The Wnt Antagonist Dickkopf-1 Increases Endothelial Progenitor Cell Angiogenic Potential

Abstract

Objective-To determine the role of Wnt antagonist Dickkopf (DKK) 1 in human endothelial colony-forming cells (ECFCs) in view of the emerging importance of Wnt pathways in vascular biology. Methods and Results-Endothelial progenitor cells have been proposed to be crucial in tumor neovascularization.Recombinant DKK1 has been tested in ECFC angiogenic properties in vitro. DKK1 enhanced ECFC proliferation and the capacity of ECFCs to form pseudotubes in Matrigel. These effects have been attributed to enhancement of vascular endothelial growth factor receptor 2, SDF-1, and CXCR4. DKK1 gene silencing has been realized on ECFCs and mesenchymal stem cells, and we found that DKK1 silencing in the 2 cell types decreased their angiogenic potential. We then examined the possible role of DKK1 in tumor neovasculogenesis and found that blood vessels of breast cancer tissues expressed DKK1 far more strongly in human breast tumors than in normal breast tissues. By studying 62 human breast tumors, we found a significant positive correlation between DKK1 expression and von Willebrand factor. In vivo, DKK1 strongly enhanced the vascularization of Matrigel plugs and increased tumor size in a xenograft model of human breast carcinoma in nude mice. W ingless related proteins (Wnts) are powerful regulators of cell proliferation and differentiation, and their signaling pathway involves proteins that participate directly in both gene transcription and cell adhesion. 1 The major signaling pathway of Wnt is the canonical pathway that results from Wnt binding to the frizzled and low-densitylipoprotein-receptor-related protein (LRP) families on the cell surface. Complex formation induces ␤-catenin nuclear entry and forms a complex with transcription factor T cell factor (TCF) and/or lymphoid enhancer factor (LEF) to activate transcription of Wnt target genes. The Wnt pathway is modulated by several Wnt antagonists, including Dickkopfs (DKKs). 2 The DKK family encodes secreted proteins of 255 to 350 amino acids and comprises 4 main members in vertebrates (DKK1 to DKK4). DKK1, the most widely studied member of this family, has been implicated in various physiological and pathological processes in human adults. DKK1 mediates inflammation in atherosclerotic lesions 3 and mobilizes progenitor cells by activating the bone marrow endosteal stem cell niche. 4 Recently, serum levels of DKK1 correlated with the extent of bone disease in patients with multiple malignant neoplasms, such as breast cancer. 5 In tumoral angiogenesis, endothelial cells have distinct gene expression profiles when compared with normal endothelial cells. Notably, they express high levels of DKK3. 6,7 However, the role of DKK1 in tumoral angiogenesis and postnatal vasculogenesis by endothelial progenitor cells (EPCs) has not yet been studied. Conclusion-DKK1 enhances angiogenic properties of ECFCs in vitro and is required for ECFCBone marrow-derived cells have been shown to contribute to tumor neovasculature. 8,9 The active cell population in bone marrow-derived cells has...

Increased plasma VEGF levels following ischemic preconditioning are associated with downregulation of miRNA-762 and miR-3072-5p

“…Beneficial effects of anti-inflammatory agents have been reported for spinal cord injury3132, and these effects are in accordance with increased mRNA expression levels of anti-inflammatory, angiogenic, and ischemia resistance genes in CD34-positive BM cells than in CD34-negative BM cells333435363738394041. In particular, GDF15, Dkk1, IL33, and FGF9 mRNA expression levels were more than 10-fold higher in CD34-positive than in CD34-negative BM cells.…”

Distinct roles of DKK1 and DKK2 in tumor angiogenesis

“…The discrepancy between glioma tumor results and our B16F10 tumor data may be explained by the complexity of Wnt signaling components and different DKK1 delivery methods. Some papers suggest that blocking Wnt signaling induces angiogenesis [33, 34]. Other papers demonstrated that Wnts, including Wnt3a and Wnt5a, stimulate proliferation and enhance tube formation of cultured human ECs [5, 35–37].…”

A Decrease in DKK1, a WNT Inhibitor, Contributes to Placental Lipid Accumulation in an Obesity-Prone Rat Model1

“…In a pregnant mouse model, DKK1 was highly expressed in the maternal decidual compartment, a culture of decidual cells in the presence of antisense DKK1 decreased trophoblast invasiveness, and treatment with antisense b-catenin increased trophoblast attachment and invasiveness, suggesting that an increase in WNT signaling may prevent decidualization and trophoblast cell invasion [70]. The inhibitive role of WNT signaling on vascularization in association with decreased DKK1 has been shown in cases of diabetic retinopathy [71], in human umbilical vein endothelial cells [72], and in human breast tumors [73]. Our data suggest that a decrease in DKK1 leading to aberrant WNT signaling results in ''fatty'' placentas with less decidual/junctional thickness and, therefore, a decrease in placental efficiency.…”