c-Met信号通路介导血管生成。我们之前报道过,气道表达人HGF转基因(HGF TG)使小鼠更容易受到4-(甲基亚硝基氨基)-1-(3-吡基)-1-丁酮(NNK)诱导的肺肿瘤发生。本研究显示,与野生型(WT)幼崽相比,未经治疗的HGF TG小鼠肺部血管化(40周)和淋巴管形成(20周)增强,这是通过微血管密度确定的。我们分析了HGF、TG和WT小鼠血管生成相关基因的mRNA表达。我们一致发现血管生成基因VEGF家族的表达显著降低,包括Vegfa、Vegfb、Vegfc和Vegfd / Figf。免疫印迹法证实全肺蛋白提取物减少。在10、20和40周龄时观察到类似的下调模式。Vandetanib, VEGFR2和VEGFR3的抑制剂,不能阻止HGF TG小鼠微血管密度的增加。在nnk处理的HGF TG小鼠的肺肿瘤中也检测到VEGF通路基因的减少。HGF - TG肺肿瘤也显示5个Cxcl家族基因的表达增加,包括Cxcl1和Cxcl2(小鼠形式的IL8)。这些结果表明,气道过度表达HGF产生的血管化增加是通过直接激活内皮细胞上的c-Met,而不是诱导VEGF通路发生的。升高的HGF也可能增加促进肺肿瘤进展的炎症介质的表达。
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引用次数: 1
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Current angiogenesis
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