血管内皮生长因子和Dll4-Notch信号通路在肿瘤血管发生中的作用

抗肿瘤血管发生是一种全新的抗肿瘤治疗策略,目前研究最多的是寻找有效抗血管内皮生长因子(VEGF)信号通路的药物.然而VEGF抑制剂并不是对所有肿瘤有效,因此,有必要进一步探索血管发生的其他信号通路.目前,Dll4-Notch信号通路被认为是抗肿瘤血管发生的新靶点,而且VEGF和Dll4-Notch信号通路在多方面相互作...     

血管内皮生长因子和Notch信号通路与肿瘤血管生成

血管内皮生长因子(VEGF)和Notch信号通路是血管发育及肿瘤血管生成的重要机制.阻断VEGF可抑制肿瘤生长和血管生成.Notch能抑制内皮形成尖端细胞,减少血管生成.实验证明,两条通路相互作用,联合阻断VEGF和Notch信号通路可协同抑制肿瘤生长.对VEGF和Notch通路的研究,将为肿瘤临床治疗提供新的方法.     

DLL4在抗肿瘤新生血管治疗中作用的研究进展

抗新生血管治疗是实体肿瘤治疗中的有效策略，近年来抗VEGFA和VEGFR2受体治疗出现了耐药现象。Notch信号转导是一种细胞间信号通路，在肿瘤新生血管生成中起重要作用。在Notch通路中，Delta样配体4（Deltalike ligand 4，DLL4）在影响肿瘤新生血管生成方面起着重要的作用，它能抑制新生血管分支形成，促进新生血管的成熟;阻断DLL4能增加无功能新生血管数量，加剧恶性肿瘤缺血缺氧，抑制肿瘤的生长。对DLL4蛋白的深入研究为肿瘤新生血管分子靶向治疗 提供新的策略和新的靶标，DLL4有可能成为继VEGF后肿瘤血管分子靶向治疗的重要靶点。     

DLLA在抗肿瘤新生血管治疗中作用的研究进展

抗新生血管治疗是实体肿瘤治疗中的有效策略，近年来抗VEGF—A和VEGF—R2受体治疗出现了耐药现象。Notch信号转导是一种细胞问信号通路，在肿瘤新生血管生成中起重要作用。在Notch通路中，Delta样配体4（Delta-likeligand4，DLL4）在影响肿瘤新生血管生成方面起着重要的作用，它能抑制新生血管分支形成，促进新生血管的成熟；阻断DLIA能增加无功能新生血管数量，加剧恶性肿瘤缺血缺氧，抑制肿瘤的生长。对DLIA蛋白的深入研究为肿瘤新生血管分子靶向治疗提供新的策略和新的靶标，DLIA有可能成为继VEGF后肿瘤血管分子靶向治疗的重要靶点。     

靶向VEGF治疗恶性肿瘤的研究进展

血管生成是肿瘤生长、侵袭、转移的基础。目前,研究表明VEGF及其家族成员在肿瘤的血管生成中发挥着重要作用。抑制VEGF的表达、活性和其下游信号传递可取得明显的抗肿瘤效应,表明VEGF是一个有效的肿瘤治疗靶点。     

VEGF与骨肿瘤抗血管生成治疗进展

VEGF和VEGFR因其在肿瘤血管生成中的重要作用而成为抗肿瘤血管生成疗法的重要靶点.目前应用单克隆抗体、小分子抑制物、可溶性受体等方法通过阻断其信号转导通路或耗竭肿瘤细胞产生的VEGF,使VEGF或VEGFR表达减少,从而抑制肿瘤血管生成,切断肿瘤血供,最终达到抑制肿瘤生长及转移的作用.全文综述了VEGF及VEGFR研究历程、分子结构及其最近几年在抗血管生成治疗方面的最新进展和应用前景.     

