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 anti-tumor 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.
Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.
Peng
P
Gao
Qiang
Q
Ding
Zhong
Z
Wu
Haowen
H
Jiang
Zujun
Z
Fang
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D007680:Kidney Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D007694:Killer Cells, Natural / Q000276:immunology; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D054357:Chemokine CXCL10; D007376:Interleukin-2; D007371:Interferon-gamma