Targeting Neuropilin-1 to Inhibit VEGF Signaling in Cancer: Comparison of Therapeutic Approaches
Figure 1
Schematics of VEGF Transport in Tumors, VEGF Receptor Binding, and Therapeutic Strategies
(A) Schematic of the in vivo model. Parenchymal cells secrete VEGF; VEGF121 is freely diffusible, but VEGF165 can be sequestered by proteoglycans in the ECM (light gray) and the basement membranes (dark gray). The isoforms bind to VEGF receptors on the endothelial cells.
(B) VEGF isoforms bind to VEGFR2 that transduces the angiogenic signal intracellularly. VEGF121 does not bind Neuropilin-1; VEGF165 may bind both VEGFR2 and Neuropilin-1 simultaneously. Thus there are two pathways for the binding of VEGF165 to the signaling VEGFR2 receptor: first by binding directly, and second by binding Neuropilin-1 and then diffusing laterally on the cell surface to couple to VEGFR2. VEGFR1, which modulates the signaling of VEGFR2, binds both isoforms of VEGF. VEGFR1 also binds directly to Neuropilin-1. This complex is permissive for VEGF121–VEGFR1 binding but not VEGF165–VEGFR1; thus, high levels of Neuropilin-1 displace VEGF165 from VEGFR1, making it available for VEGFR2 binding. Only VEGF165 binds directly to the ECM binding site (represented by GAG chains).
(C) By targeting Neuropilin-1, we can target specifically VEGF165-induced signaling. Three methods for targeting Neuropilin-1 are analyzed here: blockade of Neuropilin-1 expression (e.g., using siRNA); blockade of VEGF–Neuropilin binding (e.g., using a fragment of placental growth factor to occupy the binding site); and blockade of VEGFR–Neuropilin coupling (e.g., using an antibody for Neuropilin-1 that does not interfere with VEGF–Neuropilin binding).