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.
Highlights
Vascular endothelial growth factor C (VEGF-C) has been identified as a multifaceted factor participating in the regulation of tumor angiogenesis and lymphangiogenesis
A study further demonstrated that treatment with anti-Nrp2 antibody results in a reduction of Nrp2/VEGF receptor complex formation [70]. These results indicated that an interaction of VEGF-C with VEGF receptor-2 (VEGFR-2) or VEGF receptor-3 (VEGFR-3) as well as neuropilins can be important for lymphangiogenesis and angiogenesis
The VEGF-C signaling through both VEGFR-2 and VEGFR-3 plays a critical role in cancer progression by regulating lymphangiogenesis and angiogenesis
Summary
Vascular endothelial growth factor (VEGF) was originally characterized as vascular permeability factor (VPF) because of its unique capability of inducing vascular leakage [1]. VEGF-C, due to its central roles in lymphangiogenesis and angiogenesis in embryos and tumors, is an important member of the VEGF family [9,10,11,12,13]. After the signal sequence has been removed, two VEGF-C precursors are held together by intermolecular disulfide bonds to form an antiparallel homodimer. This dimer undergoes a series of proteolytic processes that increase the protein binding affinity to VEGFR-3 and VEGFR-2. The effect of VEGF-C in liquid and solid tumors has been reported to induce angiogenesis [28,29]
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