Abstract
BackgroundSurgical 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.Methodology/Principal FindingsAn 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/SignificanceFTY720 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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world [1]
These events are associated with elevated levels of vascular endothelial growth factor (VEGF), stem cell factor (SCF), and granulocyte colony-stimulating factor (G-CSF) that stimulate the release of endothelial progenitor cells (EPCs) from the bone marrow [5,8,9,10]
FTY720 significantly down-regulated mRNA and protein expression levels of CXCL10, VEGF, CXCR3, and CXCR4 in liver tissue at 6 hours after major hepatectomy and hepatic I/R injury compared to control group (Figure 5). Surgical stress injury such as hepatic I/R injury during liver resection and liver transplantation rapidly enhances the number of circulating EPCs [5,6,7]
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world [1]. Accumulating evidence indicated that surgical stress injury can rapidly increase the number of circulating EPC [5,6,7] These events are associated with elevated levels of vascular endothelial growth factor (VEGF), stem cell factor (SCF), and granulocyte colony-stimulating factor (G-CSF) that stimulate the release of EPCs from the bone marrow [5,8,9,10]. Surgical procedures such as liver resection and liver transplantation are the first-line treatments for hepatocellular carcinoma (HCC) patients. 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
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