The role of the VEGF-C/VEGFRs axis in tumor progression and therapy

Abstract

Vascular endothelial growth factor C (VEGF-C) has been identified as a multifaceted factor participating in the regulation of tumor angiogenesis and lymphangiogenesis. VEGF-C is not only expressed in endothelial cells, but also in tumor cells. VEGF-C signaling is important for progression of various cancer types through both VEGF receptor-2 (VEGFR-2) and VEGF receptor-3 (VEGFR-3). Likewise, both receptors are expressed mainly on endothelial cells, but also expressed in tumor cells. The dimeric VEGF-C undergoes a series of proteolytic cleavage steps that increase the protein binding affinity to VEGFR-3; however, only complete processing, removing both the N- and C-terminal propeptides, yields mature VEGF-C that can bind to VEGFR-2. The processed VEGF-C can bind and activate VEGFR-3 homodimers and VEGFR-2/VEGFR-3 heterodimers to elicit biological responses. High levels of VEGF-C expression and VEGF-C/VEGFRs signaling correlate significantly with poorer prognosis in a variety of malignancies. Therefore, the development of new drugs that selectively target the VEGF-C/VEGFRs axis seems to be an effective means to potentiate anti-tumor therapies in the future.

Figure 1

Schematic outline of the interactions of vascular endothelial growth factor C (VEGF-C) with its receptors and co-receptors leading to biological effects in tumor progression. VEGF-C can be proteolytically processed, and the mature form allows binding to VEGF receptor-2 (VEGFR-2) and increased affinity for VEGFR-3. VEGF-C expression is modulated by different manners. Binding of the dimeric VEGF-C stimulates receptor dimerization, leading to the formation of VEGFR-3/VEGFR-3 homodimers and VEGFR-2/VEGFR-3 heterodimers, which is implicated in lymphangiogenesis and angiogenesis, respectively. VEGFR Ig-like domains are involved in VEGF binding as indicated by the loop numbers in the figure. The complex network of intracellular signal transduction pathways results in tumor progression. The clinical significance of the VEGF-C/VEGFRs axes has been described in a variety of malignancies.