Anti-VEGF agents confer survival advantages to tumor-bearing mice by improving cancer-associated systemic syndrome.
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.
Xue
Yuan
Y
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
Religa
Piotr
P
Cao
Renhai
R
Hansen
Anker Jon
AJ
Lucchini
Franco
F
Jones
Bernt
B
Wu
Yan
Y
Zhu
Zhenping
Z
Pytowski
Bronislaw
B
Liang
Yuxiang
Y
Zhong
Weide
W
Vezzoni
Paolo
P
Rozell
Björn
B
Cao
Yihai
Y
D000740:Anemia / Q000503:physiopathology; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002199:Capillary Permeability; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000503:physiopathology; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A