Background. Immunosuppressive therapy is a risk factor for the increased incidence and metastatic progression of malignancies in organ graft recipients. Transforming growth factor (TGF)-β1 has been associated with tumor invasion and metastasis, and we have implicated cyclosporine-associated TGF-β1 hyperexpression in tumor progression in mice. Methods. BALB/c mice or severe combined immunodeficient-beige mice were treated with 2 or 4 mg/kg of tacrolimus, and the effect of treatment on mouse renal cancer cell pulmonary metastasis was investigated. We also determined whether tacrolimus induces TGF-β1 expression. Spleens from tacrolimus-treated mice were analyzed for level of expression of TGF-β 1 mRNA with the use of competitive-quantitative polymerase chain reaction assay, and circulating levels of TGF-β1 protein were measured with the use of an enzyme-linked immunosorbent assay. Results. Treatment with tacrolimus resulted in a dose-dependent increase in the number of pulmonary metastases in the BALB/c mice (197±16 in untreated mice, 281±26 in mice treated with 2 mg/kg of tacrolimus, and 339±25 in mice treated with 4 mg/kg of tacrolimus; no treatment vs. 4 mg/kg tacrolimus, Bonferroni's P<0.001) and in the severe combined immunodeficient-beige mice (117±18 in untreated mice, 137±19 in mice treated with 2 mg/kg of tacrolimus, and 216±29 in mice treated with 4 mg/kg of tacrolimus; no treatment vs. 4 mg/kg tacrolimus, P<0.05). Treatment with 4 mg/kg but not 2 mg/kg of tacrolimus resulted in a significant increase in the levels of expression of TGF-β1 mRNA and circulating levels of TGF-β1 protein. Conclusions. Tacrolimus has a dose-dependent effect on tumor progression and TGF-β1 expression, and tacrolimus-induced TGF-β1 overexpression may be a pathogenetic mechanism in tumor progression.
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