Tacrolimus enhances transforming growth factor-β1 expression and promotes tumor progression

Mary Maluccio, Vijay Sharma, Mila Lagman, Shefali Vyas, Hua Yang, Baogui Li, Manikkam Suthanthiran

Research output: Contribution to journalArticle

163 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)597-602
Number of pages6
JournalTransplantation
Volume76
Issue number3
DOIs
Publication statusPublished - 15 Aug 2003
Externally publishedYes

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Transforming Growth Factors
Tacrolimus
Neoplasms
SCID Mice
Neoplasm Metastasis
Therapeutics
Lung
Messenger RNA
Immunosuppressive Agents
Renal Cell Carcinoma
Cyclosporine
Proteins
Spleen
Enzyme-Linked Immunosorbent Assay

ASJC Scopus subject areas

  • Transplantation

Cite this

Tacrolimus enhances transforming growth factor-β1 expression and promotes tumor progression. / Maluccio, Mary; Sharma, Vijay; Lagman, Mila; Vyas, Shefali; Yang, Hua; Li, Baogui; Suthanthiran, Manikkam.

In: Transplantation, Vol. 76, No. 3, 15.08.2003, p. 597-602.

Research output: Contribution to journalArticle

Maluccio, Mary ; Sharma, Vijay ; Lagman, Mila ; Vyas, Shefali ; Yang, Hua ; Li, Baogui ; Suthanthiran, Manikkam. / Tacrolimus enhances transforming growth factor-β1 expression and promotes tumor progression. In: Transplantation. 2003 ; Vol. 76, No. 3. pp. 597-602.
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abstract = "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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AU - Maluccio, Mary

AU - Sharma, Vijay

AU - Lagman, Mila

AU - Vyas, Shefali

AU - Yang, Hua

AU - Li, Baogui

AU - Suthanthiran, Manikkam

PY - 2003/8/15

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N2 - 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.

AB - 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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