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

Edwina Naik, Lorraine A. O'Reilly, Marie-Liesse Labat, Delphine Merino, Ann Lin, Michele Cook, Leigh Coultas, Philippe Bouillet, Jerry M. Adams, Andreas Strasser

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1351-1358
Number of pages8
JournalJournal of Experimental Medicine
Volume208
Issue number7
DOIs
StatePublished - Jul 4 2011
Externally publishedYes

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Vascular Endothelial Growth Factor A
Endothelial Cells
Growth
Neoplasms
Proteins
Apoptosis
Pharmaceutical Preparations
Antineoplastic Agents
Blood Vessels
Up-Regulation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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Destruction of tumor vasculature and abated tumor growth upon VEGF blockade is driven by proapoptotic protein Bim in endothelial cells. / Naik, Edwina; O'Reilly, Lorraine A.; Labat, Marie-Liesse; Merino, Delphine; Lin, Ann; Cook, Michele; Coultas, Leigh; Bouillet, Philippe; Adams, Jerry M.; Strasser, Andreas.

In: Journal of Experimental Medicine, Vol. 208, No. 7, 04.07.2011, p. 1351-1358.

Research output: Contribution to journalArticle

Naik, E, O'Reilly, LA, Labat, M-L, Merino, D, Lin, A, Cook, M, Coultas, L, Bouillet, P, Adams, JM & Strasser, A 2011, 'Destruction of tumor vasculature and abated tumor growth upon VEGF blockade is driven by proapoptotic protein Bim in endothelial cells', Journal of Experimental Medicine, vol. 208, no. 7, pp. 1351-1358. https://doi.org/10.1084/jem.20100951
Naik, Edwina ; O'Reilly, Lorraine A. ; Labat, Marie-Liesse ; Merino, Delphine ; Lin, Ann ; Cook, Michele ; Coultas, Leigh ; Bouillet, Philippe ; Adams, Jerry M. ; Strasser, Andreas. / Destruction of tumor vasculature and abated tumor growth upon VEGF blockade is driven by proapoptotic protein Bim in endothelial cells. In: Journal of Experimental Medicine. 2011 ; Vol. 208, No. 7. pp. 1351-1358.
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