Secreted frizzle-related protein 2 stimulates angiogenesis via a calcineurin/NFAT signaling pathway.
Secreted frizzle-related protein 2 (SFRP2), a modulator of Wnt signaling, has recently been found to be overexpressed in the vasculature of 85% of human breast tumors; however, its role in angiogenesis is unknown. We found that SFRP2 induced angiogenesis in the mouse Matrigel plug assay and the chick chorioallantoic membrane assay. SFRP2 inhibited hypoxia induced endothelial cell apoptosis, increased endothelial cell migration, and induced endothelial tube formation. The canonical Wnt pathway was not affected by SFRP2 in endothelial cells; however, a component of the noncanonical Wnt/Ca2+ pathway was affected by SFRP2 as shown by an increase in NFATc3 in the nuclear fraction of SFRP2-treated endothelial cells. Tacrolimus, a calcineurin inhibitor that inhibits dephosphorylation of NFAT, inhibited SFRP2-induced endothelial tube formation. Tacrolimus 3 mg/kg/d inhibited the growth of SVR angiosarcoma xenografts in mice by 46% (P = 0.04). In conclusion, SFRP2 is a novel stimulator of angiogenesis that stimulates angiogenesis via a calcineurin/NFAT pathway and may be a favorable target for the inhibition of angiogenesis in solid tumors.
Courtwright
Andrew
A
Departments of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Siamakpour-Reihani
Sharareh
S
Arbiser
Jack L
JL
Banet
Natalie
N
Hilliard
Eleanor
E
Fried
Levi
L
Livasy
Chad
C
Ketelsen
David
D
Nepal
Desh Bandhu
DB
Perou
Charles M
CM
Patterson
Cam
C
Klauber-Demore
Nancy
N
D000818:Animals; D019703:Calcineurin / Q000378:metabolism / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D005260:Female; D006394:Hemangiosarcoma / Q000139:chemically induced / Q000473:pathology; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D050778:NFATC Transcription Factors / Q000378:metabolism / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000094742:Secreted Frizzled-Related Proteins
D019703:Calcineurin; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D034741:RNA, Small Interfering; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins