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.
Second Department of Surgery, Faculty of Medicine, Hiroshima University, Hiroshima, Japan.
Yuichiro
Y
Ushitora
Hirotaka
H
Tashiro
Takayuki
T
Ogawa
Yoshisato
Y
Tanimoto
Shintaro
S
Kuroda
Tsuyoshi
T
Kobayashi
Yoshihiro
Y
Miyata
Toshiyuki
T
Itamoto
Toshimasa
T
Asahara
Hideki
H
Ohdan
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000473:pathology / Q000517:prevention & control / Q000601:surgery*; D002455:Cell Division / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement; D003470:Culture Media; D015536:Down-Regulation / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control / Q000601:surgery*; D016031:Liver Transplantation / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D011409:Propylene Glycols / Q000627:therapeutic use*; D051381:Rats; D011915:Rats, Inbred BUF; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000276:immunology; D012008:Recurrence; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use
D003470:Culture Media; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine