Development of iPS cells-derived vector cells for antiangiogenic gene therapy for hepatocellular carcinoma.

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In the present study, we investigated the anti-tumor effects of anti-angiogenic gene therapy with iPS cell-derived vector cells transfected soluble VEGF receptor-1 and 2 cDNAs. At first, we tried to develop the vector cells from mouse iPS cells. However, mouse iPS cell-derived smooth cells showed less proliferative activity and less homing to tumor tissues than we had expected. So, we changed to construct mesenchymal stem cells from human iPS cells. After constructing mesenchymal stem cells, we transferred CXCR4 cDNA to mesenchymal stem cells to up-regulate the ability of homing to tumor tissues. As vector cells might produce several kinds of growth factors through the activation of HIF signaling under hypoxic condition in tumor tissues, we reduced the expression of HIF1-?? with siRNA technique. Then, we transferred soluble VEGFreceptor-1 and 2 cDNAs with adenovirus vector and injected the vector cells (1x106/week for4 weeks) to tumor-bearing mice of hepatoma cells through the til vein. After 4 weeks of initial treatment, tumor growth was suppressed comparing with non-treated control mice. Injected vector cells mainly located in the stroma of tumor tissues. Some of vector cellsdifferentiated to endothelial cells and smooth muscle cells in tumor tissues. The microvascular density in tumor tissues was decreased comparing with control group. The homing of vector cells to non-cancerous tissues was rarely detected. Severe adverse events such as bone marrow suppression or abnormality of liver function test were not observed.