Therapeutic potential of human mesenchymal stem cells producing IL-12 in a mouse xenograft model of renal cell carcinoma

Mesenchymal stem cells (MSCs) represent a new tool for delivery of therapeutic agents to cancer. The cytokine interleukin-12 (IL-12) has demonstrated a potent anti-tumor activity in a variety of mouse tumor models. In this study, human MSCs were isolated from human bone marrow and identified by phenotype analysis and differentiation assays. The antitumor activity of human MSCs stably transduced with a recombinant adenoviral vector expressing the murine IL-12 (MSC/IL-12) were evaluated in a mouse xenograft model of renal cell carcinoma (RCC). Expression and bioactivity of the transgenic protein IL-12 from adenoviral vector were confirmed prior to in vivo studies. A nude mouse model of RCC was developed by subcutaneously injection of 786-0 cells into nude mice. MSC/IL-12 was injected into the lateral tail vein with single dose. Results indicated that systemic administration of MSC/IL-12 reduced the growth of 786-0 RCC and significantly prolonged mouse survival. These transfected cells could home to tumors after intravenous injection and largely produce local IL-12 protein. In contrast, systemic level of IL-12 was modestly elevated. Further studies showed that the anti-tumor activity of the MSC/IL-12 was dependent on the presence of natural killer (NK) cells and IFN-gamma in this experimental setting. These data demonstrate the potential of adult MSC constitutively producing IL-12 to reduce the growth of RCC and enhance the tumor-bearing mouse survival. (C) 2009 Elsevier Ireland Ltd. All rights reserved.