Notch signaling in developmental and tumor angiogenesis

The discovery that Notch, a key regulator of cell fate determination, is functional in the vasculature has greatly improved our understanding of differentiation and specialization of vessels. Notch signaling has been proven to be critical for arterial specification, sprouting angiogenesis, and vessel maturation. In newly forming vascular sprouts, Notch promotes the distinction between the leading "tip" endothelial cell and the growing "stalk" cell, the endothelial cells that eventually form a new capillary. Notch signaling has also been implicated in vessel stability by regulating vascular mural cell function. More recently, macrophages carrying an activated Notch have been implicated in shaping the course of new sprout formation. Tumor vessels abide by similar principles and use Notch signaling in similar ways. An exciting discovery, made by several researchers, shows that blocking Notch function in tumor vasculature provides a means by which to suppress tumor growth. The authors discuss the developmental and physiological role of Notch in the vasculature and apply this knowledge to an overview of how Notch targeting in the tumor environment can affect tumor angiogenesis and growth.     

Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling

While significant progress has been made in understanding the induction of tumor vasculature by secreted angiogenic factors, little is known regarding contact-dependent signals that promote tumor angiogenesis. Here, we report that the Notch ligand Jagged1 induced by growth factors via mitogen-activating protein kinase (MAPK) in head and neck squamous cell carcinoma (HNSCC) cells triggered Notch activation in neighboring endothelial cells (ECs) and promoted capillary-like sprout formation. Jagged1-expressing HNSCC cells significantly enhanced neovascularization and tumor growth in vivo. Moreover, the level of Jagged1 was significantly correlated with tumor blood vessel content and associated with HNSCC development. Our results elucidate a novel mechanism by which the direct interplay between tumor cells and ECs promotes angiogenesis through MAPK and Notch signaling pathways.     

Notch signaling from tumor cells: a new mechanism of angiogenesis

Notch signaling is an evolutionarily conserved pathway and plays key roles in embryonic vascular development and angiogenesis. Multiple components of the Notch pathway are expressed in vasculature, and mice deficient for a variety of these components display embryonic lethality with vascular remodeling defects. Alteration of Notch signaling in various endothelial cells generates profound effects on angiogenesis in vitro. New evidence shows that Notch signaling from tumor cells is able to activate endothelial cells and trigger tumor angiogenesis in vitro and in a xenograft mouse tumor model. Selective interruption of Notch signaling within tumors may provide an antiangiogenic strategy.     

Notch regulation of tumor angiogenesis

The growth of new blood vessels (angiogenesis) is critical for tumor growth and progression. The highly conserved Notch signaling pathway is involved in a variety of cell fate decisions and regulates many cellular biological processes, including angiogenesis. Aberrant Notch signaling has also been implicated in tumorigenesis. Notch ligands and receptors are expressed on many different cell types present within the tumor, including tumor cells and the stromal compartment. This article highlights in particular the various mechanisms by which Notch signaling can mediate tumor angiogenesis. The most studied Notch ligands, Delta-like 4 and Jagged1, competitively regulate tumor angiogenesis. Studies have demonstrated that Delta-like 4 functions as a negative regulator of tumor angiogenesis, whereas Jagged1 promotes angiogenesis. Understanding the implications of Notch signaling in various tumor backgrounds will enable the effects of specific Notch signaling inhibition on tumor angiogenesis and growth to be evaluated as a potential for a novel antiangiogenic therapy in the clinic.     

Notch信号通路与肿瘤

Notch信号通路存在于多种动物体内,脊椎动物中有4个Notch同源体Notch1、Notch2、Notch3、Notch4,其中Notch1在肿瘤形成中起重要作用,至于其是癌基因还是抑癌基因,目前尚存争议.Notch通路是许多重要细胞信号转导通路的交汇点,对Notch1的研究可进一步阐明肿瘤发生的机制,为肿瘤基因治疗及新药开发提供一个新的有希望的靶点.     

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.     

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.     

