Destruction of tumor vasculature and abated tumor growth upon VEGF blockade is driven by proapoptotic protein Bim in endothelial cells

• Published in: The Journal of experimental medicine Vol. 208; no. 7; pp. 1351 - 1358
• Main Authors: Naik, Edwina, O'Reilly, Lorraine A, Asselin-Labat, Marie-Liesse, Merino, Delphine, Lin, Ann, Cook, Michele, Coultas, Leigh, Bouillet, Philippe, Adams, Jerry M, Strasser, Andreas
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 04.07.2011
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - physiology; Apoptosis Regulatory Proteins - deficiency; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - physiology; Bcl-2-Like Protein 11; Brief Definitive Report; Carcinoma, Lewis Lung - blood supply; Carcinoma, Lewis Lung - drug therapy; Carcinoma, Lewis Lung - pathology; Carcinoma, Lewis Lung - physiopathology; Cell Line, Tumor; Endothelial Cells - drug effects; Endothelial Cells - pathology; Endothelial Cells - physiology; Ganciclovir - pharmacology; Gene Expression - drug effects; Melanoma, Experimental - blood supply; Melanoma, Experimental - drug therapy; Melanoma, Experimental - pathology; Melanoma, Experimental - physiopathology; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - physiology; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Thymidine Kinase - genetics; Thymidine Kinase - metabolism; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - deficiency; Vascular Endothelial Growth Factor A - genetics
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20100951

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.