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Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):E9635-E9644. doi: 10.1073/pnas.1703431114. Epub 2017 Oct 23.

Off-tumor targets compromise antiangiogenic drug sensitivity by inducing kidney erythropoietin production.

Author information

1
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
2
Central Research Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, 266071, China.
3
Department of Hematology and Oncology, The Fourth Hospital of Jinan, Jinan, Shandong 250031, China.
4
Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, 171 77 Stockholm, Sweden.
5
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China.
6
Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, P. R. China; jpli3s@126.com baohongy@me.com qdfywxs@163.com yizhi_liu@aliyun.com yihai.cao@ki.se.
7
Wei Fang People's Hospital, Kui Wen District, Weifang, Shandong, China jpli3s@126.com baohongy@me.com qdfywxs@163.com yizhi_liu@aliyun.com yihai.cao@ki.se.
8
Central Research Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, 266071, China; jpli3s@126.com baohongy@me.com qdfywxs@163.com yizhi_liu@aliyun.com yihai.cao@ki.se.
9
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, China; jpli3s@126.com baohongy@me.com qdfywxs@163.com yizhi_liu@aliyun.com yihai.cao@ki.se.
10
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; jpli3s@126.com baohongy@me.com qdfywxs@163.com yizhi_liu@aliyun.com yihai.cao@ki.se.

Abstract

Anti-VEGF drugs are commonly used for treatment of a variety of cancers in human patients, and they often develop resistance. The mechanisms underlying anti-VEGF resistance in human cancer patients are largely unknown. Here, we show that in mouse tumor models and in human cancer patients, the anti-VEGF drug-induced kidney hypoxia augments circulating levels of erythropoietin (EPO). Gain-of-function studies show that EPO protects tumor vessels from anti-VEGF treatment and compromises its antitumor effects. Loss of function by blocking EPO function using a pharmacological approach markedly increases antitumor activity of anti-VEGF drugs through inhibition of tumor angiogenesis. Similarly, genetic loss-of-function data shows that deletion of EpoR in nonerythroid cells significantly increases antiangiogenic and antitumor effects of anti-VEGF therapy. Finally, in a relatively large cohort study, we show that treatment of human colorectal cancer patients with bevacizumab augments circulating EPO levels. These findings uncover a mechanism of desensitizing antiangiogenic and anticancer effects by kidney-produced EPO. Our work presents conceptual advances of our understanding of mechanisms underlying antiangiogenic drug resistance.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00957125.

KEYWORDS:

angiogenesis; drug resistance; erythropoietin; hematopoiesis; tumor

PMID:
29078273
PMCID:
PMC5692529
DOI:
10.1073/pnas.1703431114
[Indexed for MEDLINE]
Free PMC Article

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