Identification of a Wnt-Responsive Signal Transduction Pathway in Primary Endothelial Cells

Wright, Meredith; Aikawa, Mina; Szeto, Wayne; Papkoff, Jackie

doi:10.1006/bbrc.1999.1344

Cited by 116 publications

(107 citation statements)

References 37 publications

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“…Tumors treated with WIF1 demonstrated a marked decrease in CD31 protein (Figure 6a) and a significant decrease in the number of vessels per microscopic field when compared with vector ( Figure 6d). WNT1, one of the Wnt ligands inhibited by extracellular WIF1 binding, has been shown to stimulate the proliferation of human endothelial cells (Wright et al, 1999). In xenograft tumors treated with vector, WNT1 was observed as a moderate or strong cytoplasmic brown staining (Figure 6b).…”

Section: Wif1 Downregulates Wnt1 and Vegf And Inhibits Angiogenesismentioning

confidence: 99%

“…Several factors might contribute to this clinically relevant anti-angiogenic role of WIF1 such as: (1) a decrease in VEGF transcription caused by a decrease in nuclear b-catenin, a known promoter of angiogenesis by an increase in VEGF expression (Skurk et al, 2005); (2) a decrease in VEGF half-life because of a decrease in CD44, a well-established proteolysis inhibitor of VEGF (Jones et al, 2000); (3) an increase in p53 expression, as the loss of p53 has been correlated with an increased VEGF expression and tumor angiogenesis (Linderholm et al, 2001); (4) a decrease in WNT1, a protein shown to stimulate the proliferation and angiogenic functions of human endothelial cells (Wright et al, 1999;Gherghe et al, 2011); and (5) a decrease in the endothelial cell-cell adhesion molecule CD31, a protein required for neovascularization (DeLisser et al, 1997). In early-stage cervical cancer, CD31 expression is significantly associated with lymphatic vascular space invasion and tumor size (Silva-Filho et al, 2006).…”

Section: Wif1 Inhibits Cervical Cancer Growth and Invasion I Ramachanmentioning

confidence: 99%

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Wnt inhibitory factor 1 induces apoptosis and inhibits cervical cancer growth, invasion and angiogenesis in vivo

et al. 2011

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Aberrant activation of Wingless-type (Wnt)/b-catenin signaling is widespread in human cervical cancer. However, the underlying mechanisms of Wnt activation and the therapeutic potential of Wnt inhibition remain largely unknown. Here, we demonstrate that the Wnt inhibitory factor 1 (WIF1), a secreted Wnt antagonist, is downregulated in all human primary cervical tumors and cell lines analyzed. Our data reveal that WIF1 downregulation occurs due to promoter hypermethylation and is an early event in cervical oncogenesis. WIF1 re-expression upon 5-aza-2 0 -deoxycytidine treatment or WIF1 gene transfer induces significant apoptosis and G 2 /M arrest, and inhibits cervical cancer cell proliferation in vitro. Consistent with this, treatment of established mice tumor xenografts with peritumoral WIF1 gene transfer results in a significant inhibition of cancer growth and invasion. WIF1 treatment causes a significant decrease in intracellular WNT1 and TCF-4 proteins revealing novel Wnt-regulatory mechanisms. Thus, WIF1 causes a major cellular re-distribution of b-catenin and a significant inhibition of the Wnt/b-catenin pathway in tumor cells, as documented by a remarkable reversion in the expression of Wnt/b-catenin transcriptional target genes (E-cadherin, c-Myc, cyclin D1, CD44 and VEGF). Consequently, multiple critical events in tumor progression and metastasis such as cell proliferation, angiogenesis and invasion were inhibited by WIF1. In addition, WIF1 modulated the expression of specific anti-apoptotic and apoptotic proteins, thereby inducing significant apoptosis in vivo. Our findings demonstrate for the first time that WIF1 downregulation by epigenetic gene silencing is an important mechanism of Wnt activation in cervical oncogenesis. Of major clinical relevance, we show that peritumoral WIF1 gene transfer reduces not only cancer growth but also invasion in well-established tumors. Therefore, our data provide novel mechanistic insights into the role of WIF1 in cervical cancer progression, and the important preclinical validation of WIF1 as a potent drug target in cervical cancer treatment.

