FTY720 suppresses liver tumor metastasis by reducing the population of circulating endothelial progenitor cells, myeloid-derived suppressor cells and regulatory T cells

Abstract

OBJECTIVE: We aim to investigate the mechanism of suppression of liver tumor metastasis by FTY720 after liver resection underwent hepatic I/R injury by detecting the population of circulating endothelial progenitor cells (EPCs), myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). METHODS: A rat orthotropic liver tumor model was established using the rat liver tumor cell line MH7777 labeled with luciferase gene. Two weeks after orthotropic liver tumor implantation, the rats underwent liver resection (left lobe bearing tumor) and partial hepatic I/R injury (20/20 minute duration on right lobe). FTY720 (2 mg/kg, IV) was given before and after I/R injury. Tumor metastases were longitudinally monitored by Xenogen in vivo imaging system by detection of luminance signals from tumor cells. Blood samples were taken at days 0, 1, 3, 7, 14, 21 and 28 for detection of circulating EPCs (CD133+CD34+), MDSCs (His48+CD11b/c+CD80+) and Tregs (CD4+CD25+Foxp3+). Hepatic gene and protein expressions of IP10 and VEGF were detected, and Tregs (Foxp3) in lung metastatic tumor nodules were also examined. RESULTS: Lung metastasis was mainly found in the control group (4/6) compared to the treatment group (2/6). The number of circulating EPCs was significantly decreased by FTY720 treatment from day 7 to day 28 (day 7: 2 vs 21/μl, p=0.001; day 14: 2 vs 39/μl, p=0.000; day 21: 2 vs 42/μl, p=0.000; day 28: 4 vs 93/μl, p=0.000). A significantly lower level of circulating MDSCs was also found in the treatment group (day 1: 9 vs 73/μl, p=0.000; day 3: 37 vs 94/μl, p=0.010; day 7: 51 vs 109/μl, p=0.005; day 14: 76 vs 141/μl, p=0.018; day 21: 34 vs 105/μl, p=0.001; day 28: 38 vs 86/μl, p=0.003). The number of circulating Treg cells was decreased from day 14 to day 21 after treatment (day 14: 7 vs 10/μl, p=0.005; day 21: 3 vs 7/μl, p=0.003). Hepatic gene and protein expressions of IP10 and VEGF induced by hepatic I/R injury were decreased in the treatment group. Tregs were also confirmed to be present in lung metastatic nodules. CONCLUSION: FTY720 suppressed liver tumor metastasis after liver resection marred by hepatic I/R injury in a rat liver tumor model by reducing circulating EPCs, MDSCs and Tregs, which were mobilized by IP10 and VEGF.