Curcumin Inhibits Lymphangiogenesis in vitro and in vivo through Suppressing VEGF Receptor Signaling

Curcumin, a major curcuminoid of turmeric, has been shown to inhibit tumor growth and metastasis; while the underlying mechanisms are not well understood. Here we investigated the effects of curcumin on lymphangiogenesis (de novo formation of lymphatic vessels), which is a critical process implicated in tumor metastasis. Our results showed that curcumin inhibited lymphangiogenesis in vitro and in vivo, through suppressing vascular endothelial growth factor (VEGF) receptor signaling. Curcumin inhibited VEGF‐C‐induced infiltration of LYVE‐1‐positive lymphatic endothelial cells in a Matrigel plug assay in mice, demonstrating its anti‐lymphangiogenic effects in vivo. In human dermal microvascular lymphatic endothelial cells (HMVEC‐dLy), curcumin inhibited multiple lymphangiogenic responses, including cell proliferation, migration and capillary‐like tube formation in a dose‐dependent manner. Curcumin inhibited lymphangiogenesis, through suppressing the expressions of VEGF receptors (VEGFR2 and VEGFR3), and phosphorylation of downstream signaling proteins such as ERK and FAK. Finally, curcumin sulfate and curcumin glucuronide, two major metabolites of curcumin, had little effect on lymphangiogenic responses in HMVEC‐dLy cells. Together, our results demonstrate that curcumin inhibited lymphangiogenesis in vitro and in vivo through suppressing VEGF receptor signaling, suggesting a novel mechanism for the anti‐metastatic effects of curcumin.