title: A novel cancer therapeutic using thrombospondin 1 in dendritic cells.
abstract: Induction of thrombospondin 1 (TSP-1) is generally assumed to suppress tumor growth through inhibiting angiogenesis; however, it is less clear how TSP-1 in dendritic cells (DCs) influences tumor progression. We investigated tumor growth and immune mechanism by downregulation of TSP-1 in dendritic cells. Administration of TSP-1 small hairpin RNA (shRNA) through the skin produced anticancer therapeutic effects. Tumor-infiltrating CD4(+) and CD8(+) T cells were increased after the administration of TSP-1 shRNA. The expression of interleukin-12 and interferon-γ in the lymph nodes was enhanced by injection of TSP-1 shRNA. Lymphocytes from the mice injected with TSP-1 shRNA selectively killed the tumor cells, and the cytotoxicity of lymphocytes was abolished by depletion of CD8(+) T cells. Injection of CD11c(+) TSP-1-knockout (TSP-1-KO) bone marrow-derived DCs (BMDCs) delayed tumor growth in tumor-bearing mice. Similarly, antitumor activity induced by TSP-1-KO BMDCs was abrogated by depletion of CD8(+) T cells. In contrast, the administration of shRNAs targeting TSP-2, another TSP family member, did not extend the survival of tumor-bearing mice. Finally, TSP-1 shRNA functioned as an immunotherapeutic adjuvant to augment the therapeutic efficacy of Neu DNA vaccination. Collectively, the downregulation of TSP-1 in DCs produces an effective antitumor response that is opposite to the protumor effects by silencing of TSP-1 within tumor cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Tzu-Yang
authors.initials: TY
authors.lastname: Weng
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Shih-Shien
authors.initials: SS
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center for Infectious Diseases and Signal Research, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Meng-Chi
authors.initials: MC
authors.lastname: Yen
authors.affiliation: Institute of Biomedical Sciences, College of Life Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Chi-Chen
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Department of Senior Citizen Services Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Chen
authors.affiliation: School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chiu-Mei
authors.initials: CM
authors.lastname: Lin
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Wei-Ching
authors.initials: WC
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Wang
authors.affiliation: National Institute of Cancer Research, National Health Research Institute, Tainan, Taiwan.
authors.forename: Jang-Yang
authors.initials: JY
authors.lastname: Chang
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center for Infectious Diseases and Signal Research, National Cheng Kung University, Tainan, Taiwan. Electronic address: a1211207@mail.ncku.edu.tw.
authors.forename: Ming-Derg
authors.initials: MD
authors.lastname: Lai
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D020868:Gene Silencing; D015316:Genetic Therapy; D007111:Immunity, Cellular; D007167:Immunotherapy; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D009389:Neovascularization, Pathologic; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D012867:Skin / Q000378:metabolism; D019700:Thrombospondin 1 / Q000172:deficiency / Q000235:genetics*; D019699:Thrombospondins / Q000172:deficiency / Q000235:genetics; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology; D000099262:Thrombospondin 2
chemical_list: D019496:Cancer Vaccines; D034741:RNA, Small Interfering; D019700:Thrombospondin 1; D019699:Thrombospondins; D019444:Vaccines, DNA; D000099262:Thrombospondin 2