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Cyclosporine induces cancer progression by a cell-autonomous mechanism

Abstract

Malignancy is a common and dreaded complication following organ transplantation1,2,3,4. The high incidence of neoplasm and its aggressive progression, which are associated with immunosuppressive therapy, are thought to be due to the resulting impairment of the organ recipient's immune-surveillance system5,6,7,8,9. Here we report a mechanism for the heightened malignancy that is independent of host immunity. We show that cyclosporine (cyclosporin A), an immunosuppressant that has had a major impact on improving patient outcome following organ transplantation4,5, induces phenotypic changes, including invasiveness of non-transformed cells, by a cell-autonomous mechanism. Our studies show that cyclosporine treatment of adenocarcinoma cells results in striking morphological alterations, including membrane ruffling and numerous pseudopodial protrusions, increased cell motility, and anchorage-independent (invasive) growth. These changes are prevented by treatment with monoclonal antibodies directed at transforming growth factor-β (TGF-β). In vivo, cyclosporine enhances tumour growth in immunodeficient SCID–beige mice; anti-TGF-β monoclonal antibodies but not control antibodies prevent the cyclosporine-induced increase in the number of metastases. Our findings suggest that immunosuppressants like cyclosporine can promote cancer progression by a direct cellular effect that is independent of its effect on the host's immune cells, and that cyclosporine-induced TGF-β production is involved in this.

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Figure 1: Cyclosporine induces A-549 cells to acquire an invasive phenotype.
Figure 2: Cyclosporine stimulates the motility of A-549 cells.
Figure 3: Anchorage-independent growth of cyclosporine-conditioned A-549 cells.
Figure 4: Cyclosporine induces renal cancer cells to acquire an invasive phenotype and promotes tumour growth in vivo.
Figure 5: Potential mechanisms for cyclosporine-associated tumour progression.

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Acknowledgements

We thank Y. Suzuki for technical assistance, B. Li, R. Ding, A. Khanna, V. K. Sharma and A. Niwa for their help; P. August, M. Ono and Y. Ichiyoshi for critical review of the manuscript; B.Pratt, D. Pappas and D. Felson for the generous gift and advice regarding 1D11.16 antibodies direct at TGF-β; and L. Stackhouse for help in the preparation of this manuscript. This work was supported in part by a grant from the Ministry of Education, Science and Culture, Japan (M.H.), Kanagawa Academy of Science and Technology, Japan (M.H.), and by an award from the National Institutes of Health, USA (M.S.).

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Hojo, M., Morimoto, T., Maluccio, M. et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 397, 530–534 (1999). https://doi.org/10.1038/17401

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