Anti-angiogenesis gene therapy for hepatocellular carcinoma via systemic injection of mesenchymal stem cells engineered to secrete soluble Flt-1

摘要

Anti-angiogenesis gene therapy has attracted interest as a potential treatment for hepatocellular carcinoma (HCC). Studies have indicated that soluble fms-like tyrosine kinase-1 (sFlt-1) may suppress angiogenesis by sequestering free vascular endothelial growth factor (VEGF) or by forming inactive heterodimers with VEGF receptor-2. Mesenchymal stem cells (MSCs) have been widely used as prospective delivery vehicles for therapeutic agents, owing to their ability to migrate towards tumor sites. In the present study, a subcutaneous HCC mouse model was used to assess the anti-angiogenesis effects of lentivirus-transfected MSCs engineered to secrete sFlt-1 (LV-sFlt-1-MSCs). LV-sFlt-1-MSCs effectively secreted sFlt-1, which inhibited tube formation in vitro. MSCs labeled with green fluorescence protein primarily migrated to tumor sites in vivo. An immunohistochemical assay indicated that microvessel density was reduced in mice treated with LV-sFlt-1-MSCs, compared with the control group treated with PBS. Additionally, LV-sFlt-1-MSCs inhibited tumor growth and prolonged survival in an HCC mouse model via systemic injection. Overall, the present study was designed to investigate the potential of LV-sFlt-1-MSCs for anti-angiogenesis gene therapy in HCC.