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Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis

Members of the transforming growth factor β (TGF-β) family have been genetically linked to vascular formation during embryogenesis. However, contradictory studies about the role of TGF-β and other family members with reported vascular functions, such as bone morphogenetic protein (BMP) 9, in physiol...

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Autores principales: Cunha, Sara I., Pardali, Evangelia, Thorikay, Midory, Anderberg, Charlotte, Hawinkels, Lukas, Goumans, Marie-José, Seehra, Jasbir, Heldin, Carl-Henrik, ten Dijke, Peter, Pietras, Kristian
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812548/
https://www.ncbi.nlm.nih.gov/pubmed/20065063
http://dx.doi.org/10.1084/jem.20091309
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author Cunha, Sara I.
Pardali, Evangelia
Thorikay, Midory
Anderberg, Charlotte
Hawinkels, Lukas
Goumans, Marie-José
Seehra, Jasbir
Heldin, Carl-Henrik
ten Dijke, Peter
Pietras, Kristian
author_facet Cunha, Sara I.
Pardali, Evangelia
Thorikay, Midory
Anderberg, Charlotte
Hawinkels, Lukas
Goumans, Marie-José
Seehra, Jasbir
Heldin, Carl-Henrik
ten Dijke, Peter
Pietras, Kristian
author_sort Cunha, Sara I.
collection PubMed
description Members of the transforming growth factor β (TGF-β) family have been genetically linked to vascular formation during embryogenesis. However, contradictory studies about the role of TGF-β 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-β 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-F(c) 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-β 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-β family members in tumor angiogenesis and offer mechanistic insight for the forthcoming clinical development of drugs blocking ALK1 in oncology.
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spelling pubmed-28125482010-07-18 Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis Cunha, Sara I. Pardali, Evangelia Thorikay, Midory Anderberg, Charlotte Hawinkels, Lukas Goumans, Marie-José Seehra, Jasbir Heldin, Carl-Henrik ten Dijke, Peter Pietras, Kristian J Exp Med Article Members of the transforming growth factor β (TGF-β) family have been genetically linked to vascular formation during embryogenesis. However, contradictory studies about the role of TGF-β 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-β 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-F(c) 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-β 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-β family members in tumor angiogenesis and offer mechanistic insight for the forthcoming clinical development of drugs blocking ALK1 in oncology. The Rockefeller University Press 2010-01-18 /pmc/articles/PMC2812548/ /pubmed/20065063 http://dx.doi.org/10.1084/jem.20091309 Text en © 2010 Cunha et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Cunha, Sara I.
Pardali, Evangelia
Thorikay, Midory
Anderberg, Charlotte
Hawinkels, Lukas
Goumans, Marie-José
Seehra, Jasbir
Heldin, Carl-Henrik
ten Dijke, Peter
Pietras, Kristian
Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis
title Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis
title_full Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis
title_fullStr Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis
title_full_unstemmed Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis
title_short Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis
title_sort genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812548/
https://www.ncbi.nlm.nih.gov/pubmed/20065063
http://dx.doi.org/10.1084/jem.20091309
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