ALK1-Fc inhibits multiple mediators of angiogenesis and suppresses tumor growth.
Activin receptor-like kinase-1 (ALK1) is a type I, endothelial cell-specific member of the transforming growth factor-beta superfamily of receptors known to play an essential role in modulating angiogenesis and vessel maintenance. In the present study, we sought to examine the angiogenic and tumorigenic effects mediated upon the inhibition of ALK1 signaling using a soluble chimeric protein (ALK1-Fc). Of 29 transforming growth factor-beta-related ligands screened by surface plasmon resonance, only bone morphogenetic protein (BMP9) and BMP10 displayed high-affinity binding to ALK1-Fc. In cell-based assays, ALK1-Fc inhibited BMP9-mediated Id-1 expression in human umbilical vein endothelial cells and inhibited cord formation by these cells on a Matrigel substrate. In a chick chorioallantoic membrane assay, ALK1-Fc reduced vascular endothelial growth factor-, fibroblast growth factor-, and BMP10-mediated vessel formation. The growth of B16 melanoma explants was also inhibited significantly by ALK1-Fc in this assay. Finally, ALK1-Fc treatment reduced tumor burden in mice receiving orthotopic grafts of MCF7 mammary adenocarcinoma cells. These data show the efficacy of chimeric ALK1-Fc proteins in mitigating vessel formation and support the view that ALK1-Fc is a powerful antiangiogenic agent capable of blocking vascularization.
Mitchell
Dianne
D
Acceleron Pharma, Cambridge, MA 02139, USA.
Pobre
Eileen G
EG
Mulivor
Aaron W
AW
Grinberg
Asya V
AV
Castonguay
Roselyne
R
Monnell
Travis E
TE
Solban
Nicolas
N
Ucran
Jeffrey A
JA
Pearsall
R Scott
RS
Underwood
Kathryn W
KW
Seehra
Jasbir
J
Kumar
Ravindra
R
D030301:Activin Receptors, Type II / Q000378:metabolism*; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology; D055427:Growth Differentiation Factor 2 / Q000378:metabolism; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000378:metabolism
C541386:BMP10 protein, human; C119152:Bmp10 protein, mouse; D019485:Bone Morphogenetic Proteins; D055427:Growth Differentiation Factor 2; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II; C000591618:ALK1-Fc fusion protein, human