Overall, to the best of our knowledge, this is the first study that investigates the mechanism of EGFL7 in a co-culture system mimicking osteosarcoma, and we determined that EGFL7 siRNA interfered with osteosarcoma tumor cells and could attenuate the migration, adhesion, and angiogenesis of HUVEC with the participation of the PI3K-Akt pathway and VEGF. The gene discussed is VEGFA; the disease is neoplasm.