期刊
CELL REPORTS
卷 36, 期 7, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2021.109549
关键词
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类别
资金
- NIH [UH3TR000943, P50CA217685, R35CA209904, P30CA016672, ACN15006-001]
- National Cancer Institute
- Pacific Northwest National Laboratory (PNNL)
- Ovarian Cancer Research Alliance
- Blanton-Davis Ovarian Cancer Research Program
- American Cancer Society Research Professor Award
- Frank McGraw Memorial Chair in Cancer Research
- Foundation for Women's Cancer Research grant [FP00009883]
- Sprint for Life Research Award
- MD Anderson Ovarian Cancer Moon Shot Program
- NIH institutional training grant [5T32CA009599]
- Cancer Prevention & Research Institute of Texas Research Training Program [RP101502, RP140106, RP170067]
- NIH Partnership for Excellence in Cancer Research [U54CA096300/U54CA096297]
- NIH/NCI [P30CA016672, DE-AC05-76RL01830, NIHP30CA016672, P30CA16672]
- NIH Common Fund's exRNA Communication Program
Research shows that cancer-derived small extracellular vesicles package increased VEGF and other factors in response to anti-VEGF therapy, potentially leading to drug resistance. These small EV-VEGF are not targeted by antibodies, triggering intracrine VEGF signaling in endothelial cells, promoting tumor angiogenesis and growth despite treatment.
Despite wide use of anti-vascular endothelial growth factor (VEGF) therapy for many solid cancers, most individuals become resistant to this therapy, leading to disease progression. Therefore, new biomarkers and strategies for blocking adaptive resistance of cancer to anti-VEGF therapy are needed. As described here, we demonstrate that cancer-derived small extracellular vesicles package increasing quantities of VEGF and other factors in response to anti-VEGF therapy. The packaging process of VEGF into small extracellular vesicles (EVs) ismediated by the tetraspanin CD63. Furthermore, small EV-VEGF (eVEGF) is not accessible to anti-VEGF antibodies and can trigger intracrine VEGF signaling in endothelial cells. eVEGF promotes angiogenesis and enhances tumor growth despite bevacizumab treatment. These data demonstrate a mechanism where VEGF is partitioned into small EVs and promotes tumor angiogenesis and progression. These findings have clinical implications for biomarkers and therapeutic strategies for ovarian cancer.
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