Suppression of Hepatocellular Carcinoma Recurrence After Rat Liver Transplantation by FTY720, a Sphingosine-1-phosphate Analog

BACKGROUND.: Although the outcome of liver transplant patients with hepatocellular carcinoma (HCC) has improved with the introduction of strict criteria, tumor recurrence still remains a significant problem. Sphingosine-1-phosphate (S1P) is a phospholipid mediator that can induce diverse cellular responses, such as proliferation, migration, adhesion, and cell-rounding, in cancer cells. We investigated whether FTY720, a S1P analog, suppresses tumor recurrence after experimental liver transplantation in a rat HCC model. METHODS.: HCC-bearing rats were subjected to orthotropic liver transplantation. HCC cells were analyzed for cell migration, proliferation, and S1P receptors. RESULTS.: FTY720 induced the down-regulation of the S1P-1 receptor of HCC cells and suppressed both cancer cell migration and proliferation. FTY720 also suppressed mitogen-activated protein kinase phosphorylation. The suppression of tumor recurrence after liver transplantation and a significant prolongation of survival were observed in the FTY720-treated rats, in comparison with FTY720-untreated rats. CONCLUSION.: FTY720 suppresses the invasiveness and proliferation of HCC through a down-regulating S1P-1 receptor to suppress the recurrence of HCC after liver transplantation; FTY720 may be used as a new antimetastatic agent for the prevention of tumor recurrence after liver transplantation.