Notch信号通路与脑肿瘤

Notch信号通路作为一个对细胞的生长发育具有广泛多样化影响的信号途径,也与肿瘤的发生、发展相关.对于不同的肿瘤或同一肿瘤的不同级别、不同发展阶段Notch信号通路可能具有不同作用.Notch信号在一些脑肿瘤(脑胶质瘤、髓母细胞瘤、神经母细胞瘤、脑膜瘤)中异常表达,且参与这些脑肿瘤的发生、发展.     

Molecular mechanisms of tumor angiogenesis

Tumors have been recently recognized as aberrant organs composed of a complex mixture of highly interactive cells that in addition to the cancer cell include stroma (fibroblasts, adipocytes, and myofibroblasts), inflammatory (innate and adaptive immune cells), and vascular cells (endothelial and mural cells). While initially cancer cells co-opt tissue-resident vessels, the tumor eventually recruits its own vascular supply. The process of tumor neovascularization proceeds through the combined output of inductive signals from the entire cellular constituency of the tumor. During the last two decades, the identification and mechanistic outcome of signaling pathways that mediate tumor angiogenesis have been elucidated. Interestingly, many of the genes and signaling pathways activated in tumor angiogenesis are identical to those operational during developmental vascular growth, but they lack feedback regulatory control and are highly affected by inflammatory cells and hypoxia. Consequently, tumor vessels are abnormal, fragile, and hyperpermeable. The lack of hierarchy and inconsistent investment of mural cells dampen the ability of the vessels to effectively perfuse the tumor, and the resulting hypoxia installs a vicious cycle that continuously perpetuates a state of vascular inefficiency. Pharmacological targeting of blood vessels, mainly through the VEGF signaling pathway, has proven effective in normalizing tumor vessels. This normalization improves perfusion and distribution of chemotherapeutic drugs with resulting tumor suppression and moderate increase in overall survival. However, resistance to antiangiogenic therapy occurs frequently and constitutes a critical barrier in the inhibition of tumor growth. A concrete understanding of the chief signaling pathways that stimulate vascular growth in tumors and their cross-talk will continue to be essential to further refine and effectively abort the angiogenic response in cancer.     

VEGF receptor signaling in tumor angiogenesis

The growth of human tumors and development of metastases depend on the de novo formation of blood vessels. The formation of new blood vessels is tightly regulated by specific growth factors that target receptor tyrosine kinases (RTKs). Vascular endothelial growth factor (VEGF) and the Flk-1/KDR RTK have been implicated as the key endothelial cell-specific factor signaling pathway required for pathological angiogenesis, including tumor neovascularization. Inhibition of the VEGF tyrosine kinase signaling pathway blocks new blood vessel formation in growing tumors, leading to stasis or regression of tumor growth. Advances in understanding the biology of angiogenesis have led to the development of several therapeutic modalities for the inhibition of the VEGF tyrosine kinase signaling pathway. A number of these modalities are under investigation in clinical studies to evaluate their potential to treat human cancers.     

Improving tumor response to radiotherapy by targeting angiogenesis signaling pathways

Radiotherapy is one of the most widely used treatments for cancer; however, the development of tumor radioresistance is an ongoing problem. Agents that target tumor angiogenesis are being used in combination with radiotherapy to improve the therapeutic index without a clear understanding of how these agents may affect radiosensitization. This article discusses recently published studies that may shed some light on the underlying signaling mechanisms that are involved in the interactions of antiangiogenic agents with ionizing radiation.     

Notch3 signaling initiates choroid plexus tumor formation

Notch3 has been studied in the context of brain development, but whether it plays a role in the formation of brain tumors is unclear. We demonstrate that the introduction of constitutively active Notch3 into periventricular cells of embryonic day 9.5 mice causes the formation of choroid plexus tumors (CPTs). Tumors arose in the fourth ventricles in 83% of animals and were associated with hydrocephalus. They were microscopically highly similar to choroid plexus papillomas in humans, with an ongoing proliferation rate of 4-6%. Signs of Notch pathway activity were also present in human choroid plexus lesions, and receptor mRNA levels in papillomas were elevated over those in non-neoplastic choroid plexus. Notch2 was overexpressed approximately 500-fold in one case, suggesting that the role of this pathway in CPTs may not be specific to Notch3. Our findings indicate that activated Notch3 can function as an oncogene in the developing brain, and link the Notch pathway to human CPT pathogenesis.     

