Adiponectin as a novel therapy for the suppression of liver cancer growth and metastasis

Abstract

Background: Recently, adipocyte-derived factor – adiponectin has been demonstrated to be able to suppress angiogenesis in addition to its antiinflammatory function. It will have great clinical impact to explore the possibility of the application of adiponectin in liver cancer therapy, together with the underlying liver diseases, such as liver cirrhosis and NASH. In the present study, we aim to investigate the effect of adiponectin in the suppression of liver cancer growth and metastasis. Material and Methods: 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. Once the subcutaneous tumor reached 1 cm 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 animals were sacrificed at day 30, 40 and 50 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 a-SMA staining. Cell signaling related to invasion, migration (ROCK-Rho, CAK and FAK) and angiogenesis (VEGF) were compared. The effect of adiponectin on hepatic stellate cell was also investigated by in vitro functional study. Results: 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 at different time points. The hepatic stellate cell activation by a-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 CAK and FAK was down-regulated in the adponectin treatment groups by immunostaining. Gene and Protein expression of Rho, ROCK and VEGF in the liver tumors was also suppressed. 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