Inactivation of VEGFB Blocks Tumor Growth and Metastasis by Skewing Macrophages to M1 Phenotype

Abstract VEGFB has high sequence homology and shares receptor VEGFR1 with VEGFA and PlGF. However, its function is poorly understood. Using VEGFA repression (VegfaDown), VEGFB knockout (Vegfb−/−) and VEGFB over expression (aP2-Vegfb167, aP2-Vegfb186) mouse models, we identified VEGFB167 as a strong promoter of tumor growth. Universal Vegfb inactivation significantly retards tumor growth and metastasis of B16 and U14 cancer cells. VEGFB deletion led to an inactivation of VEGFR1 pathway, blocking of tumor-associated macrophage transformation towards M1 phenotype and creation of a microenvironment that represses tumor growth and metastasis. Genetic VEGFA repression showed reduced inhibitory effect on U14 and no effect on B16 tumor growth in comparison to VEGFB. The inhibitory effect by inactivating VEGFB on tumor growth and tumor cell metastasis is significantly better than VEGFA. The study demonstrates VEGFB is an oncogene and drug target for VEGFB-sensitive cancers.