Post-transplantation malignancy: a cell autonomous mechanism with implications for therapy.
Malignancy is a dreaded complication following organ transplantation. Immunosuppressive therapy-induced impairment of the host immune system is the prevailing hypothesis for the high incidence and aggressive progression of post-transplant neoplasm. We summarize our observations supporting an autonomous cellular mechanism for cyclosporine and tacrolimus associated metastases. Cyclosporine conferred tumor invasiveness by a direct effect on the tumor cells and promoted metastases in T-, B-, and NK cell deficient SCID- beige mice, and anti-TGF-beta antibodies reduced metastases. Tacrolimus, another calcineurin inhibitor widely used in transplantation, induced TGF-beta secretion by tumor cells and promoted metastases in the SCID- beige mice. The immunosuppressive macrolide rapamycin reversed an invasive phenotype to a non-invasive one, reduced circulating levels of TGF-beta1 and prevented tumor growth and metastases in the immocompetant BALB/c mice and in the SCID-beige mice. Our studies, in addition to demonstrating a cell autonomous mechanism for tumor progression, advance TGF-beta blockade as an anti-tumor strategy.
Suthanthiran
Manikkam
M
Division of Nephrology and Department of Transplantation Medicine, 525 East 68th Street, Box 3, New York, NY 10065, USA. msuthan@med.cornell.edu
Hojo
Minoru
M
Maluccio
Mary
M
Boffa
Daniel J
DJ
Luan
Fu L
FL
D000230:Adenocarcinoma / Q000556:secondary; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000009:adverse effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects; D007680:Kidney Neoplasms; D008175:Lung Neoplasms / Q000209:etiology / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000209:etiology* / Q000628:therapy; D016377:Organ Transplantation / Q000009:adverse effects*; D010641:Phenotype; D020123:Sirolimus / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus