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

Abstract

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.

Effect of FGF/FGFR pathway blocking on lung adenocarcinoma and its cancer‐associated fibroblasts

“…Tumour neoangiogensis requires VEGF, which is secreted in the tumour microenvironment. VEGF‐A activates VEGFR2 on nearby ECs to induce their sprouting into the tumour . VEGF‐independent angiogenesis has also been described .…”

Identification of a FGF18-expressing alveolar myofibroblast that is developmentally cleared during alveologenesis

“…Monocyte-derived phagocytes (alveolar macrophages and dendritic cells) are present in the lung throughout alveologenesis and contain lineage-labeled particles from alveolar myofibroblasts at least through postnatal day 31, suggesting a role in removal of dead alveolar myofibroblasts through a phagocytic process. (Oladipupo et al, 2018), rabbit anti-NG2 (1:200, MilliporeSigma; ab5320) (Kato et al, 2018), rat anti-CD68 (1:200, Bio-Rad, MCA1957) (Menon and Fisher, 2015), rat anti-F4/80 (1:100, Bio-Rad, MCA497R) (Hasan et al, 2013) and rabbit anti-Desmin (1:100, Abcam, ab8592) (Walton et al, 2016).…”

Regulation Networks Driving Vasculogenic Mimicry in Solid Tumors

“…VEGF signaling via tyrosine kinase receptor VEGF receptor 2 (Flk-1) has a critical role in tumor angiogenesis and promotion of VM in cancer (71,72). Blood vessels detected in the VM of glioblastoma cells are integrated by mural cell-lined vasculature.…”

“…Also, low miR-200a expression has been associated with tumor grade and metastasis (88). VEGF expression has been detected in hypoxic environments, and its secretion by tumor cells plays a crucial role in the tumor angiogenesis and VM formation (71,72). Salinas-Vera et al reported that miR-765 decreased VEGF expression after hypoxic conditions in ovarian cancer.…”