Inhibition of Angiogenesis and Vascular Tumor Growth by Interferon-Producing Cells

Albini, Adriana; Marchisone, Chiara; Grosso, Federica; Benelli, Roberto; Masiello, Luciana; Tacchetti, Carlo; Bono, Marı́a Rosa; Ferrantini, Maria; Rozera, Carmela; Truini, Mauro; Belardelli, Filippo; Santi, Leonardo; Noonan, Douglas M.

doi:10.1016/s0002-9440(10)65007-9

Cited by 117 publications

(84 citation statements)

References 33 publications

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“…These findings support the hypothesis that the antiangiogenic effect of IFN-g on human endothelial cells required other mechanisms besides apoptosis. Human IFN-g inhibits endothelial migration and proliferation (Brouty-Boye and Zetter, 1980;Friesel et al, 1987;Tsuruoka et al, 1988;Albini et al, 2000) and has strong antiproliferative effects on NB tumour cells (Ponzoni et al, 1992;Airoldi et al, 2004), from which the human endothelial cells derived. Thus, the antiangiogenic effect was likely due to a combination of apoptosis and reduced proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…Precisely, murine IFN-g produced by either CD4 þ or CD8 þ cells inhibits tumour-induced angiogenesis in syngeneic tumour models (Saiki et al, 1992;Qin and Blankenstein, 2000;Blankenstein and Qin, 2003). Human IFN-g inhibits proliferation and migration of human endothelial cells and capillary tube formation in vitro (BroutyBoye and Zetter, 1980;Friesel et al, 1987;Tsuruoka et al, 1988;Maheshwari et al, 1991;Albini et al, 2000) and represses lymphocyte-induced tumour angiogenesis (Sidky and Borden, 1987).…”

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confidence: 99%

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Angiogenesis in a human neuroblastoma xenograft model: mechanisms and inhibition by tumour-derived interferon-γ

et al. 2006

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Tumour progression in neuroblastoma (NB) patients correlates with high vascular index. We have previously shown that the ACN NB cell line is tumorigenic and angiogenic in immunodeficient mice, and that interferon-g (IFN-g) gene transfer dampens ACN tumorigenicity. As IFN-g represses lymphocyte-induced tumour angiogenesis in various murine models and inhibits proliferation and migration of human endothelial cells, we have investigated the antiangiogenic activity of tumour-derived IFN-g and the underlying mechanism(s). In addition, we characterised the tumour vasculature of the ACN xenografts, using the chick embryo chorioallantoic membrane assay. We show that the ACN/IFN-g xenografts had a lower microvessel density and less in vivo angiogenic potential than the vector-transfected ACN/neo. The vascular channels of both xenografts were formed by a mixed endothelial cell population of murine and human origin, as assessed by the FICTION (fluorescence immunophenotyping and interphase cytogenetics) technique. With respect to ACN/neo, the ACN/IFN-g xenografts showed more terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling-positive human and murine endothelial cells, suggesting that inhibition of angiogenesis by IFN-g was dependent on the induction of apoptosis, likely mediated by nitric oxide. Once the dual origin of tumour vasculature is confirmed in NB patients, the xenograft model described here will prove useful in testing the efficacy of different antiangiogenic compounds.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Angiogenesis in a human neuroblastoma xenograft model: mechanisms and inhibition by tumour-derived interferon-γ

et al. 2006

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“…3A). Because it has been demonstrated that IFNs inhibit endothelial cell migration across the basal lamina propria [4,5], we tested the effect of IFI16 expression on VEGF and bFGF-induced invasion (transmigration) of a reconstituted basal lamina in modified Boyden chambers. In this assay [35,36], cells transmigrate from an upper well through a porous filter coated with Matrigel toward chemoattractants (i.e.…”

Section: Inhibition Of Huvec Chemotaxis Invasion and Tube Morphogenmentioning

confidence: 99%

“…Anti-angiogenic therapy uses negative neovascularization regulators to suppress pro-angiogenic signals or increase inhibitory signals [3]. IFNs, along with their role in viral interference and cell proliferation, possess potent antiangiogenic activity [4][5][6]. They down-regulate the expression of several proangiogenic molecules, such as bFGF [7], matrix metalloproteases (MMP-2 and MMP-9) [8][9][10], and IL-8 [11].…”

Section: Introductionmentioning

confidence: 99%

The interferon-inducible IFI16 gene inhibits tube morphogenesis and proliferation of primary, but not HPV16 E6/E7-immortalized human endothelial cells

