Figure 5.

VEGF and Notch interaction in physiological and tumor angiogenesis. Notch controls tip/stalk endothelial cells balance in tight cooperation with VEGF. 1. VEGF may be produced by cancer cells, for example, in breast cancer cells, leptin through IL-1 and Notch1, induces VEGF/VEGFR-2 upregulation (190), or by the neighboring cells of the tumor microenvironment (TME). VEGF engages VEGFR2/3 and neuropilin 1 (Nrp1) receptors on endothelial cells, activating a signaling that promotes Dll4 expression and determines the differentiation toward a tip cell type. Dll4 expressed on tip cells triggers Notch signaling in the neighboring cells suppressing the tip cell phenotype and inducing the differentiation in stalk cell. Notch activation in stalk cells either decreases VEGFR1/2/3 expression or stimulates antiangiogenic soluble splice variant of VEGFR1 (sVEGFR1) leading to a reduced sensitivity to VEGF (213). Oppositely to Dll4, Jagged1 expressed by stalk cells antagonizes Dll4-mediated Notch signaling in stalk cells, thereby increasing tip cell number and sprouting (214). 2. B-cell lymphoma cells release FGF4 that engages FGFR1 on the endothelial cells. FGFR1 activation induces Jagged1 upregulation that, in turn, triggers Notch2 signaling in lymphoma cells promoting their proliferation, tumor aggressiveness, and chemoresistance (215). 3. Notch1 signaling in endothelial cells may be activated by tumor-derived ligands, i.e., Jagged1 and Dll4 expressed by lung carcinoma and melanoma cells, or by Jagged1 expressed by neutrophils. Notch1 activation promotes endothelial cell senescence and expression of the adhesion molecule, VCAM1, that promotes neutrophil infiltration and tumor cell metastasis (216). 4. In models of tumor dormancy of colorectal carcinoma and T cell acute lymphoblastic leukemia (T-ALL) it was shown that Dll4 expressed on tumor endothelial cells can trigger Notch3 pathway activation in tumor cells conferring tumorigenic properties to the dormant cells (217).