Niclosamide: An Established Antihelminthic Drug as a Potential Therapy Against S100A4-Mediated Metastatic Colon Tumors

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Progression of cancers because of the ability of primary tumor cells to grow outside their local environment and spread to distant sites (metastasize) is a major problem and a major cause of death from cancers. Patients with non-metastatic local stage I tumor have a 5-year survival rate of 90%, which drops to approximately 10% in patients with distant metastasis at the time of diagnosis. Therefore, it is important to identify genes that mediate metastasis and develop effective therapies against these potential targets.

S100A4 is a small calcium-binding protein of 101 amino acids in length that shows elevated expression in various cancers, including colon, breast, gastric, lung, colon, and liver, and is associated with metastasis ( 1 , 2 ). High levels of S100A4 expression are associated with poor prognosis, presumably because of its effect on metastasis formation ( 1 , 2 ). Studies in experimental mouse models have demonstrated that overexpression of S100A4 is capable of inducing metastasis and highly invasive primary tumors ( 3 , 4 ). S100A4 itself is not tumorigenic because transgenic mice expressing high levels of S100A4 do not develop tumors per se ( 3 ). However, when transgenic mice expressing high levels of S100A4 are mated with mice expressing mouse mammary tumor virus (MMTV) promoter-driven NEU (rodent ortholog of HER2) and exhibiting spontaneous tumor formation, the resulting female progeny expressing both S100A4 and NEU shows increased invasiveness of primary tumors and the appearance of metastasis in the lungs compared with littermates expressing only NEU ( 4 ). Furthermore, S100A4-null mice injected with highly metastatic mouse carcinoma cells show no metastasis ( 5 ). Thus, S100A4 appears to play a critical function in metastasis. Although the molecular mechanism underlying the prometastatic function of S100A4 is not fully understood, S100A4 has been shown to affect a number of cellular features associated with metastasis including epithelial–mesenchymal transition, enhanced migration and invasion, cell adhesion, angiogenesis, and survival ( 1 , 2 ). Given the potential role of S100A4 in mediating metastasis of human cancers, targeted therapies against the expression of S100A4 might be useful in treating tumors that show high S100A4 expression.