Anti-VEGF agents confer survival advantages to tumor-bearing mice by improving cancer-associated systemic syndrome
Abstract
The underlying mechanism by which anti-VEGF agents prolong cancer patient survival is poorly understood. We show that in a mouse tumor model, VEGF systemically impairs functions of multiple organs including those in the hematopoietic and endocrine systems, leading to early death. Anti-VEGF antibody, bevacizumab, and anti-VEGF receptor 2 (VEGFR-2), but not anti-VEGFR-1, reversed VEGF-induced cancer-associated systemic syndrome (CASS) and prevented death in tumor-bearing mice. Surprisingly, VEGFR2 blockage improved survival by rescuing mice from CASS without significantly compromising tumor growth, suggesting that "off-tumor" VEGF targets are more sensitive than the tumor vasculature to anti-VEGF drugs. Similarly, VEGF-induced CASS occurred in a spontaneous breast cancer mouse model overexpressing neu. Clinically, VEGF expression and CASS severity positively correlated in various human cancers. These findings define novel therapeutic targets of anti-VEGF agents and provide mechanistic insights into the action of this new class of clinically available anti-VEGF cancer drugs.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- November 2008
- DOI:
- 10.1073/pnas.0807967105
- Bibcode:
- 2008PNAS..10518513X
- Keywords:
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- angiogenesis;
- antiangiogenic therapy;
- cancer syndrome;
- tumor growth;
- VEGF;
- Biological Sciences:Medical Sciences