TY - JOUR
T1 - Anti-VEGF agents confer survival advantages to tumor-bearing mice by improving cancer-associated systemic syndrome
AU - Xue, Yuan
AU - Religa, Piotr
AU - Cao, Renhai
AU - Hansen, Anker Jon
AU - Lucchini, Franco
AU - Jones, Bernt
AU - Wu, Yan
AU - Zhu, Zhenping
AU - Pytowski, Bronislaw
AU - Liang, Yuxiang
AU - Zhong, Weide
AU - Vezzoni, Paolo
AU - Rozell, Björn
AU - Cao, Yihai
PY - 2008/11/25
Y1 - 2008/11/25
N2 - 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-VEGFagentsandprovide mechanistic insights into the action of this new class of clinically available anti-VEGF cancer drugs.
AB - 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-VEGFagentsandprovide mechanistic insights into the action of this new class of clinically available anti-VEGF cancer drugs.
KW - Angiogenesis
KW - Antiangiogenic therapy
KW - Cancer syndrome
KW - Tumor growth
KW - VEGF
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U2 - 10.1073/pnas.0807967105
DO - 10.1073/pnas.0807967105
M3 - Article
C2 - 19017793
AN - SCOPUS:57449113426
VL - 105
SP - 18513
EP - 18518
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 47
ER -