VEGFD and cancer: VEGFR-3, activated by VEGF-C and VEGF-D, contributes relatively independently to lymphatic vessel formation.170,171 Activated VEGFR-3 mediates the differentiation, migration, proliferation and survival of lymphatic endothelial cells by activating the RAS/MAPK/ERK pathway and the PI3K–AKT/PKB pathway.169–171 Although the VEGFR-3 expression level in tumor cells remains controversial, high levels of VEGF-C and VEGF-D have been observed in tumors with lymphatic metastasis, which is considered a potential explanation for cancer migration through lymphatic vessels.172