Vascular endothelial growth factors (VEGFs) are the key regulators of vasculogenesis
in normal and oncological development. VEGF-A is the most studied angiogenic factor
secreted by malignant tumor cells under hypoxic and inflammatory stress, which made
VEGF-A a rational target for anticancer therapy. However, inhibition of VEGF-A by
monoclonal antibody drugs led to the upregulation of VEGF-D. VEGF-D was primarily
described as a lymphangiogenic factor; however, VEGF-D’s blood angiogenic potential
comparable to VEGF-A has already been demonstrated in glioblastoma and colorectal
carcinoma. These findings suggested a role for VEGF-D in facilitating malignant tumor
growth by bypassing the anti-VEGF-A antiangiogenic therapy. Owing to its high mitogenic
ability, higher affinity for VEGFR-2, and higher expression in cancer, VEGF-D might
even be a stronger angiogenic driver and, hence, a better therapeutic target than
VEGF-A. In this review, we summarized the angiogenic role of VEGF-D in blood vasculogenesis
and its targetability as an antiangiogenic therapy in cancer.
