Blocking ephrinB2 with highly specific antibodies inhibits angiogenesis, lymphangiogenesis, and tumor growth
| Autor: | Joaquim Soriano, Sergio de Frutos, Sergio Ferreiro, Antonio Rodríguez, Jorge L. Martínez-Torrecuadrada, Marta Cañamero, Marco Marenchino, David Olmeda, Manuel Pérez-Martínez, Sagrario Ortega, María Angeles Abéngozar, Diego Megías |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Angiogenesis
Immunology Down-Regulation Mice Nude Ephrin-B2 Mice SCID Biology Biochemistry Antibodies Neovascularization Mice Antibody Specificity Neoplasms medicine Human Umbilical Vein Endothelial Cells Tumor Cells Cultured Ephrin Animals Humans Amino Acid Sequence Molecular Targeted Therapy Lymphangiogenesis Neovascularization Pathologic Erythropoietin-producing hepatocellular (Eph) receptor Cell Biology Hematology Actin cytoskeleton Molecular biology Xenograft Model Antitumor Assays Endothelial stem cell Vascular endothelial growth factor A HEK293 Cells Cancer research Female Immunotherapy medicine.symptom |
| Zdroj: | Blood. 119(19) |
| ISSN: | 1528-0020 |
| Popis: | Membrane-anchored ephrinB2 and its receptor EphB4 are involved in the formation of blood and lymphatic vessels in normal and pathologic conditions. Eph/ephrin activation requires cell-cell interactions and leads to bidirectional signaling pathways in both ligand- and receptor-expressing cells. To investigate the functional consequences of blocking ephrinB2 activity, 2 highly specific human single-chain Fv (scFv) Ab fragments against ephrinB2 were generated and characterized. Both Ab fragments suppressed endothelial cell migration and tube formation in vitro in response to VEGF and provoked abnormal cell motility and actin cytoskeleton alterations in isolated endothelial cells. As only one of them (B11) competed for binding of ephrinB2 to EphB4, these data suggest an EphB-receptor–independent blocking mechanism. Anti-ephrinB2 therapy reduced VEGF-induced neovascularization in a mouse Matrigel plug assay. Moreover, systemic administration of ephrinB2-blocking Abs caused a drastic reduction in the number of blood and lymphatic vessels in xenografted mice and a concomitant reduction in tumor growth. Our results show for the first time that specific Ab-based ephrinB2 targeting may represent an effective therapeutic strategy to be used as an alternative or in combination with existing antiangiogenic drugs for treating patients with cancer and other angiogenesis-related diseases. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|