ALK1-Fc Inhibits Multiple Mediators of Angiogenesis and Suppresses Tumor Growth
| Autor: | Ravindra Kumar, Roselyne Castonguay, Travis E. Monnell, Jasbir Seehra, Kathryn W. Underwood, Dianne C. Mitchell, Aaron W. Mulivor, Eileen Pobre, R. Scott Pearsall, Nicolas Solban, Jeffrey A. Ucran, Asya Grinberg |
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| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
medicine.medical_specialty Angiogenesis Activin Receptors Type II Recombinant Fusion Proteins CHO Cells Biology Vascular endothelial growth inhibitor Fibroblast growth factor Mice chemistry.chemical_compound Cricetulus Cricetinae Neoplasms Internal medicine Growth Differentiation Factor 2 medicine Animals Humans Growth factor receptor inhibitor Matrigel Neovascularization Pathologic Endothelial Cells Surface Plasmon Resonance Immunoglobulin Fc Fragments Cell biology Vascular endothelial growth factor Endocrinology Oncology chemistry Vascular endothelial growth factor C Bone Morphogenetic Proteins Telangiectasia Hereditary Hemorrhagic Endothelium Vascular Transforming growth factor |
| Zdroj: | Molecular Cancer Therapeutics. 9:379-388 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | Activin receptor–like kinase-1 (ALK1) is a type I, endothelial cell–specific member of the transforming growth factor-β 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-β–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. Mol Cancer Ther; 9(2); 379– |
| Databáze: | OpenAIRE |
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