Modulation of Endothelial Cell Growth Arrest and Apoptosis by Vascular Endothelial Growth Inhibitor

Yu, Jun; Shen, Tian; Metheny-Barlow, Linda J.; Chew, Li‐Jin; Hayes, Andrew; Pan, Hongna; Yu, Guoliang; Li, Luyuan

doi:10.1161/hh2401.101909

Cited by 92 publications

(109 citation statements)

References 29 publications

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“…We showed that VEGI is a potent and specific inhibitor of endothelial cell growth (4 -6). VEGI exhibits two distinctly different activities on endothelial cells: growth arrest of G 0 -G 1 cells and apoptosis of proliferating cells (7). These findings suggest that VEGI may have an important role in the regulation of vascular homeostasis.…”

mentioning

confidence: 88%

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VEGI-192, a New Isoform of TNFSF15, Specifically Eliminates Tumor Vascular Endothelial Cells and Suppresses Tumor Growth

Hou

Medynski²,

Wu³

et al. 2005

Clinical Cancer Research

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Purpose: We determined the antiangiogenic and anticancer activity of VEGI-192, a new isoform of TNFSF15 (VEGI,TL1), with a Lewis lung cancer murine tumor model. Experimental Design: Recombinant human VEGI-192 was produced in Escherichia coli and purified to apparent homogeneity.The protein was given systemically via i.p., i.v., or s.c. injections to tumor-bearing C57BL/6 mice. Tumor growth rates, animal survival rates, and general toxicity were determined. Effect on endothelial cell/smooth muscle cell ratio of the tumor vasculature was analyzed. Results: Systemic administration ofVEGI-192 gave rise to a marked inhibition of tumor growth. As much as 50% inhibition of the tumor growth rate was achieved with treatment initiated when the tumor volumes reached nearly 5% of the body weight. Inhibition of tumor formation was also observed when VEGI-192 was given at the time of tumor inoculation. Consistently, we observed an increased survival time of the treated animals.TheVEGI-192-treated animals showed no liver or kidney toxicity. The treatment eliminated tumor endothelial cells but not vascular smooth muscle cells, which remained associated with a residual vascular structure consisting of the basement membrane. In addition, we carried out immunohistochemical analysis of rat kidneys and found that vascular endothelial cell growth inhibitor (VEGI) expression is largely limited to endothelial cells. Conclusions: Our findings indicate thatVEGI is an endogenous inhibitor of angiogenesis, and that systemic administration of the VEGI-192 isoform resulted in inhibition of tumor angiogenesis and growth.The recent success of applying an antiangiogenic agent Avastin (1) in clinical settings for cancer treatment provided the first set of evidence to support the hypothesis that inhibition of tumor neovascularization can bring significant benefit to cancer therapy (2). Because neovascularization under either physiologic or pathologic conditions is controlled by a balance of endogenous proangiogenic and antiangiogenic factors, an important approach to develop therapeutic agents for cancers and other angiogenesis-driven diseases is to use endogenous antiangiogenic factors (3).We previously reported the discovery of an endothelial cellspecific gene product, vascular endothelial cell growth inhibitor (VEGI, TNFSF15), which exhibits 20% to 30% sequence homology to the tumor necrosis factor superfamily (4, 5). VEGI mRNA was found in many normal adult tissues, suggesting a physiologic role for this unique gene in the maintenance of the normal vasculature (6). We showed that VEGI is a potent and specific inhibitor of endothelial cell growth (4 -6). VEGI exhibits two distinctly different activities on endothelial cells: growth arrest of G 0 -G 1 cells and apoptosis of proliferating cells (7). These findings suggest that VEGI may have an important role in the regulation of vascular homeostasis.There are three differential splicing variants of VEGI (7). The initially reported VEGI protein is composed of 174 amino acids (4, 5). Hydr...

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mentioning

confidence: 88%

“…There are three differential splicing variants of VEGI (7). The initially reported VEGI protein is composed of 174 amino acids (4,5).…”

mentioning

confidence: 99%

VEGI-192, a New Isoform of TNFSF15, Specifically Eliminates Tumor Vascular Endothelial Cells and Suppresses Tumor Growth

Hou

Medynski²,

Wu³

et al. 2005

Clinical Cancer Research

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“…VEGI induces growth arrest in endothelial cells synchronized in the G0/G1 phases of the cell cycle, preventing their progression to the S phase through inhibition of pRb hyperphosphorylation by CDKs (Yu et al, 2001). In the presence of VEGI, the activity of CDK4 and CDK6 kinase is inactivated, indicating a possible role of VEGI in the activation of inhibitors of these CDKs, such as p27 kip .…”

