Impaired tumor growth and angiogenesis in mice heterozygous for Vegfr2 (Flk1).

VEGF signaling through its tyrosine kinase receptor, VEGFR2 (FLK1), is critical for tumor angiogenesis. Previous studies have identified a critical gene dosage effect of VegfA in embryonic development and vessel homeostasis, neovascularization, and tumor growth, and potent inhibitors of VEGFR2 have been used to treat a variety of cancers. Inhibition of FGFR signaling has also been considered as an antiangiogenic approach to treat a variety of cancers. Inhibition of VEGFR2 with neutralizing antibodies or with pharmacological inhibitors of the VEGFR tyrosine kinase domain has at least short-term efficacy with some cancers; however, also affects vessel homeostasis, leading to adverse complications. We investigate gene dosage effects of Vegfr2, Fgfr1, and Fgfr2 in three independent mouse models of tumorigenesis: two-stage skin chemical carcinogenesis, and sub-cutaneous transplantation of B16F0 melanoma and Lewis Lung Carcinoma (LLC). Mice heterozygous for Vegfr2 display profound defects in supporting tumor growth and angiogenesis. Unexpectedly, additional deletion of endothelial Fgfr1 and Fgfr2 in Vegfr2 heterozygous mice shows similar tumor growth and angiogenesis as the Vegfr2 heterozygous mice. Notably, hematopoietic deletion of two alleles of Vegfr2 had minimal impact on tumor growth, with little effect on angiogenesis, reinforcing the importance of endothelial Vegfr2 heterozygosity. These studies reveal previously unrecognized Vegfr2 gene dosage effects in tumor angiogenesis and a lack of synergy between VEGFR2 and endothelial FGFR1/2 signaling during tumor growth.