VEGF-VEGFR Signals in Health and Disease

Abstract

Vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) system has been shown to play central roles not only in physiological angiogenesis, but also in pathological angiogenesis in diseases such as cancer. Based on these findings, a variety of anti-angiogenic drugs, including anti-VEGF antibodies and VEGFR/multi-receptor kinase inhibitors have been developed and approved for the clinical use. While the clinical efficacy of these drugs has been clearly demonstrated in cancer patients, they have not been shown to be effective in curing cancer, suggesting that further improvement in their design is necessary. Abnormal expression of an endogenous VEGF-inhibitor sFlt-1 has been shown to be involved in a variety of diseases, such as preeclampsia and aged macular degeneration. In addition, various factors modulating angiogenic processes have been recently isolated. Given this complexity then, extensive studies on the interrelationship between VEGF signals and other angiogenesis-regulatory systems will be important for developing future strategies to suppress diseases with an angiogenic component.

Keywords: Angiogenic signals; Anti-Angiogenic therapy; VEGF; VEGF receptor.

Fig. 1.

VEGF-VEGFR system: a crucial regulator of angiogenesis and lymphangiogenesis. Genes encoding all VEGF family members except VEGF-E are present in the mammalian genome. Abnormally high or low expression of sFlt-1 correlates with a variety of diseases.

Fig. 2.

A summary of the clinical use of anti-angiogenic therapy. Anti VEGF neutralizing antibodies (Bevacizumab, Ranibizumab), VEGF₁₆₅-neutralizing RNA aptamer (Pegaptanib), VEGFR1-R2 fusion peptide (VEGF-A-Trap) and VEGFR/multi TK inhibitors (Sorafenib, Sunitinib, etc.) were approved for clinical use. Bevacizumab and VEGFR/multi TK inhibitors are for the treatment of cancer. Others are for the treatment of AMD.

Fig. 3.

Hypothetical response of tumors to anti-angiogenic therapy. The double stresses of hypoxia and low nutrition in tumor cells after anti-angiogenic therapy, might result in the acquisition of resistance to drugs.

Fig. 4.

Anti-tumor angiogenesis therapy: is targeting VEGF signals effective in later stages of cancer? The clinical efficacy of anti VEGF signal drugs may decrease in later stages of cancer, prompting the search for novel anti-angiogenic drugs.

Fig. 5.

sFlt-1 (soluble VEGF receptor-1) is important for the maintenance of the photoreceptor avascular area in the eye. AMD (aged macular degeneration) is characterized by a decrease in sFlt-1 levels, resulting in increased in VEGF levels and inappropriate angiogenesis (Luo et al., 2013).