Figure 3.

Intracellular signaling pathways in lymphangiogenesis. Signaling via VEGF-C/D and VEGFR-3 is the most well-known pathway for lymphangiogenesis. VEGF-C or VEGF-D binds to its receptor VEGFR-3 in the plasma membrane of LyECs, which facilitates signal transduction through various intracellular signaling pathways, leading to lymphangiogenesis. In the liver, activated macrophages in chronic inflammatory conditions, such as chronic hepatitis and liver cirrhosis, secrete VEGF-C and/or VEGF-D. Malignant liver tumors, such as HCC and intrahepatic cholangiocarcinoma, also secrete VEGF-C and/or VEGF-D. Furthermore, these malignant tumors activate tumor-associated macrophages, which also secrete VEGF-C and/or VEGF-D. Secreted VEGF-C and VEGF-D are likely related to lymphangiogenesis in liver diseases through VEGFR-3–mediated pathways.