The Wnt antagonist Dickkopf-1 increases endothelial progenitor cell angiogenic potential.
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.


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.


CONCLUSIONS
DKK1 enhances angiogenic properties of ECFCs in vitro and is required for ECFC and mesenchymal stem cell angiogenic phenotypes in vivo. DKK1 also increases tumoral angiogenesis. Thus, we demonstrated a major role of DKK1 in angiogenic processes.
Smadja
David M
DM
Université Paris Descartes, Paris, France. david.smadja@egp.aphp.fr
d'Audigier
Clément
C
Weiswald
Louis-Bastien
LB
Badoual
Cécile
C
Dangles-Marie
Virginie
V
Mauge
Laetitia
L
Evrard
Solène
S
Laurendeau
Ingrid
I
Lallemand
François
F
Germain
Stéphane
S
Grelac
Françoise
F
Dizier
Blandine
B
Vidaud
Michel
M
Bièche
Ivan
I
Gaussem
Pascale
P
D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D005312:Fetal Blood / Q000166:cytology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D010641:Phenotype; D034622:RNA Interference; D019718:Receptors, CXCR4 / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; C501126:DKK1 protein, human; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D051153:Wnt Proteins; D014841:von Willebrand Factor; D040301:Vascular Endothelial Growth Factor Receptor-2