Cyclosporine induces cancer progression by a cell-autonomous mechanism

Malignancy is a common and dreaded complication following, organ transplant ation(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 sy stem(5-9). Here we report a mechanism for the heightened malignancy that is independent of host immunity. We show that cyclosporine (cyclosporin A), a n immunosuppressant that has had a major impact on improving patient outcom e following organ transplantation(4,5), induces phenotypic changes, includi ng invasiveness of non-transformed cells, by a cell-autonomous mechanism. O ur studies show that cyclosporine treatment of adenocarcinoma cells results in striking morphological alterations, including membrane ruffling and num erous pseudopodial protrusions, increased cell motility, and anchorage-inde pendent (invasive) growth. These changes are prevented by treatment with mo noclonal 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 preve nt the cyclosporine-induced increase in the number of metastases. Our findi ngs suggest that immunosuppressants like cyclosporine can promote cancer pr ogression 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.