Cyclosporine induces cancer progression by a cell-autonomous mechanism.
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-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.
Hojo
M
M
Department of Transplantation Medicine and Extracorporeal Therapy, Weill Medical College of Cornell University, New York, New York 10021, USA.
Morimoto
T
T
Maluccio
M
M
Asano
T
T
Morimoto
K
K
Lagman
M
M
Shimbo
T
T
Suthanthiran
M
M
D000818:Animals; D000906:Antibodies / Q000276:immunology; D002273:Carcinogens / Q000633:toxicity*; D002292:Carcinoma, Renal Cell / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D016572:Cyclosporine / Q000009:adverse effects* / Q000633:toxicity; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000633:toxicity; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008855:Microscopy, Electron, Scanning; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010641:Phenotype; D011554:Pseudopodia / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000906:Antibodies; D002273:Carcinogens; D007166:Immunosuppressive Agents; D016212:Transforming Growth Factor beta; D016572:Cyclosporine