VEGF-C

Official Full Name

vascular endothelial growth factor C

Organism

Homo sapiens

GeneID

7424

Background

The protein encoded by this gene is a member of the platelet-derived growth factor/vascular endothelial growth factor (PDGF/VEGF) family. The encoded protein promotes angiogenesis and endothelial cell growth, and can also affect the permeability of blood vessels. The proprotein is further cleaved into a fully processed form that can bind and activate VEGFR-2 and VEGFR-3 receptors. [provided by RefSeq, Apr 2014]

Synonyms

VRP; Flt4-L; LMPH1D; LMPHM4;

Bio Chemical Class

Growth factor

Protein Sequence

MHLLGFFSVACSLLAAALLPGPREAPAAAAAFESGLDLSDAEPDAGEATAYASKDLEEQLRSVSSVDELMTVLYPEYWKMYKCQLRKGGWQHNREQANLNSRTEETIKFAAAHYNTEILKSIDNEWRKTQCMPREVCIDVGKEFGVATNTFFKPPCVSVYRCGGCCNSEGLQCMNTSTSYLSKTLFEITVPLSQGPKPVTISFANHTSCRCMSKLDVYRQVHSIIRRSLPATLPQCQAANKTCPTNYMWNNHICRCLAQEDFMFSSDAGDDSTDGFHDICGPNKELDEETCQCVCRAGLRPASCGPHKELDRNSCQCVCKNKLFPSQCGANREFDENTCQCVCKRTCPRNQPLNPGKCACECTESPQKCLLKGKKFHHQTCSCYRRPCTNRQKACEPGFSYSEEVCRCVPSYWKRPQMS

Open

Disease

Retinopathy, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

2 +

Discontinued Drug

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Detailed Information

Vascular Endothelial Growth Factor C (VEGFC) is located on human chromosome 4q34.3 and belongs to the PDGF/VEGF growth factor family. The gene encodes a precursor protein that undergoes complex proteolytic processing to achieve full biological activity. The initially synthesized VEGFC precursor is an immature 58–60 kDa form, which is gradually cleaved by enzymes such as plasmin, urokinase-type plasminogen activator (uPA), and tissue proteinase D, ultimately forming a 21–23 kDa mature dimer. The mature VEGFC protein consists of two identical monomers linked by disulfide bonds and retains the cystine knot motif characteristic of VEGF family members. Importantly, the extent of VEGFC proteolysis determines receptor specificity: fully processed VEGFC efficiently activates VEGFR2 and VEGFR3, whereas partially processed forms primarily interact with VEGFR3.

VEGFC expression is regulated by multiple transcription factors and signaling pathways. Pro-inflammatory cytokines such as TNF-α and IL-1β can upregulate VEGFC, reflecting how inflammatory microenvironments promote lymphangiogenesis. Oncogenic mutations and tumor suppressor gene alterations also modulate VEGFC transcription through distinct mechanisms. Hypoxia, a hallmark of solid tumor microenvironments, indirectly influences VEGFC via HIF-1α-dependent pathways. At the post-transcriptional level, microRNAs including miR-31, miR-128, and miR-182 target VEGFC mRNA, fine-tuning its expression in both physiological lymphatic development and pathological lymphatic proliferation.

Biological Functions and Signaling Mechanisms

VEGFC is a selective lymphatic endothelial cell stimulator that primarily signals through VEGFR3 (Flt4). Upon receptor binding, VEGFR3 undergoes tyrosine phosphorylation, initiating the signaling cascade that regulates lymphangiogenesis. During embryonic development, VEGFC is essential for the formation of primitive lymph sacs and the establishment of the lymphatic network. Genetic knockout studies demonstrate that Vegfc-deficient mice exhibit embryonic lethality due to complete lymphatic absence. In adult tissues, VEGFC supports lymphatic endothelial cell survival and differentiation, maintaining the structural integrity and functional homeostasis of lymphatic vessels.

Figure 1. VEGF-A/VEGFR-2 signaling pathways. (Melincovici CS, et al., 2018)

In addition to lymphatic regulation, VEGFC contributes to angiogenesis, particularly in venous vasculature, although its effect on blood vessels is weaker compared with lymphangiogenesis. VEGFC-mediated lymphangiogenesis involves sequential cellular processes: increasing lymphatic endothelial permeability to promote fluid and protein extravasation, stimulating endothelial cell migration, proliferation, and survival to guide lymphatic sprouting, and ultimately forming new lymphatic vessels that remodel into functional networks. Newly formed lymphatic vessels are often immature and hyperpermeable, facilitating tumor cell entry and metastasis. VEGFC also plays roles in nervous system development, cardiovascular regulation, immune cell trafficking, and lipid metabolism, highlighting its broader biological significance.

Clinical Pathological Significance

VEGFC expression is closely associated with lymphatic metastasis in various solid tumors. Elevated VEGFC levels are frequently observed in tumor tissues compared with normal or benign counterparts. Its overexpression correlates with advanced tumor stage, lymph node involvement, and poor prognosis, supporting its role as a molecular marker of tumor progression and metastatic potential. In addition to its structural contribution to lymphatic expansion, VEGFC can actively attract tumor cells by inducing chemokine secretion from lymphatic endothelial cells, further facilitating metastatic spread.

Targeted Therapeutic Strategies and Prospects

Given the central role of the VEGFC/VEGFR3 signaling axis in lymphatic metastasis, targeting this pathway has emerged as a promising anti-metastatic approach. Strategies include monoclonal antibodies against VEGFC or VEGFR3, small-molecule tyrosine kinase inhibitors, soluble receptor decoys, and gene-silencing techniques. Preclinical studies demonstrate that blocking VEGFR3 or suppressing VEGFC expression reduces lymphangiogenesis and metastatic dissemination, providing a foundation for clinical translation.

A major challenge in VEGFC-targeted therapy is balancing efficacy with physiological lymphatic function. Chronic inhibition of VEGFR3 can impair lymphatic homeostasis, causing tissue edema and compromised immunity. Consequently, next-generation approaches focus on spatial and temporal regulation, such as localized drug delivery, conditionally activated antibodies, and optimized dosing regimens. Combination therapies, including VEGFC inhibitors with immunotherapy, are being explored to simultaneously block metastatic pathways and enhance anti-tumor immune responses.

Challenges and Future Directions

Development of VEGFC-targeted therapies faces dual challenges: preserving normal lymphatic function and overcoming potential resistance mechanisms. Tumor cells may evade therapy by upregulating alternative lymphangiogenic factors or activating bypass signaling pathways. Future research priorities include the development of bispecific antibodies targeting VEGFC and additional metastasis-related pathways, tumor-targeted nanodelivery systems to improve local drug concentration, identification of predictive biomarkers for personalized therapy, and early intervention strategies to prevent micro-metastatic lymphatic remodeling before stable metastatic channels form.

Reference

Melincovici CS, Boşca AB, Şuşman S, et al. Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom J Morphol Embryol. 2018;59(2):455-467.
Pérez-Gutiérrez L, Ferrara N. Biology and therapeutic targeting of vascular endothelial growth factor A. Nat Rev Mol Cell Biol. 2023 Nov;24(11):816-834.

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