title: FTY720 suppresses liver tumor metastasis by reducing the population of circulating endothelial progenitor cells.
abstract: BACKGROUND
  Surgical procedures such as liver resection and liver transplantation are the first-line treatments for hepatocellular carcinoma (HCC) patients. However, the high incidence of tumor recurrence and metastasis after liver surgery remains a major problem. Recent studies have shown that hepatic ischemia-reperfusion (I/R) injury and endothelial progenitor cells (EPCs) contribute to tumor growth and metastasis. We aim to investigate the mechanism of FTY720, which was originally applied as an immunomodulator, on suppression of liver tumor metastasis after liver resection and partial hepatic I/R injury.
  
  
  RESULTS
  An orthotopic liver tumor model in Buffalo rat was established using the hepatocellular carcinoma cell line McA-RH7777. Two weeks after orthotopic liver tumor implantation, the rats underwent liver resection for tumor-bearing lobe and partial hepatic I/R injury. FTY720 (2 mg/kg) was administered through the inferior caval vein before and after I/R injury. Blood samples were taken at days 0, 1, 3, 7, 14, 21 and 28 for detection of circulating EPCs (CD133+CD34+). Our results showed that intrahepatic and lung metastases were significantly inhibited together with less tumor angiogenesis by FTY720 treatment. The number of circulating EPCs was also significantly decreased by FTY720 treatment from day 7 to day 28. Hepatic gene expressions of CXCL10, VEGF, CXCR3, CXCR4 induced by hepatic I/R injury were down-regulated in the treatment group.
  
  
  CONCLUSIONS
  FTY720 suppressed liver tumor metastasis after liver resection marred by hepatic I/R injury in a rat liver tumor model by attenuating hepatic I/R injury and reducing circulating EPCs.
authors.affiliation: Department of Surgery, Centre for Cancer Research and State Key Laboratory of Liver Research,The University of Hong Kong, Hong Kong, China.
authors.forename: Chang Xian
authors.initials: CX
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Shao
authors.forename: Kevin T P
authors.initials: KT
authors.lastname: Ng
authors.forename: Xiao Bing
authors.initials: XB
authors.lastname: Liu
authors.forename: Chang Chun
authors.initials: CC
authors.lastname: Ling
authors.forename: Yuen Yuen
authors.initials: YY
authors.lastname: Ma
authors.forename: Wei
authors.initials: W
authors.lastname: Geng
authors.forename: Sheung Tat
authors.initials: ST
authors.lastname: Fan
authors.forename: Chung Mau
authors.initials: CM
authors.lastname: Lo
authors.forename: Kwan
authors.initials: K
authors.lastname: Man
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology* / Q000601:surgery; D045744:Cell Line, Tumor; D000068876:Fingolimod Hydrochloride; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000601:surgery; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000601:surgery; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D011409:Propylene Glycols; D051381:Rats; D015427:Reperfusion Injury; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000502:physiology; D013234:Stem Cells / Q000166:cytology*; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine