Tacrolimus Enhances Transforming Growth Factor-

Background. Immunosuppressive therapy is a risk factor for the increased incidence and metastatic progression of malignancies in organ graft recipients. Transforming growth factor (TGF)1 has been associated with tumor invasion and metastasis, and we have implicated cyclosporine-associated TGF1 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 TGF1 expression. Spleens from tacrolimus-treated mice were analyzed for level of expression of TGF1 mRNA with the use of competitive-quantitative polymerase chain reaction assay, and circulating levels of TGF1 protein were measured with the use of an enzyme-linked immunosorbent assay. Results. Treatment with tacrolimus resulted in a dosedependent 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 TGF1 mRNA and circulating levels of TGF1 protein. Conclusions. Tacrolimus has a dose-dependent effect on tumor progression and TGF1 expression, and tacrolimus-induced TGF1 overexpression may be a pathogenetic mechanism in tumor progression.