Radiation-Induced Myofibroblasts Promote Tumor Growth via Mitochondrial ROS–Activated TGFβ Signaling
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- Tsutomu Shimura
- 1Department of Environmental Health, National Institute of Public Health, Minami, Wako, Saitama, Japan.
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- Megumi Sasatani
- 2Department of Experimental Oncology, Research Center for Radiation Genome Medicine, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, Hiroshima, Japan.
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- Hidehiko Kawai
- 2Department of Experimental Oncology, Research Center for Radiation Genome Medicine, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, Hiroshima, Japan.
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- Kenji Kamiya
- 2Department of Experimental Oncology, Research Center for Radiation Genome Medicine, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, Hiroshima, Japan.
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- Junya Kobayashi
- 3Department of Genome Dynamics, Radiation Biology Center, Kyoto University, Kyoto, Japan.
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- Kenshi Komatsu
- 3Department of Genome Dynamics, Radiation Biology Center, Kyoto University, Kyoto, Japan.
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- Naoki Kunugita
- 1Department of Environmental Health, National Institute of Public Health, Minami, Wako, Saitama, Japan.
書誌事項
- 公開日
- 2018-11-01
- 資源種別
- journal article
- DOI
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- 10.1158/1541-7786.mcr-18-0321
- 公開者
- American Association for Cancer Research (AACR)
この論文をさがす
説明
<jats:title>Abstract</jats:title> <jats:p>Fibroblasts are a key stromal cell in the tumor microenvironment (TME) and promote tumor growth via release of various growth factors. Stromal fibroblasts in cancer, called cancer-associated fibroblasts (CAF), are related to myofibroblasts, an activated form of fibroblast. While investigating the role of stroma fibroblasts on radiation-related carcinogenesis, it was observed following long-term fractionated radiation (FR) that the morphology of human diploid fibroblasts changed from smaller spindle shapes to larger flat shapes. These cells expressed smooth muscle actin (α-SMA) and platelet-derived growth factor receptors, markers of myofibroblasts and CAFs, respectively. Long-term FR induces progressive damage to the fibroblast nucleus and mitochondria via increases in mitochondrial reactive oxygen species (ROS) levels. Here, it is demonstrated that long-term FR-induced α-SMA–positive cells have decreased mitochondrial membrane potential and activated oxidative stress responses. Antioxidant N-acetyl cysteine suppressed radiation-induced mitochondrial damage and generation of myofibroblasts. These results indicate that mitochondrial ROS are associated with the acquisition of myofibroblasts after long-term FR. Mechanistically, mitochondrial ROS activated TGFβ signaling which in turn mediated the expression of α-SMA in radiation-induced myofibroblasts. Finally, in vivo tumor growth analysis in a human tumor xenograft model system revealed that long-term FR-induced myofibroblasts promote tumor growth by enhancing angiogenesis.</jats:p> <jats:p>Implications: Radiation affects malignant cancer cells directly and indirectly via molecular alterations in stromal fibroblasts such as activation of TGFβ and angiogenic signaling pathways. Mol Cancer Res; 16(11); 1676–86. ©2018 AACR.</jats:p>
収録刊行物
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- Molecular Cancer Research
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Molecular Cancer Research 16 (11), 1676-1686, 2018-11-01
American Association for Cancer Research (AACR)