Ravera

Gioia

Andrea

et al. 2004

Experimental Cell Research

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Immunohistochemical analysis has demonstrated that the human IFI16 gene, in addition to the hematopoietic tissues, is highly expressed in endothelial cells and squamous stratified epithelia. In this study, we have developed a reliable HSV-derived replication-defective vector (TO-IFI16) to efficiently transduce IFI16 into primary human umbilical vein endothelial cells (HUVEC), which are usually poorly transfectable. HUVEC infection with TO-IFI16 virus suppressed endothelial migration, invasion and formation of capillary-like structures in vitro. In parallel, sustained IFI16 expression inhibited HUVEC cell cycle progression, accompanied by significant induction of p53, p21, and hypophosphorylated pRb. Further support for the involvement of these pathways in IFI16 activity came from the finding that infection with TO-IFI16 virus does not impair the in vitro angiogenic activity and cell cycle progression of HUVEC immortalized by HPV16 E6/E7 oncogenes, which are known to inactivate both p53 and pRb systems. This use of a reliable viral system for gene delivery into primary human endothelial cells assigns a potent angiostatic activity to an IFN-inducible gene, namely IFI16, and thus throws further light on antiangiogenic therapy employing IFNs. D

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“…It is well known that IFN-b has many biological effects. 42,43 IFN-b exhibits antitumor effects via various mechanisms, such as upregulation of MHC class I, 44 activation of macrophages and NK cells, 45 downregulation of angiogenic agents 46 and inhibition of tumor cell proliferation. 47 It is likely that inhibition of tumor cell proliferation by IFN-b is one of the most important mechanisms in our study, because the cell growth inhibitory effect of IFN-b was often higher than that of IFN-a and g 47,48 and, in fact, the in vitro growth of CT-26 cells was efficiently inhibited by IFN-b.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic effect of intravenous delivery of lipoplexes containing the interferon-β gene and poly I: poly C in a murine lung metastasis model

et al. 2003

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We have evaluated and compared the efficacy of systemic administration of lipoplex formulations containing plasmids encoding IFN-b or IFN-g, and a synthetic double-strand RNA poly I:poly C (pI:pC), a type I IFN inducer, in a lung metastasis model in which colon carcinoma CT-26 cells were inoculated intravenously into immunocompatible mice. Injection of lipoplexes containing plasmid DNA, regardless of IFN gene insertion, stimulated a transient increase in the serum concentration of proinflammatory cytokines such as tumor necrosis factor (TNF)-a and IFN-g, while injection of lipoplexes containing pI:pC led to a low level of TNF-a and undetectable IFN-g production. Furthermore, injection of these lipoplexes containing plasmids resulted in the production of a mixture of type I and type II IFNs, partly derived from the inserted IFN genes, in lung tissue cultures. In tumor-prophylactic experiments, intravenous injection of lipoplexes containing plasmid, regardless of IFN gene insertion, showed a significant reduction in lung metastatic nodules probably due to proinflammatory cytokines such as TNF-a and IFN-g nonspecifically induced by the CpG motifs in the plasmid and the type I IFNs produced. On the other hand, the antimetastatic effect of pI:pC-lipoplex seemed to be due mainly to IFN-b induced by pI:pC. In established lung metastasis experiments, a single intravenous administration of lipoplexes containing IFN-b gene or pI:pC, but not other lipoplexes, showed a significant therapeutic effect on the tumor metastasis: reduction in tumor nodules and prolongation of survival time of tumor-burden mice. The therapeutic effects were specifically impaired by anti-IFN-b antibody treatment, indicating that IFN-b produced by the lipoplexes played an important role in the suppression of established metastatic lung tumors. Thus, the local IFN-b in the lung delivered by intravenous administration of lipoplex containing IFN-b gene or pI:pC may be a convenient and useful method of inhibiting established metastatic lung tumors.

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Inhibition of Angiogenesis and Vascular Tumor Growth by Interferon-Producing Cells

Cited by 117 publications

References 33 publications

Angiogenesis in a human neuroblastoma xenograft model: mechanisms and inhibition by tumour-derived interferon-γ

Angiogenesis in a human neuroblastoma xenograft model: mechanisms and inhibition by tumour-derived interferon-γ

The interferon-inducible IFI16 gene inhibits tube morphogenesis and proliferation of primary, but not HPV16 E6/E7-immortalized human endothelial cells

Therapeutic effect of intravenous delivery of lipoplexes containing the interferon-β gene and poly I: poly C in a murine lung metastasis model

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