Targeting Vascular Endothelial Growth Factor in Patients With Squamous Cell Lung Cancer

Abstract

Vascular endothelial growth factors (VEGFs) and their receptors are primary regulators of physiologic and pathologic angiogenesis and lymphangiogenesis. There are five members of the VEGF family, including VEGF-A (or VEGF), VEGF-B, VEGF-C, VEGF-D, and placental growth factor, and three structurally related receptors: VEGFR-1, VEGFR-2, and VEGFR-3. VEGF produced from tumor cells induces activation of VEGF/VEGFR signaling axis, triggering several signaling pathways in endothelial cells and cancer cells, which leads to neovascularization and tumor development. Targeting antiangiogenesis has become a key therapeutic strategy for cancer treatment. Angiogenesis is regulated mainly by the binding of VEGF to VEGFR-2, which causes autophosphorylation in several tyrosine residues at the kinase domain and C-terminal tail, with activation of downstream pathways leading to endothelial cell proliferation, survival, migration, and permeability (Fig 1). The major VEGFR-2 phosphorylation sites are Tyr and Tyr, with the former creating a binding site for phospholipase C , SH-2 domain-containing adaptor protein B, and SHC-related adaptor protein, whereas the latter is involved in the activation of guanosine triphosphate binding protein cell division cycle 42 and p38 mitogen-activated protein kinase (MAPK). Phospholipase C activates the MAPK pathway through protein kinase C and Raf, leading to cell proliferation. Binding of SH-2 domain-containing adaptor protein B to VEGFR-2 Tyr causes VEGF-dependent phosphatidylinositol 3 -kinase activation, which increases endothelial cell survival through inhibition of proapoptotic B-cell lymphoma protein 2–associated death promoter and caspase 9 by its downstream effector Akt and increases expression of the antiapoptotic