Section: Modulation Of Retinoblastoma Family Members By Antiangiogenimentioning

confidence: 99%

Involvement of RB gene family in tumor angiogenesis

Gabellini¹,

Bufalo²,

Zupi³

2006

Oncogene

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Angiogenesis, the development of new blood vessels from pre-existing vessels, represents a fundamental step in tumor progression and metastatization. The induction of vasculature is required for growth of the tumor mass, to ensure an adequate supply of oxygen and metabolites to the tumor beyond a critical size. Tumor angiogenesis is a highly regulated process that is controlled physiologically by the tumor microenvironment and genetically by alteration of several oncogenes or tumor suppressor genes. We will focus on recent demonstrations regarding the involvement of the retinoblastoma family proteins (phosphorylated retinoblastoma (pRb), p107 and pRb2/p130) at different levels of the angiogenic process. pRb and its homologs can regulate the expression of pro-and antiangiogenic factors, such as the vascular endothelial growth factor, through an E2F-dependent mechanism. Moreover, pRb is able to modulate also the transcriptional activity of several angiogenesis-related factors like HIF-1, Id2 and Oct-1. pRb2/p130 is required for both differentiation and mobilization of bone marrow-derived endothelial cell precursors and endothelial sprouting from neighboring vessels. The involvement of the pRb pathway in the angiogenesis process has also been demonstrated by different cellular models expressing viral oncoproteins, like human papilloma virus. Moreover, some natural and synthetic compounds demonstrate their antiangiogenetic activity with a mechanism of action involving pRb. Finally, the possible prognostic value of immunohistochemical evaluation of pRb and/or pRb2/p130 expression can represent a useful tool for the characterization of the angiogenic phenotype of specific tumor histotypes.

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“…VEGI is another endothelial cell-specific gene and a potent inhibitor of endothelial cell proliferation, angiogenesis [9] . VEGI could mediate early G(1) arrest in G(0)/G(1) endothelial cells responding to growth stimuli, and programmed death in proliferating endothelial cells [10] . In our laboratory two recombinant proteins have been used to treat tumor-bearing nude mice, but the inhibitory effect was not satisfactory.…”

Section: Introductionmentioning

confidence: 99%

Effects of endostatin-vascular endothelial growth inhibitor chimeric recombinant adenoviruses on antiangiogenesis

Pan

Wang²,

Zhang³

et al. 2004

WJG

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AIM:To investigate the inhibitory effects of endostatinvascular endothelial growth inhibitor (VEGI 151 ) recombinant adenoviruses on neovascularization. METHODS:We used recombinant adenoviruses to treat human vascular endothelial cell line ECV304, human hepatocellular carcinoma cell line HepG2, and murine fibroblast cell line L929, in order to study the chimeric gene expression in these cell lines. Chick choriallantic membrane (CAM) model, rabbit inflammatory corneal neovascularization (CNV) model, and liver cancer-bearing nude mice model were employed to investigate the negative biological effect of fusion molecules on neovascularization in vivo. RESULTS:Western blot showed that the molecular weight of fusion protein was about 41kD after infection of ECV304, HepG2 and L929 cells with supernatant of AdhENDO-VEGI 151 . The fusion protein showed a specific inhibitory effect on the proliferation of ECV304 cells, but no inhibitory effect on the growth of HepG2 and L929 cells (F=13112.13, P=0.0001). In the chick choriallantic membrane (CAM) assay, the expressed fusion protein significantly inhibited neovascularization. Rabbit inflammatory corneal neovascularization (CNV) induced by intrastromal sutures resulted in a uniform neovascular response. In this model, direct subconjunctival injection of AdhENDO-VEGI 151 expressed the fusion protein in vivo and suppressed the development of CNV. Topical application of AdhENDO-VEGI 151 led to a significant suppression of CNV (F=1413.11, P=0.0001

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Modulation of Endothelial Cell Growth Arrest and Apoptosis by Vascular Endothelial Growth Inhibitor

Cited by 92 publications

References 29 publications

VEGI-192, a New Isoform of TNFSF15, Specifically Eliminates Tumor Vascular Endothelial Cells and Suppresses Tumor Growth

VEGI-192, a New Isoform of TNFSF15, Specifically Eliminates Tumor Vascular Endothelial Cells and Suppresses Tumor Growth

Involvement of RB gene family in tumor angiogenesis

Effects of endostatin-vascular endothelial growth inhibitor chimeric recombinant adenoviruses on antiangiogenesis

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