Vascular Endothelial Growth Factor C (VEGF-C) is a PDGF/VEGF family protein. It plays a significant role in the formation and upkeep of the body’s vascular and lymphatic systems. The VEGFC gene, located on chromosome 4q34, encodes this protein. VEGF-C functions as a signaling molecule.
Normal Functions of VEGF-C
VEGF-C primarily promotes the growth of new lymphatic vessels, a process known as lymphangiogenesis. It acts on lymphatic endothelial cells, mainly through its receptor VEGFR-3, supporting their survival, growth, and migration. This function is particularly active during embryonic development when the lymphatic system is first forming.
VEGF-C also contributes to maintaining the integrity of existing lymphatic vessels. It helps regulate tissue fluid balance by ensuring proper drainage of interstitial fluid from tissues back into the bloodstream.
VEGF-C also influences immune cell trafficking. It helps facilitate the organized movement of immune cells within the lymphatic network, which surveys the body for pathogens and abnormal cells.
While its main role is in the lymphatic system, VEGF-C can also promote the growth of blood vessels, known as angiogenesis, and regulate their permeability. This secondary effect on blood vessels can be mediated by both its primary receptor VEGFR-3 and its secondary receptor VEGFR-2.
VEGF-C in Health Conditions
Cancer Metastasis
Elevated levels of VEGF-C can significantly impact cancer progression, particularly in lymphatic metastasis. Tumors often produce increased amounts of VEGF-C, which stimulates the growth of new lymphatic vessels in and around the tumor. This increased lymphatic network provides a pathway for cancer cells to escape the primary tumor.
The newly formed lymphatic vessels act as conduits, allowing cancer cells to spread to regional lymph nodes. High VEGF-C expression in primary tumors correlates with increased lymph node metastasis and a poorer prognosis in various cancers, including thyroid, prostate, gastric, colorectal, and lung cancers.
VEGF-C can also interact with tumor cells directly, as some cancer cells express VEGF receptors like VEGFR-2 and VEGFR-3, enabling them to receive autocrine signals that promote aggressive phenotypes. Tumor-associated macrophages also contribute to increased VEGF-C in the tumor microenvironment, further aiding cancer progression. Immune cells like natural killer (NK) cells can also receive VEGF-C signals, potentially leading to immune suppressive functions that favor tumor growth.
Lymphedema
Impaired VEGF-C signaling or issues with lymphatic vessel development can lead to lymphedema, a condition characterized by swelling due to the buildup of lymphatic fluid. Primary lymphedema results from genetic or developmental abnormalities in the lymphatic system, where a lack of functional lymphatic vessels can be caused by inactivating mutations in pathways essential for lymphatic development, such as those involving VEGF-C and VEGFR3.
Secondary lymphedema often arises from damage to previously healthy lymphatic vessels, commonly occurring after cancer treatments like surgery or radiation therapy. In these cases, the lymphatic system’s ability to drain fluid is compromised, leading to chronic swelling. While VEGF-C levels may increase in response to lymphatic injury in lymphedema, this elevation often fails to repair the lymphatic damage effectively, and in some instances, can even exacerbate the condition by promoting less efficient drainage and inflammation.
Other Conditions
Beyond cancer and lymphedema, VEGF-C also has emerging roles in other health conditions. For example, it is involved in neural development and blood pressure regulation. Altered VEGF-C expression has been observed in certain inflammatory diseases, where it can influence fluid drainage and immune cell trafficking, contributing to the inflammatory response.
In cardiovascular issues, stimulating lymphangiogenesis with recombinant VEGF-C has shown promise in improving inflammation resolution and heart function in models of ischemic hearts. This suggests a broader involvement of VEGF-C in maintaining tissue health and responding to injury across different organ systems.
Targeting VEGF-C for Treatment
Understanding VEGF-C’s roles in disease has led to targeted therapeutic strategies. One primary approach involves inhibiting the VEGF-C/VEGFR-3 pathway to curb disease progression. This strategy is particularly relevant in cancer, where blocking VEGF-C activity or its receptor (VEGFR-3) can reduce lymphatic metastasis.
Therapeutic interventions aim to disrupt the interaction between VEGF-C and its receptors. This can be achieved through various mechanisms, such as using monoclonal antibodies that specifically bind to and neutralize VEGF-C. Other approaches involve small molecules that inhibit the kinase activity of VEGFR-3, preventing the receptor from transmitting signals even when VEGF-C is present.
Conversely, in conditions like lymphedema, where lymphatic function is compromised, promoting lymphangiogenesis through VEGF-C modulation is a promising avenue. Stimulating VEGF-C activity or delivering the protein itself can encourage the growth of new, functional lymphatic vessels, helping to restore proper fluid drainage. For instance, gene therapy involving the transfer of plasmid DNA encoding human VEGF-C has shown potential in animal models of secondary lymphedema, leading to improved lymphatic vessel formation and reduced swelling.
Ongoing research continues to explore new ways to modulate VEGF-C for therapeutic benefit. This includes investigating the combined use of anti-VEGF-C therapies with other treatments to enhance efficacy, especially in cancer. Additionally, studies are exploring the potential of utilizing stem cells, which can secrete lymphangiogenic factors like VEGF-C, to promote lymphatic regeneration in damaged tissues.