Jagged1/Notch通路与肿瘤血管生成的研究进展

肿瘤的增殖、浸润和转移与肿瘤血管生成(tumor angiogenesis)密切相关,因此抗肿瘤血管生成己经成为肿瘤综合治疗的重要策略。Notch通路在内皮细胞的发育分化、干细胞分化、血管形成及肿瘤发生发展过程中具有重要作用。最近的一系列研究发现,Jagged1作为表达于肿瘤细胞表面的配体之一,可影响Notch信号通路,增强癌细胞VEGF活性,刺激肿瘤新生血管形成从而促进肿瘤生长、侵袭及转移。这一发现为完善肿瘤新生血管与肿瘤生长关系学说提供了新的研究方向。     

肿瘤中血管生成信号通路相关药物临床转化研究现状

血管生成在肿瘤发生、增殖、侵袭和转移的全程中都扮演着重要角色,以肿瘤血管生成信号通路中的关键分子为靶点开发抗肿瘤药物是目前药物研发的热点。肿瘤相关的血管生成信号通路包括VEGF/VEEFR、血管生成素及其受体、血小板源生长因子及其受体、Delta-like Ligand/Notch、成纤维细胞生长因子及其受体、肝细胞生长因子及其受体、转化生长因子及其受体、内皮素系统等。与肿瘤血管生成通路相关的药物中,贝伐单抗（bevacizumab)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)等药物已经获得FDA的批准,在直肠癌、肾癌、非小细胞肺癌、肝癌、胃肠间质瘤等肿瘤患者中取得了良好效果,数十种尚未被FDA批准的抗血管生成药物也正在全球进行各期临床试验。本文总结肿瘤血管生成信号通路的基础研究及其相关药物临床转化的研究进展。     

血管内皮细胞生长因子及其表达调控研究进展

现有研究表明血管内皮细胞生长因子（vascular endothelial growth factor,VEGF）在调节血管生成中发挥着重要作用。VEGF的表达调控受多种因素的影响,其异常表达与肿瘤及某些疾病的发生有着密切的关系。通过研究VEGF的表达调控及其参与的重要信号通路,寻找出调控VEGF表达及其生物学功能的药物作用靶点,对于肿瘤及某些疾病的治疗具有重要的理论意义和实际应用价值。本文将着重对VEGF家族及其受体、VEGF的表达调控等方面进行综述。     

以VEGF及其受体为靶点的抗肿瘤血管生成研究进展

肿瘤的抗血管治疗是目前的研究热点之一。现综述以VEGF及VEGFR为靶点的抗肿瘤血管生成治疗策略。     

Delta-like 4/Notch signaling and its therapeutic implications.

Intense research efforts have been focused toward the identification of regulators of angiogenesis and the development of antiangiogenesis-based cancer therapies. The approval of anti-vascular endothelial growth factor (VEGF) monoclonal antibody (bevacizumab) for use in colorectal and lung cancer provides clinical validation for targeting angiogenesis for the treatment of cancer. Delta-like 4 (Dll4)-mediated Notch signaling represents another key pathway essential for vascular development. Recent studies yield substantial insights into the role of Dll4 in angiogenesis. Dll4 is downstream of VEGF signaling and its activation triggers a negative feedback that restrains the effects of VEGF. Attenuation of Dll4/Notch signaling results in chaotic vascular network with excessive branching and sprouting. In preclinical studies, blocking of Dll4/Notch signaling is associated with a paradoxical increase in tumor vessel density, yet causes marked growth inhibition due to functionally defective vasculature. Dll4 blockade holds promise as an additional strategy for angiogenesis-based cancer therapy, especially when resistance to and/or escape from existing therapies evolve.     

VEGF and Delta-Notch: interacting signalling pathways in tumour angiogenesis

Tumour angiogenesis has become an important target for antitumour therapy, with most current therapies aimed at blocking the VEGF pathway. However, not all tumours are responsive to VEGF blockers, and some tumours that are responsive initially may become resistant during the course of treatment, thus there is a need to explore other angiogenesis signalling pathways. Recently, the Delta-Notch pathway, and particularly the ligand Delta-like 4 (Dll4), was identified as a new target in tumour angiogenesis. An important feature in angiogenesis is the manifold ways in which the VEGF and Delta-Notch pathways interact. The emerging picture is that the VEGF pathway acts as a potent upstream activating stimulus for angiogenesis, whereas Delta-Notch helps to guide cell fate decisions that appropriately shape the activation. Here we review the two signalling pathways and what is currently known about the ways in which they interact during tumour angiogenesis.     

