Suppression of orthotopically implanted hepatocarcinoma in mice by umbilical cord-derived mesenchymal stem cells with sTRAIL gene expression driven by AFP promoter

Abstract

Mesenchymal stem cells (MSCs) are promising vehicles for delivering therapeutic agents in tumor therapy. Human umbilical cord-derived mesenchymal stem cells (HUMSCs) resemble bone marrow-derived MSCs with respect to hepatic differentiation potential in injured livers in animals, while their hepatic differentiation under the hepatocarcinoma microenvironment is unclear. In this study, HUMSCs were isolated and transduced by lentiviral vectors coding the soluble human tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) gene driven by alpha-fetoprotein (AFP) promoter to investigate the therapeutic effects of these HUMSC against orthotopically implanted hepatocarcinoma in mice. We showed that HUMSCs can be transduced by lentivirus efficiently. HUMSCs developed cuboidal morphology, and expressed AFP and albumin in a two-step protocol. HUMSCs were capable of migrating to hepatocarcinoma in vitro as well as in vivo. In the orthotopical hepatocarcinoma microenvironment, the AFP promoter was activated during the early hepatic differentiation of HUMSCs. After intravenous injected, MSC.AFPILZ-sTRAIL expressed sTRAIL exclusively at the tumor site, and exhibited significant antitumor activity. This effect was stronger when in combination with 5-FU. The treatment was tolerated well in mice. Collectively, our results provide a potential strategy for targeted tumor therapy relying on the use of the tumor tropism and specific differentiation of HUMSCs as vehicles.