ANGPT2 and cancer: VEGF-targeted therapies for resistant cancers, including CRC associated with resistance to bevacizumab, show an increasingly controlled proliferation and progression in preclinical studies upon targeting of both VEGF and angiopoietin-2; in fact, the angiopoietin/TIE (tyrosine kinase with Ig-like and EGF-like domains) signaling RTK pathway, involved in vascular formation and stabilization by mediating the downstream RAS/RAF and PI3K/AKT pathways, is negatively regulated by angiopoietin-2 [65,66,67,68].