title: Irradiation-induced localization of IL-12-expressing mesenchymal stem cells to enhance the curative effect in murine metastatic hepatoma.
abstract: Irradiation in conjunction with gene therapy is considered for efficient cancer treatment. Mesenchymal stem cells (MSCs), due to their irradiation-promotable tumor tropism, are ideal delivery vehicles for gene therapy. In this study, we investigated whether treatment with radiation and interleukin (IL)-12-expressing MSCs (MSCs/IL-12) exerts improved antitumor effects on murine metastatic hepatoma. HCa-I and Hepa 1-6 cells were utilized to generate heterotopic murine hepatoma models. Tumor-bearing mice were treated with irradiation or MSCs/IL-12 alone, or a combination. Monocyte chemoattractant protein-1 (MCP-1/CCL2) expression was assessed in irradiated hepatoma tissues to confirm a chemotactic effect. Combination treatment strategies were established and their therapeutic efficacies were evaluated by monitoring tumor growth, metastasis and survival rate. IL-12 expression was assessed and the apoptotic activity and immunological alterations in the tumor microenvironment were examined. MCP-1/CCL2 expression and localization of MSCs/IL-12 increased in the irradiated murine hepatoma cells. The antitumor effects, including suppression of pulmonary metastasis and survival rate improvements, were increased by the combination treatment with irradiation and MSCs/IL-12. IL-12 expression was increased in tumor cells, causing proliferation of cluster of differentiation 8(+) T-lymphocytes and natural killer cells. The apoptotic activity increased, indicating that the cytotoxicity of immune cells was involved in the antitumor effect of the combined treatment. Treatment with irradiation and MSCs/IL-12 showed effectiveness in treating murine metastatic hepatoma. IL-12-induced proliferation of immune cells played an important role in apoptosis of tumor cells. Our results suggest that treatment with irradiation and MSCs/IL-12 may be a useful strategy for enhancing antitumor activity in metastatic hepatoma.
authors: Department of Radiation Oncology, Yonsei University Medical College, Seoul, South Korea.
authors: Keun-Yeong
authors: KY
authors: Jeong
authors: Department of Radiation Oncology, Yonsei University Medical College, Seoul, South Korea.
authors: Eun-Jung
authors: EJ
authors: Lee
authors: Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Gyeongbuk, South Korea.
authors: Su Jin
authors: SJ
authors: Kim
authors: Department of Radiation Oncology, Yonsei University Medical College, Seoul, South Korea.
authors: Seung-Hyun
authors: SH
authors: Yang
authors: Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Gyeongbuk, South Korea.
authors: Young Chul
authors: YC
authors: Sung
authors: Department of Radiation Oncology, Yonsei University Medical College, Seoul, South Korea.
authors: Jinsil
authors: J
authors: Seong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D015316:Genetic Therapy; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000528:radiation effects*; D051379:Mice; D009000:Monocytes / Q000378:metabolism / Q000528:radiation effects; D009362:Neoplasm Metastasis; D011839:Radiation, Ionizing; D011878:Radiotherapy; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D018664:Interleukin-12
keywords: HCC; IL-12; gene therapy; irradiation; mesenchymal stem cell; metastasis