Abstract
Metastasis is the main cause of mortality in cancer patients. Although there are many anti-cancer drugs targeting tumor growth, anti-metastatic agents are rarely developed. Angiogenesis and lymphangiogenesis are crucial for cancer progression; in particular, lymphangiogenesis is pivotal for metastasis in cancer. Here we report that lithium inhibits colon cancer metastasis by blocking lymphangiogenesis. Lithium reduces the expression of transforming growth factor-β-induced protein (TGFBIp) in colon cancer cells by inhibiting Smad3 phosphorylation via GSK3β inactivation. Moreover, lithium inhibits lymphatic endothelial cell migration, which is increased upon TGFBIp expression in tumor cells. Lithium had no significant effect on SW620 tumor growth in vitro and in vivo; however, it inhibited lymphangiogenesis in tumors. In tumor xenografts model, lithium was found to prevent metastasis to the lungs, liver, and lymph nodes by inhibiting TGFBIp-induced tumor lymphangiogenesis. Collectively, our findings demonstrate a novel role of lithium in the inhibition of colon cancer metastasis by blocking TGFBIp expression, and thereby TGFBIp-induced lymphangiogenesis, in primary tumors.
Highlights
Tumor lymphangiogenesis and metastasis to distant organs[8]
We suggested that TGFBIp exerts a stronger effect on lymphatic vessels than on blood vessels, and further that TGFBIp is a potential target to block tumor lymphangiogenesis and metastasis[8]
To assess the effect of lithium on TGFBIp expression in SW620 colon cancer cells, which highly expressed the TGFBIp protein[8,26], colon cancer cells were cultured with lithium carbonate, and TGFBIp expression was analyzed
Summary
Tumor lymphangiogenesis and metastasis to distant organs[8]. TGFBIp had a minor effect on migration, tube formation, and sprouting of human umbilical vein endothelial cells, and the inhibition of TGFBIp expression showed only weak anti-angiogenic activity[8]. Lithium inhibits lymphatic endothelial cell (LEC) migration induced by TGFBIp. we demonstrated that lithium has activity against lymphangiogenesis and angiogenesis, has no effect on the growth of a primary colon cancer tumor xenograft, and strongly inhibits its metastasis to the lungs, liver, and lymph nodes by blocking lymphangiogenesis in primary tumors. We demonstrated that lithium has activity against lymphangiogenesis and angiogenesis, has no effect on the growth of a primary colon cancer tumor xenograft, and strongly inhibits its metastasis to the lungs, liver, and lymph nodes by blocking lymphangiogenesis in primary tumors Taken together, these data suggest that lithium functions as an anti-tumor metastasis factor by inhibiting TGFBIp expression and TGFBIp-induced tumor lymphangiogenesis in primary tumors
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