Cyclosporine induces cancer progression by a cell-autonomous mechanism

被引:909
作者
Hojo, M
Morimoto, T
Maluccio, M
Asano, T
Morimoto, K
Lagman, M
Shimbo, T
Suthanthiran, M
机构
[1] Cornell Univ, Weill Med Coll, Dept Transplantat Med & Extracorporeal Therapy, Div Nephrol, New York, NY 10021 USA
[2] Cornell Univ, Weill Med Coll, Dept Med, New York, NY 10021 USA
[3] Cornell Univ, Weill Med Coll, Dept Surg, New York, NY 10021 USA
[4] Teikyo Univ, Sch Med, Mizonokuchi Hosp, Dept Pediat,Takatsu Ku, Kawasaki, Kanagawa 213, Japan
[5] NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA
[6] Natl Def Med Coll, Dept Urol, Tokorozawa, Saitama 359, Japan
关键词
D O I
10.1038/17401
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Malignancy is a common and dreaded complication following, organ transplantation(1-4). 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 system(5-9). 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 transplantation(4,5), 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-beta (TGF-beta). In vivo, cyclosporine enhances tumour growth in immunodeficient SCID-beige Mice; anti-TGF-beta 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-beta production is involved in this.
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页码:530 / 534
页数:5
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