Fat-derived hormone adiponetin suppresses liver tumor growth and metastases

Abstract

Recently, fat-derived hormone adiponectin has been demonstrated to be able to suppress angiogenesis in addition to its anti-inflammatory function. In the present study, we aim to investigate the effect of adiponectin on liver cancer growth and metastasis in an orthotopic nude mice liver cancer model. The orthotopic liver tumor nude mice models with different metastatic potential were applied. 5×106 MHCC97H or MHCC97L cells were injected subcutaneously into the right flank of the mice. The HCC cell lines were stably labeled with luciferase gene. Once the subcutaneous tumor reached 1cm in diameter, it was removed and cut into about 1-2 mm cubes which were implanted into the left liver lobe of another group of nude mice. Ad-adiponectin (1×108) (treatment group) or Ad-luciferase (control group) was injected via portal vein after tumor implantation. The tumor growth and metastasis were monitored by Xenogen in vivo imaging system. The animals were sacrificed at week 5, 6 and 7 after tumor implantation. The tumor growth and proliferation (Ki67) and local/distant metastases were compared among the groups. Hepatic stellate cell activation in the tumor tissue was detected by α-SMA staining. Cell signaling related to invasion, migration (Rac, CAK and FAK) and angiogenesis (VEGF) were compared. The tumor-nontumor margin was examined under electron microscopy. The tumor growth was significantly inhibited by adiponectin treatment at different time points accompanied with the lower incidence of lung metastasis compared to the control groups. The observation of Xenogen IVIS was confirmed by histopathological examination. The hepatic stellate cell activation by α-SMA staining in the liver tumors was suppressed by adiponectin treatment. The treatment group got lower incidence of Ki67 positive tumor cells. Protein expression of RAC, CAK, FAK and VEGF was down-regulated in the adponectin treatment groups by immunostaining. Tumor vascular endothelial cell damage was found in the treatment group under electron microscopy. In conclusion, adiponectin treatment significantly inhibited liver tumor growth and metastasis by suppression of hepatic stellate cell activation in tumor and down-regulation of cell invasion and angiogenesis pathways.