Cyclosporine induces cancer progression by a cell-autonomous mechanism

Minoru Hojo, Takashi Morimoto, Mary Maluccio, Tomohiko Asano, Kengo Morimoto, Milagros Lagman, Toshikazu Shimbo, Manikkam Suthanthiran

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872 Scopus citations

Abstract

Malignancy is a common and dreaded complication following organ transplantation. 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 system. 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 transplantation, 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.

Original languageEnglish (US)
Pages (from-to)530-534
Number of pages5
JournalNature
Volume397
Issue number6719
DOIs
StatePublished - Feb 11 1999

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    Hojo, M., Morimoto, T., Maluccio, M., Asano, T., Morimoto, K., Lagman, M., Shimbo, T., & Suthanthiran, M. (1999). Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature, 397(6719), 530-534. https://doi.org/10.1038/17401