Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 45, Pages E9635-E9644Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1703431114
Keywords
tumor; angiogenesis; erythropoietin; drug resistance; hematopoiesis
Categories
Funding
- European Research Council Advanced Grant ANGIOFAT [250021]
- Swedish Research Council
- Swedish Cancer Foundation
- Karolinska Institute Foundation
- Torsten Soderbergs Foundation
- Maud and Birger Gustavsson Foundation
- NOVO Nordisk Foundation
- Knut and Alice Wallenbergs foundation
- Karolinska Institute distinguished professor award
- Swedish Cancer Foundation Fellowship
- Novo Nordisk Fonden [NNF14OC0012835] Funding Source: researchfish
- European Research Council (ERC) [250021] Funding Source: European Research Council (ERC)
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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.
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