Cyclosporine induces cancer progression by a cell-autonomous mechanism

Minoru Hojo, Takashi Morimoto, Mary Maluccio, Tomohiko Asano, Kengo Morimoto, Milagros Lagman, Toshikazu Shimbo and Manikkam Suthanthiran
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Minoru Hojo: Weill Medical College of Cornell University
Takashi Morimoto: New York University School of Medicine
Mary Maluccio: Weill Medical College of Cornell University
Tomohiko Asano: National Defense Medical College
Kengo Morimoto: Mizonokuchi Hospital, Teikyo University School of Medicine
Milagros Lagman: Weill Medical College of Cornell University
Toshikazu Shimbo: Mizonokuchi Hospital, Teikyo University School of Medicine
Manikkam Suthanthiran: Weill Medical College of Cornell University

Nature, 1999, vol. 397, issue 6719, 530-534

Abstract: 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.

Date: 1999
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DOI: 10.1038/17401

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