The vasohibin family: Novel regulators of angiogenesis
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Angiogenesis inhibitor
Interferons (IFNs) have proven antitumor activity against a variety of human malignancies, which may result, at least in part, from inhibition of angiogenesis. The objective of this study was to identify IFN-stimulated genes (ISGs) that played a role in mediation of angiogenic inhibition. IFN-beta was a more potent antiangiogenic agent compared to IFN-alpha2b (80% versus 20%, respectively) and suggests that IFNs inhibited angiogenesis by preventing endothelial cell differentiation, and not by direct antiproliferative effects. To identify ISGs that were key inhibitors of angiogenesis, we utilized an in vitro fibrin gel angiogenic assay which closely recapitulated the in vivo processes of angiogenesis. DNA microarray analysis of IFN-beta-treated endothelial cells in the fibrin gel assay identified 11 ISGs that were induced >10-fold during angiogenesis inhibition. Recombinant IP-10 inhibited angiogenesis in a dose-dependent fashion, but was a less effective inhibitor compared to IFN-beta, suggesting that additional ISGs are involved in inhibiting angiogenesis. ISG20 was upregulated by microarray analysis, but did not inhibit angiogenesis when overexpressed in human umbilical vein endothelial cells (HUVECs). However, a dominant negative mutant of ISG20 inhibited angiogenesis by 43%. Results suggest that IFN-induced angiogenic inhibition was likely mediated by multiple ISGs; our novel finding is that decreased exonuclease activity in HUVECs associated with expression of the ISG20 ExoII mutant inhibited angiogenesis.
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The carcinoma was an angiogenesis dependent disease,the relations between the growth,metastasis of tumor cells and angiogenesis were rather close.The angiogenesis inhibitor was an effective means of limiting both the size and metastasis of solid tumors.A synthetic analog of fumagillin, TNP-470,which potently inhibits angiogenesis by blocking endothelial cell proliferation,was currently undergoing clinical trials for treatment of a variety of cancers.The recent progresses on the antitumor effect of angiogenesis inhibitor TNP-470 were reviewed and summarized.
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Numerous lines of evidence have shown that angiogenesis plays a pivotal role in the development of tumors. Therefore anti-angiogenesis therapy represents a potentially promising approach to cancer therapy. Recently, a new inhibitor called vasohibin was discovered to operate as an intrinsic and highly specific feedback inhibitor in the process of angiogenesis. However, to date, reports on the antitumor and anti-angiogenic properties of vasohibin have been very limited. To explore the potential of vasohibin as an anti-angiogenesis therapeutic, we constructed a recombinant adenovirus encoding vasohibin. Our data showed that the recombinant adenovirus encoding vasohibin could prevent tumor angiogenesis and tumor growth. Notably, angiogenesis in the tumors was prevented without any apparent side-effects. Therefore, the findings suggested that the recombinant adenovirus encoding vasohibin might be valuable as a potential strategy for antitumor angiogenesis therapy in the clinic.
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The brain-specific angiogenesis inhibitor 1 gene has been isolated in an attempt to find fragments with p53 "functional" binding sites. As reported herein and by others, brain-specific angiogenesis inhibitor 1 expression is present in some normal tissues, but is reduced or lost in tumour tissues. Such data and its particular structure prompted the hypothesis that brain-specific angiogenesis inhibitor 1 may act as a mediator in the local angiogenesis balance. We herein demonstrate that brain-specific angiogenesis inhibitor 1 over-expression suppresses tumour angiogenesis, delaying significantly the human tumour growth in immunodeficient mice. The inhibitory effect of brain-specific angiogenesis inhibitor 1 was documented using our intravital microscopy system, strongly implicating brain-specific angiogenesis inhibitor 1 as a mediator in the control of tumour angiogenesis. In contrast, in vitro tumour cell proliferation was not inhibited by brain-specific angiogenesis inhibitor 1 transfection, whereas some level of cytotoxicity was assessed for endothelial cells. Immunohistochemical analysis of tumour samples confirmed a reduction in the microvessel density index in brain-specific angiogenesis inhibitor 1-overexpressing tumours. At messenger level, moderate changes could be detected, involving the down-regulation of vascular endothelial growth factor and collagenase-1 expression. Furthermore, brain-specific angiogenesis inhibitor 1 expression that was lost in a selection of human cancer cell lines could be restored by wild-type p53 adenoviral transfection. Brain-specific angiogenesis inhibitor 1 should be considered for gene therapy and development of efficient drugs based on endogenous antiangiogenic molecules.
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Angiogenesis, the formation of new blood vessels, is seen during embryonic development and tumor progression, but the mechanisms have remained unclear. Recent data indicate that developmental and tumor angiogenesis can be induced by cellular oncogenes, leading to the enhanced activity of molecules stimulating angiogenesis. However, activated oncogenes might also facilitate angiogenesis by down-regulating endogenous inhibitors of angiogenesis. We report here that enhanced expression of the N-myc oncogene in human neuroblastoma cells down-regulates an inhibitor of endothelial cell proliferation, identified by amino acid sequencing as being identical with activin A, a developmentally regulated protein. Down-regulation appears to involve interaction of the N-Myc protein with the activin A promoter. In addition, activin A inhibits both endothelial cell proliferation in vitro and angiogenesis in vivo, and it induces hemorrhage in vivo. We suggest that the N-myc-induced down-regulation of activin A could contribute to developmental and tumor angiogenesis.
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