title: γ-Irradiated cancer cells promote tumor growth by activation of Toll-like receptor 1-mediated inducible nitric oxide synthase in macrophages.
abstract: RT is commonly used to treat malignant tumors. However, tumor regrowth is a major limitation to RT as an antitumor treatment. In the present study, we investigated the tumor-promoting effects of high-dose (or ablative) RT treatments on tumor-bearing mice. We focused on the role of macrophages that interact with IR-CCs in the TME, which cause tumor regrowth. We observed that CT26(H-2(d)) tumor growth was enhanced by i.v. injection of IR-CT26 cells compared with NR control CT26 cells. The levels of iNOS gene expression and NO production from RAW264.7 macrophages (H-2(d)) in response to the interaction with IR-CT26 cells were higher than with NR-CT26 cells. When CT26 tumor-bearing mice were treated i.v. with L-NMMA, a NOS inhibitor, the reduction in in vivo tumor growth was higher in the IR-CT26-injected group compared with the NR-CT26-injected control group. In vivo CT26 tumor growth was decreased after transplanting PEM extracted from L-NMMA-treated, tumor-bearing mice. Although iNOS activity was reduced by inhibiting TLR1 expression with TLR1-siRNA, it was enhanced by TLR1 overexpression. Transcriptional activation and protein expression levels of iNOS were also decreased in the presence of TLR1-siRNA but increased as a result of TLR1 overexpression. These results demonstrate that postradiotherapeutic tumor regrowth may be caused by interaction of IR-CCs with macrophages that induce TLR1-mediated iNOS expression and NO production. Our data suggest that iNOS in macrophages could be a useful target to regulate postradiotherapeutic responses in hosts and subsequently limit tumor regrowth.
authors: *Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea; and Molecular Imaging Research Center, Korea Institute of Radiological and Medical Science, Seoul, Korea.
authors: Yun-Kyoung
authors: YK
authors: Ryu
authors: *Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea; and Molecular Imaging Research Center, Korea Institute of Radiological and Medical Science, Seoul, Korea.
authors: Mi-Hee
authors: MH
authors: Lee
authors: *Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea; and Molecular Imaging Research Center, Korea Institute of Radiological and Medical Science, Seoul, Korea.
authors: Jiyoung
authors: J
authors: Lee
authors: *Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea; and Molecular Imaging Research Center, Korea Institute of Radiological and Medical Science, Seoul, Korea.
authors: Jae-Wook
authors: JW
authors: Lee
authors: *Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea; and Molecular Imaging Research Center, Korea Institute of Radiological and Medical Science, Seoul, Korea.
authors: Su-Jin
authors: SJ
authors: Jang
authors: *Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea; and Molecular Imaging Research Center, Korea Institute of Radiological and Medical Science, Seoul, Korea.
authors: Joo-Hyun
authors: JH
authors: Kang
authors: *Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea; and Molecular Imaging Research Center, Korea Institute of Radiological and Medical Science, Seoul, Korea eunyimoon@sejong.ac.kr.
authors: Eun-Yi
authors: EY
authors: Moon
mesh_terms: D016475:3T3 Cells; D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy*; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy*; D018450:Disease Progression; D004790:Enzyme Induction; D005720:Gamma Rays; D008264:Macrophages / Q000145:classification / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000502:physiology*; D012008:Recurrence; D051194:Toll-Like Receptor 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D059016:Tumor Microenvironment / Q000528:radiation effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D009363:Neoplasm Proteins; D051194:Toll-Like Receptor 1; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: NO; TLR1; iNOS; postradiotherapeutic effect; radiotherapy