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Section: Wif1 Downregulates Wnt1 and Vegf And Inhibits Angiogenesismentioning

confidence: 99%

Section: Wif1 Inhibits Cervical Cancer Growth and Invasion I Ramachanmentioning

confidence: 99%

Wnt inhibitory factor 1 induces apoptosis and inhibits cervical cancer growth, invasion and angiogenesis in vivo

et al. 2011

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“…Expression of Wnt ligands, such as Wnt-5a, Wnt-7a, Wnt10b, and Wnt-13, has been observed in human and mouse microvascular endothelial cells in vitro (33)(34)(35). Fz-4, Fz-5, and Fz-6 are expressed in human umbilical vein endothelial cells (HUVECs) (34).…”

Section: Canonical Wnt Signaling In Vascular Endothelial Cellsmentioning

confidence: 99%

“…Ectopic expression of Wnts in endothelial cells in vitro elicits cellular responses critical for angiogenesis. Ectopic overexpression of Wnt-1, a canonical Wnt ligand, in mouse brain microvascular endothelial cells increases cellular proliferation (33). LacZ staining in transgenic mice expressing LacZ gene under the control of the b-catenin-TCF/Lef complex-responsive element reveals the detectable activation in the vasculature during embryonic development (36).…”

Section: Canonical Wnt Signaling In Vascular Endothelial Cellsmentioning

confidence: 99%

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

et al. 2012

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SummaryThe Wnt signaling pathway is involved in a wide range of developmental and physiological processes, such as cell fate specification, tissue morphogenesis, and homeostasis. Thus, its dysregulation has been found in multiple diseases, including some cardiovascular disorders. The loss or gain of function of Wnt pathway components results in abnormal vascular development and angiogenesis. Further study has revealed that Wnt signaling in endothelial cells appears to contribute to vascular morphogenesis and endothelial cell specification. Owing to the significance of Wnt signaling in angiogenesis, Wnt antagonists have been considered potential treatments for neovascular disorders. In line with this, members of the Dkk protein family (Dkks), well-known Wnt antagonists, have been recently found to regulate angiogenesis. This review summarizes our present knowledge of the roles of Wnt signaling and Wnt antagonists, particularly Dkks, in angiogenic regulation and explores the therapeutic potential of Wnt antagonists.

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“…For example, expression of Wnt5a in zebra fish or Xenopus embryos can stimulate intracellular Ca 2ϩ fluxes (Slusarski et al, 1997), and Wnt5a regulates morphogenetic movements during gastrulation independently of canonical signaling (Kilian et al, 2003). Consistent with noncanonical signaling, ectopic overexpression of Wnt5a in human primary endothelial cells did not stabilize cytosolic ␤-catenin or activate ␤-catenin/ TCF-mediated transcription (Wright et al, 1999;Masckauchan et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Wnt5a Signaling Induces Proliferation and Survival of Endothelial Cells In Vitro and Expression of MMP-1 and Tie-2

Masckauchán

Agalliu

Vorontchikhina

et al. 2006

MBoC

197

162

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Wnts are lipid-modified secreted glycoproteins that regulate diverse biological processes. We report that Wnt5a, which functions in noncanonical Wnt signaling, has activity on endothelial cells. Wnt5a is endogenously expressed in human primary endothelial cells and is expressed in murine vasculature at several sites in mouse embryos and tissues. Expression of exogenous Wnt5a in human endothelial cells promoted angiogenesis. Wnt5a induced noncanonical Wnt signaling in endothelial cells, as measured by Dishevelled and ERK1/2 phosphorylation, and inhibition of canonical Wnt signaling, a known property of Wnt5a. Wnt5a induced endothelial cell proliferation and enhanced cell survival under serum-deprived conditions. The Wnt5a-mediated proliferation was blocked by Frizzled-4 extracellular domain. Wnt5a expression enhanced capillary-like network formation, whereas reduction of Wnt5a expression decreased network formation. Reduced Wnt5a expression inhibited endothelial cell migration. Screening for Wnt5a-regulated genes in cultured endothelial cells identified several encoding angiogenic regulators, including matrix metalloproteinase-1, an interstitial collagenase, and Tie-2, a receptor for angiopoietins. Thus, Wnt5a acts through noncanonical Wnt signaling to promote angiogenesis.

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Identification of a Wnt-Responsive Signal Transduction Pathway in Primary Endothelial Cells

Cited by 116 publications

References 37 publications

Wnt inhibitory factor 1 induces apoptosis and inhibits cervical cancer growth, invasion and angiogenesis in vivo

Wnt inhibitory factor 1 induces apoptosis and inhibits cervical cancer growth, invasion and angiogenesis in vivo

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

Wnt5a Signaling Induces Proliferation and Survival of Endothelial Cells In Vitro and Expression of MMP-1 and Tie-2

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