Notch signaling regulates tumor angiogenesis by diverse mechanisms

The Notch signaling pathway is fundamental to proper cardiovascular development and is now recognized as an important player in tumor angiogenesis. Two key Notch ligands have been implicated in tumor angiogenesis, Delta-like 4 and Jagged1. We introduce the proteins and how they work in normal developing vasculature and then discuss differing models describing the action of these Notch ligands in tumor angiogenesis. Endothelial Dll4 expression activates Notch resulting in restriction of new sprout development; for instance, in growing retinal vessels. In agreement with this activity, inhibition of Dll4-mediated Notch signaling in tumors results in hypersprouting of nonfunctional vasculature. This Dll4 inhibition may paradoxically lead to increased angiogenesis but poor tumor growth because the newly growing vessels are not functional. In contrast, Jagged1 has been described as a Notch ligand expressed in tumor cells that can have a positive influence on tumor angiogenesis, possibly by activating Notch on tumor endothelium. A novel Notch inhibitor, the Notch1 decoy, which blocks both Dll4 and Jagged1 has been recently shown to restrict tumor vessel growth. We discuss these models and speculate on therapeutic approaches.     

Biological roles of the Delta family Notch ligand Dll4 in tumor and endothelial cells in ovarian cancer

Emerging evidence suggests that the Notch/Delta-like ligand 4 (Dll4) pathway may offer important new targets for antiangiogenesis approaches. In this study, we investigated the clinical and biological significance of Dll4 in ovarian cancer. Dll4 was overexpressed in 72% of tumors examined in which it was an independent predictor of poor survival. Patients with tumors responding to anti-VEGF therapy had lower levels of Dll4 than patients with stable or progressive disease. Under hypoxic conditions, VEGF increased Dll4 expression in the tumor vasculature. Immobilized Dll4 also downregulated VEGFR2 expression in endothelial cells directly through methylation of the VEGFR2 promoter. RNAi-mediated silencing of Dll4 in ovarian tumor cells and tumor-associated endothelial cells inhibited cell growth and angiogenesis, accompanied by induction of hypoxia in the tumor microenvironment. Combining Dll4-targeted siRNA with bevacizumab resulted in greater inhibition of tumor growth, compared with control or treatment with bevacizumab alone. Together, our findings establish that Dll4 plays a functionally important role in both the tumor and endothelial compartments of ovarian cancer and that targeting Dll4 in combination with anti-VEGF treatment might improve outcomes of ovarian cancer treatment.     

Importance of fibroblast growth factor receptor in neovascularization and tumor escape from antiangiogenic therapy

Therapeutic inhibition of pathways involved in angiogenesis has become the standard of care in renal cell carcinoma (RCC). Most currently available antiangiogenic agents inhibit the vascular endothelial growth factor (VEGF) pathway. Although these drugs have produced exciting benefits, some tumors do not respond to these agents. In addition most if not all tumors that initially respond will eventually develop resistance. Tumor escape from antiangiogenic therapy may include various signaling pathways that are involved in angiogenesis, including the fibroblast growth factor (FGF) signaling pathway. Emerging preclinical data suggest that FGF and VEGF act distinctly and synergistically to promote tumor vascularization. The current review discusses the role of FGF signaling in resistance to anti-VEGF therapies and outlines potential therapeutic implications.     

Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor

Angiogenesis, or the formation of new capillary blood vessels, occurs primarily during human development and reproduction; however, aberrant regulation of angiogenesis is also a fundamental process found in several pathologic conditions, including cancer. As a process required for invasion and metastasis, tumor angiogenesis constitutes an important point of control of cancer progression. Although not yet completely understood, the complex process of tumor angiogenesis involves highly regulated orchestration of multiple signaling pathways. The proangiogenic signaling molecule vascular endothelial growth factor (VEGF) and its cognate receptor (VEGF receptor 2 [VEGFR-2]) play a central role in angiogenesis and often are highly expressed in human cancers, and initial clinical efforts to develop antiangiogenic treatments focused largely on inhibiting VEGF/VEGFR signaling. Such approaches, however, often lead to transient responses and further disease progression because angiogenesis is regulated by multiple pathways that are able to compensate for each other when single pathways are inhibited. The platelet-derived growth factor (PDGF) and PDGF receptor (PDGFR) and fibroblast growth factor (FGF) and FGF receptor (FGFR) pathways, for example, provide potential escape mechanisms from anti-VEGF/VEGFR therapy that could facilitate resumption of tumor growth. Accordingly, more recent treatments have focused on inhibiting multiple signaling pathways simultaneously. This comprehensive review discusses the limitations of inhibiting VEGF signaling alone as an antiangiogenic strategy, the importance of other angiogenic pathways including PDGF/PDGFR and FGF/FGFR, and the novel current and emerging agents that target multiple angiogenic pathways for the treatment of advanced solid tumors.

Implications for Practice:

Significant advances in cancer treatment have been achieved with the development of antiangiogenic agents, the majority of which have focused on inhibition of the vascular endothelial growth factor (VEGF) pathway. VEGF targeting alone, however, has not proven to be as efficacious as originally hoped, and it is increasingly clear that there are many interconnected and compensatory pathways that can overcome VEGF-targeted inhibition of angiogenesis. Maximizing the potential of antiangiogenic therapy is likely to require a broader therapeutic approach using a new generation of multitargeted antiangiogenic agents.     

Vascular endothelial growth factor: regulation in the mouse skin carcinogenesis model and use in antiangiogenesis cancer therapy

Of the various mechanisms responsible for tumor neovascularization, the angiogenesis process, in particular vascular endothelial growth factor (VEGF), is described here as a target for cancer therapy. While hypoxia is a trigger of tumor angiogenesis, various alterations in oncogenes and tumor suppressor genes also have been reported to induce VEGF expression in tumors. The regulation of VEGF has been investigated in chemically induced mouse squamous cell carcinoma of the skin. In this cancer model, VEGF expression appears to be dependent on ras oncogene activation as well as the epidermal growth factor receptor. Thus, in addition to VEGF, oncogene signaling pathways may be relevant targets in antiangiogenesis cancer therapies. The central role of VEGF in angiogenesis has led to the development of several drugs targeting the pathway of this growth factor. The present paper provides an overview of these drugs and their stage of development. In the near future, clinical trials using anti-VEGF drugs and other antiangiogenic agents, such as endostatin and angiostatin, will yield valuable information about their potential for cancer therapy.     

Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo

The vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. However, clinical trials targeting the VEGF pathway are often ineffective, suggesting that other factors/pathways are also important in tumor angiogenesis. We have previously shown that the Notch ligand Delta-like 4 (DLL4) is up-regulated in tumor vasculature. Here, we show that DLL4, when expressed in tumor cells, functions as a negative regulator of tumor angiogenesis by reducing the number of blood vessels in all five types of xenografts, but acts as a positive driver for tumor growth in two of them (human glioblastoma and prostate cancer). The growth of in vivo models was not related to the effects on growth in vitro. DLL4 expressed in the tumor cells activated Notch signaling in host stromal/endothelial cells, increased blood vessel size, and improved vascular function within tumors. The promotion of tumor growth was, to some extent, due to a reduction of tumor hypoxia and apoptosis. DLL4-expressing tumor cells responded to anti-VEGF therapy with bevacizumab. A soluble form of DLL4 (D4ECD-Fc) blocked tumor growth in both bevacizumab-sensitive and bevacizumab-resistant tumors by disrupting vascular function despite increased tumor vessel density. In addition, we show that DLL4 is up-regulated in tumor cells and tumor endothelial cells of human glioblastoma. Our findings provide a rational basis for the development of novel antiangiogenic strategies via blockade of DLL4/Notch signaling and suggest that combined approaches for interrupting both DLL4 and VEGF pathways may improve antiangiogenic therapy.