Integrin beta4 signaling promotes tumor angiogenesis

Mice carrying a targeted deletion of the signaling portion of the integrin beta4 subunit display drastically reduced angiogenesis in response to bFGF in the Matrigel plug assay and to hypoxia in the retinal neovascularization model. Molecular cytology indicates that alpha6beta4 signaling promotes branching of beta4+ medium- and small-size vessels into beta4- microvessels without exerting a direct effect on endothelial cell proliferation or survival. Signaling studies reveal that alpha6beta4 signaling induces endothelial cell migration and invasion by promoting nuclear translocation of P-ERK and NF-kappaB. Upon subcutaneous implantation of various cancer cells, the mutant mice develop smaller and significantly less vascularized tumors than wild-type controls. These results provide genetic evidence that alpha6beta4 signaling promotes the onset of the invasive phase of pathological angiogenesis and hence identify a novel target for antiangiogenic therapy.     

Induction of Notch signaling by tumor necrosis factor in rheumatoid synovial fibroblasts

Rheumatoid arthritis (RA) is characterized by progressive inflammation associated with abberrant proliferation of synoviocytes. In order to explore the characteristics of rheumatoid synovial fibroblasts (RSF), we performed the comparative gene expression profile analysis between RSF and normal synovial fibroblasts (NSF) upon tumor necrosis factor (TNF) stimulation. As an initial screening for the genes preferentially induced by TNF in RSF compared with NSF, we have adopted a cDNA array containing well-defined sets of genes responsible for cell growth, cell fate determination, and cellular invasiveness. Differentially expressed genes of interest were confirmed using real-time RT-PCR. We found that TNF induced the expression of Notch-1, Notch-4, and Jagged-2 in RSF. The expression of these proteins was detected in the RA synovial tissues. The nucleus of RA synoviocytes showed strong staining with anti-Notch-1 and Notch-4 antibody. TNF induced the nuclear translocation of Notch intracellular domain in RSF, indicating the elicitation of the Notch signaling. Notch-1, Notch-4, and Jagged-2 proteins were also detected in the developing synovium of mouse embryo. Thus, RSF may have re-acquired the primordial phenotype, accounting for the hyperproliferation and aggressive invasiveness, exhibiting tumor-like phenotype.     

Progress in molecular mechanisms of tumor metastasis and angiogenesis

The development of metastases is the major cause of death for cancer patients, however, the mechanisms of tumor invasion and acquisition of capability to metastasize remain unclear. During the past decade, knowledge regarding the molecular and cellular processes involved in the regulation of tumor metastases has dramatically increased and has been focussed on cross-talk between selected cancer cells and the specific organ microenvironment. The three-step development of the invasive phenotype of cancer cells is described: cell attachment, local proteolysis and cell migration. The molecular analysis of invasion-associated cellular activities, mainly the role of homotypic and heterotypic cell-cell adhesions, cell-matrix interactions, proteolysis mechanisms and migration properties of cancer cells, are also discussed. The role of tumor phenotype and microenvironment in the metastatic predilection for a specific organ site is pointed out, considering the recent reports which indicate that the capacity to metastasize might be acquired early during multistep tumorigenesis, thereby also predicting the site of metastasis. In addition, this review summarizes the current knowledge regarding angiogenesis regulation in progressive tumor growth and in the complex, multistep nature of tumor cell dissemination. A better understanding of the linkage between genetic and epigenetic events in metastases development may result in new anticancer treatment strategies.     

Notch信号通路与肿瘤细胞凋亡的研究进展

Notch信号通路是一种生物进化中高度保守的信号转导通路,在多种细胞的增殖、分化和凋亡中起到关键作用.目前Notch信号通路的配体和受体,以及信号转导途径已经基本研究阐明,有关Notch信号通路与肿瘤细胞凋亡的研究也取得了较大的进展.本文综述了Notch信号通路对血液恶性肿瘤和实体肿瘤细胞凋亡的影响及机制的最新研究结果...