Destruction of tumor vasculature and abated tumor growth upon VEGF blockade is driven by proapoptotic protein Bim in endothelial cells
- Author(s)
- Naik, E; O'Reilly, LA; Asselin-Labat, ML; Merino, D; Lin, A; Cook, M; Coultas, L; Bouillet, P; Adams, JM; Strasser, A;
- Details
- Publication Year 2011-07-04,Volume 208,Issue #7,Page 1351-1358
- Journal Title
- JOURNAL OF EXPERIMENTAL MEDICINE
- Publication Type
- Journal Article
- Abstract
- For malignant growth, solid cancers must stimulate the formation of new blood vessels by producing vascular endothelial growth factor (VEGF-A), which is required for the survival of tumor-associated vessels. Novel anticancer agents that block VEGF-A signaling trigger endothelial cell (EC) apoptosis and vascular regression preferentially within tumors, but how the ECs die is not understood. In this study, we demonstrate that VEGF-A deprivation, provoked either by drug-induced tumor shrinkage or direct VEGF-A blockade, up-regulates the proapoptotic BH3 (Bcl-2 homology 3)-only Bcl-2 family member Bim in ECs. Importantly, the tumor growth inhibitory activity of a VEGF-A antagonist required Bim-induced apoptosis of ECs. These findings thus reveal the mechanism by which VEGF-A blockade induces EC apoptosis and impairs tumor growth. They also indicate that drugs mimicking BH3-only proteins may be exploited to kill tumor cells not only directly but also indirectly by ablating the tumor vasculature.
- Publisher
- ROCKEFELLER UNIV PRESS
- Keywords
- BCL-2 FAMILY; APOPTOTIC RESPONSES; REQUIRES BIM; SOLID TUMORS; BH3 MIMETICS; EXPRESSION; INHIBITOR; HOMEOSTASIS; XENOGRAFTS; MEMBER
- Publisher's Version
- https://doi.org/10.1084/jem.20100951
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2011-07-04 12:00:00