Destruction of tumor vasculature and abated tumor growth upon VEGF blockade is driven by proapoptotic protein Bim in endothelial cells
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
Rights Notice
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Creation Date: 2011-07-04 12:00:00
Last Modified: 0001-01-01 12:00:00
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