ALK1-Fc inhibits multiple mediators of angiogenesis and suppresses tumor growth.

Abstract:

: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.

journal_name

Mol Cancer Ther

authors

Mitchell D,Pobre EG,Mulivor AW,Grinberg AV,Castonguay R,Monnell TE,Solban N,Ucran JA,Pearsall RS,Underwood KW,Seehra J,Kumar R

doi

10.1158/1535-7163.MCT-09-0650

subject

Has Abstract

pub_date

2010-02-01 00:00:00

pages

379-88

issue

2

eissn

1535-7163

issn

1538-8514

pii

1535-7163.MCT-09-0650

journal_volume

9

pub_type

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