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Secreted Frizzle-Related Protein 2 Stimulates Angiogenesis via a Calcineurin/NFAT Signaling Pathway

Departments of ¹ Surgery, ² Pathology, and ³ Genetics, ⁴ Lineberger Comprehensive Cancer Center, and ⁵ Carolina Cardiovascular Biology Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina and ⁶ Department of Dermatology, Emory University School of Medicine and Atlanta VA Medical Center, Atlanta, Georgia

Requests for reprints: Nancy Klauber-DeMore, University of North Carolina at Chapel Hill, 170 Manning Drive, Physician's Office Building, CB 7213, Chapel Hill, NC 27599. Phone: 919-966-8007; Fax: 919-966-8806; E-mail: nancy_demore{at}med.unc.edu.

Key Words: breast cancer • angiosarcoma • tumor endothelial marker • tacrolimus • endothelial cells

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. [Cancer Res 2009;69(11):4621–8]