Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis.
Members of the transforming growth factor beta (TGF-beta) family have been genetically linked to vascular formation during embryogenesis. However, contradictory studies about the role of TGF-beta and other family members with reported vascular functions, such as bone morphogenetic protein (BMP) 9, in physiological and pathological angiogenesis make the need for mechanistic studies apparent. We demonstrate, by genetic and pharmacological means, that the TGF-beta and BMP9 receptor activin receptor-like kinase (ALK) 1 represents a new therapeutic target for tumor angiogenesis. Diminution of ALK1 gene dosage or systemic treatment with the ALK1-Fc fusion protein RAP-041 retarded tumor growth and progression by inhibition of angiogenesis in a transgenic mouse model of multistep tumorigenesis. Furthermore, RAP-041 significantly impaired the in vitro and in vivo angiogenic response toward vascular endothelial growth factor A and basic fibroblast growth factor. In seeking the mechanism for the observed effects, we uncovered an unexpected signaling synergy between TGF-beta and BMP9, through which the combined action of the two factors augmented the endothelial cell response to angiogenic stimuli. We delineate a decisive role for signaling by TGF-beta family members in tumor angiogenesis and offer mechanistic insight for the forthcoming clinical development of drugs blocking ALK1 in oncology.
Cunha
Sara I
SI
Department of Medical Biochemistry and Biophysics, Division of Matrix Biology, Karolinska Institutet, Stockholm SE-171 77, Sweden.
Pardali
Evangelia
E
Thorikay
Midory
M
Anderberg
Charlotte
C
Hawinkels
Lukas
L
Goumans
Marie-José
MJ
Seehra
Jasbir
J
Heldin
Carl-Henrik
CH
ten Dijke
Peter
P
Pietras
Kristian
K
D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D018628:Gene Dosage / Q000235:genetics; D055427:Growth Differentiation Factor 2 / Q000235:genetics / Q000378:metabolism; D055412:Growth Differentiation Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
C525887:GDF2 protein, human; C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D055412:Growth Differentiation Factors; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016222:Fibroblast Growth Factor 2; C425364:ACVRL1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498931:Acvrl1 protein, mouse