ArticleProceedings of the National Academy of Sciences of the United States of America2017
Off-tumor targets compromise antiangiogenic drug sensitivity by inducing kidney erythropoietin production.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 17 citations in OpenAlex.
- Inhibition of Endothelial HIF-1α by IDF-11774 Attenuates Retinal Neovascularization and Vascular Leakage.Investigative ophthalmology & visual science · 2025Article
- Anti-angiogenic tyrosine kinase inhibitors and the pathophysiology of their toxic effects: revisiting the treatment of anemia in metastatic cancers.Experimental hematology & oncology · 2025Article
- Injectable thermosensitive hydrogel loading erythropoietin and FK506 alleviates gingival inflammation and promotes periodontal tissue regeneration.Frontiers in bioengineering and biotechnology · 2023Article
- ENO1 expression and Erk phosphorylation in PDAC and their effects on tumor cell apoptosis in a hypoxic microenvironment.Cancer biology & medicine · 2022Article
- Lenvatinib for effectively treating antiangiogenic drug-resistant nasopharyngeal carcinoma.Cell death & disease · 2022Article
- Kallistatin prevents ovarian hyperstimulation syndrome by regulating vascular leakage.Journal of cellular and molecular medicine · 2022Article
- Targeting Stress Erythropoiesis Pathways in Cancer.Frontiers in physiology · 2022Review
- Improved indocyanine green retention after short-term lenvatinib withdrawal in three patients with hepatocellular carcinoma.Clinical journal of gastroenterology · 2021Article
- Twist1 accelerates tumour vasculogenic mimicry by inhibiting Claudin15 expression in triple-negative breast cancer.Journal of cellular and molecular medicine · 2020Article
- Article
- M2 macrophages mediate sorafenib resistance by secreting HGF in a feed-forward manner in hepatocellular carcinoma.British journal of cancer · 2019Article
- VEGF expands erythropoiesis via hypoxia-independent induction of erythropoietin in noncanonical perivascular stromal cells.The Journal of experimental medicine · 2019Article
Corrections and comments
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Authors and funding
19 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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