Tacrolimus enhances transforming growth factor-beta1 expression and promotes tumor progression.
BACKGROUND
Immunosuppressive therapy is a risk factor for the increased incidence and metastatic progression of malignancies in organ graft recipients. Transforming growth factor (TGF)-beta(1) has been associated with tumor invasion and metastasis, and we have implicated cyclosporine-associated TGF-beta(1) 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-beta(1) expression. Spleens from tacrolimus-treated mice were analyzed for level of expression of TGF-beta(1) mRNA with the use of competitive-quantitative polymerase chain reaction assay, and circulating levels of TGF-beta(1) 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-beta(1) mRNA and circulating levels of TGF-beta(1) protein.


CONCLUSIONS
Tacrolimus has a dose-dependent effect on tumor progression and TGF-beta(1) expression, and tacrolimus-induced TGF-beta(1) overexpression may be a pathogenetic mechanism in tumor progression.
Maluccio
Mary
M
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
Sharma
Vijay
V
Lagman
Mila
M
Vyas
Shefali
S
Yang
Hua
H
Li
Baogui
B
Suthanthiran
Manikkam
M
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000473:pathology; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000473:pathology; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000473:pathology; D009369:Neoplasms / Q000473:pathology*; D013154:Spleen / Q000737:chemistry; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000032:analysis*; D053773:Transforming Growth Factor beta1
D007166:Immunosuppressive Agents; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016559:Tacrolimus