Anti-angiogenesis therapy is one major approach of cancer therapies nowadays.
Unfortunately, anti-angiogenesis therapy targeting VEGF-A was recently stumbled by the drugresistance
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 VEGF121 and
VEGF165, which was connected by Fc region of human IgG1 to enhance dimerization. We found that
the treatment of VEGF121-VEGF165 chimeric protein reduces proliferation, migration, invasion, and
tube formation in endothelial and/or cancer cells through competing VEGF165 homodimer in a paracrine and an autocrine
manner. Furthermore, the fusion protein attenuated autocrine VEGFR2-HIF-1α-VEGF165/Lon signaling through PI3KAKT-
mTOR pathway in cancer cells. In conclusion, our data demonstrated that the chimeric VEGF121-VEGF165 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 VEGF121-VEGF165 targets not only
paracrine angiogenic cascade of endothelial cells but also autocrine PI3K-AKT-mTOR-mediated VEGFR2-HIF-1α-
VEGF165/Lon signaling that drives drug resistance in tumor cells. Our study will open up the patient opportunities to
combat drug resistance to antiangiogenic therapy.