Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 208, Issue 7, Pages 1351-1358Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20100951
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Funding
- Cancer Council of Victoria
- National Health and Medical Research Council (Canberra) [461221, 461299, 516703]
- National Institutes of Health [CA43540]
- Australian Research Council
- Leukemia and Lymphoma Society (Specialized Center of Research) [7413]
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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.
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