期刊
CURRENT CANCER DRUG TARGETS
卷 16, 期 3, 页码 275-286出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/156800961603160206125352
关键词
Anti-angiogenesis; drug resistance; hypoxia; lon; the chimeric fusion; VEGF(121)-VEGF(165)
类别
资金
- Ministry of Science and Technology [MOST103-2627-M-400-001, MOST103-2320-B-400-022-MY3]
- Ministry of Health and Welfare [MOHW103-TDU-212-114005]
- National Health Research Institutes, Taiwan [103A1-CA-PP-07, 104A1-CA-PP-07]
Anti-angiogenesis therapy is one major approach of cancer therapies nowadays. Unfortunately, anti-angiogenesis therapy targeting VEGF-A was recently stumbled by the drug-resistance that results from adaptive mechanisms, such as intratumor hypoxia. To obtain a more efficient therapeutic response, we created and identified a novel chimeric fusion of VEGF(121) and VEGF(165), which was connected by Fc region of human IgG1 to enhance dimerization. We found that the treatment of VEGF(121)-VEGF(165) chimeric protein reduces proliferation, migration, invasion, and tube formation in endothelial and/or cancer cells through competing VEGF(165) homodimer in a paracrine and an autocrine manner. Furthermore, the fusion protein attenuated autocrine VEGFR2-HIF-1 alpha-VEGF(165)/Lon signaling through PI3K-AKT-mTOR pathway in cancer cells. In conclusion, our data demonstrated that the chimeric VEGF(121)-VEGF(165) arrests the tube formation of endothelial cells and interferes with tumor cell growth, migration and invasion, suggesting that it could be a potential drug as an angiogenesis antagonist in cancer therapy. The VEGF(121)-VEGF(165) targets not only paracrine angiogenic cascade of endothelial cells but also autocrine PI3K-AKT-mTOR-mediated VEGFR2-HIF-1 alpha-VEGF(165)/Lon signaling that drives drug resistance in tumor cells. Our study will open up the patient opportunities to combat drug resistance to antiangiogenic therapy.
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