研究者詳細 - 藤原　智洋

論文 - 藤原　智洋

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Role of catecholamine synthases in the maintenance of cancer stem-like cells in malignant peripheral nerve sheath tumors. 国際誌

Haruyoshi Katayama, Atsushi Fujimura, Rongsheng Huang, Yusuke Otani, Takuto Itano, Tomohiro Fujiwara, Toshiyuki Kunisada, Eiji Nakata, Toshifumi Ozaki

Cancer science 115 ( 3 ) 871 - 882 2024年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Malignant peripheral nerve sheath tumors (MPNSTs) are malignant tumors that are derived from Schwann cell lineage around peripheral nerves. As in many other cancer types, cancer stem cells (CSCs) have been identified in MPNSTs, and they are considered the cause of treatment resistance, recurrence, and metastasis. As an element defining the cancer stemness of MPNSTs, we previously reported a molecular mechanism by which exogenous adrenaline activates a core cancer stemness factor, YAP/TAZ, through β2 adrenoceptor (ADRB2). In this study, we found that MPNST cells express catecholamine synthases and that these enzymes are essential for maintaining cancer stemness, such as the ability to self-renew and maintain an undifferentiated state. Through gene knockdown and inhibition of these enzymes, we confirmed that catecholamines are indeed synthesized in MPNST cells. The results confirmed that catecholamine synthase knockdown in MPNST cells reduces the activity of YAP/TAZ. These data suggest that a mechanism of YAP/TAZ activation by de novo synthesized adrenaline, as well as exogenous adrenaline, may exist in the maintenance of cancer stemness of MPNST cells. This mechanism not only helps to understand the pathology of MPNST, but could also contribute to the development of therapeutic strategies for MPNST.

DOI： 10.1111/cas.16077

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悪性末梢神経鞘腫瘍において転写因子PRRX1はTOP2Aと相互作用し悪性化を促進させる

たき平将太, 中田英二, 板野拓人, 藤原智洋, 国定俊之, 大曽根達則, 山田大祐, 高尾知佳, 宝田剛志, 尾崎敏文

日本整形外科学会雑誌 98 ( 2 ) S76 - S76 2024年3月

肉腫におけるがん遺伝子パネルによるfusion gene同定の意義

中田英二, 藤原智洋, 板野拓人, 片山晴喜, 二川摩周, 山元英崇, 国定俊之, 尾崎敏文

日本整形外科学会雑誌 98 ( 3 ) S1246 - S1246 2024年3月

AIとDXを用いた骨・軟部腫瘍診療への新たな挑戦

長谷井嬢, 中原龍一, 藤原智洋, 中田英二, 国定俊之, 尾崎敏文

日本整形外科学会雑誌 98 ( 3 ) S1371 - S1371 2024年3月

術前がん患者の各ロコモ度テストにおける関連因子

堅山佳美, 中田英二, 近藤彩奈, 濱田全紀, 藤原智洋, 国定俊之, 尾崎敏文

日本整形外科学会雑誌 98 ( 3 ) S1321 - S1321 2024年3月

悪性末梢神経鞘腫瘍において転写因子PRRX1はTOP2Aと相互作用し悪性化を促進させる

たき平将太, 中田英二, 板野拓人, 藤原智洋, 国定俊之, 大曽根達則, 山田大祐, 高尾知佳, 宝田剛志, 尾崎敏文

日本整形外科学会雑誌 98 ( 2 ) S76 - S76 2024年3月

遺伝性骨・軟部腫瘍外来における肉腫発生at-risk者への取り組み

二川摩周, 中田英二, 山本英喜, 深野智華, 加藤芙美乃, 大住理沙, 藤原智洋, 国定俊之, 平沢晃, 尾崎敏文

日本レックリングハウゼン病学会学術大会プログラム・抄録集 15回 25 - 25 2024年2月

Inhibitory Effect of a Tankyrase Inhibitor on Mechanical Stress-Induced Protease Expression in Human Articular Chondrocytes. 国際誌

Yoshifumi Hotta, Keiichiro Nishida, Aki Yoshida, Yoshihisa Nasu, Ryuichi Nakahara, Shuichi Naniwa, Noriyuki Shimizu, Chinatsu Ichikawa, Deting Lin, Tomohiro Fujiwara, Toshifumi Ozaki

International journal of molecular sciences 25 ( 3 ) 2024年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

We investigated the effects of a Tankyrase (TNKS-1/2) inhibitor on mechanical stress-induced gene expression in human chondrocytes and examined TNKS-1/2 expression in human osteoarthritis (OA) cartilage. Cells were seeded onto stretch chambers and incubated with or without a TNKS-1/2 inhibitor (XAV939) for 12 h. Uni-axial cyclic tensile strain (CTS) (0.5 Hz, 8% elongation, 30 min) was applied and the gene expression of type II collagen a1 chain (COL2A1), aggrecan (ACAN), SRY-box9 (SOX9), TNKS-1/2, a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), and matrix metalloproteinase-13 (MMP-13) were examined by real-time PCR. The expression of ADAMTS-5, MMP-13, nuclear translocation of nuclear factor-κB (NF-κB), and β-catenin were examined by immunocytochemistry and Western blotting. The concentration of IL-1β in the supernatant was examined by enzyme-linked immunosorbent assay (ELISA). TNKS-1/2 expression was assessed by immunohistochemistry in human OA cartilage obtained at the total knee arthroplasty. TNKS-1/2 expression was increased after CTS. The expression of anabolic factors were decreased by CTS, however, these declines were abrogated by XAV939. XAV939 suppressed the CTS-induced expression of catabolic factors, the release of IL-1β, as well as the nuclear translocation of NF-κB and β-catenin. TNKS-1/2 expression increased in mild and moderate OA cartilage. Our results demonstrated that XAV939 suppressed mechanical stress-induced expression of catabolic proteases by the inhibition of NF-κB and activation of β-catenin, indicating that TNKS-1/2 expression might be associated with OA pathogenesis.

DOI： 10.3390/ijms25031443

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Fluorescence-guided assessment of bone and soft-tissue sarcomas for predicting the efficacy of telomerase-specific oncolytic adenovirus. 国際誌

Koji Uotani, Hiroshi Tazawa, Joe Hasei, Tomohiro Fujiwara, Aki Yoshida, Yasuaki Yamakawa, Toshinori Omori, Kazuhisa Sugiu, Tadashi Komatsubara, Hiroya Kondo, Takuya Morita, Masahiro Kiyono, Suguru Yokoo, Toshiaki Hata, Toshiyuki Kunisada, Ken Takeda, Yasuo Urata, Toshiyoshi Fujiwara, Toshifumi Ozaki

PloS one 19 ( 2 ) e0298292 2024年

記述言語：英語掲載種別：研究論文（学術雑誌）

Bone and soft-tissue sarcomas are rare malignancies with histological diversity and tumor heterogeneity, leading to the lack of a common molecular target. Telomerase is a key enzyme for keeping the telomere length and human telomerase reverse transcriptase (hTERT) expression is often activated in most human cancers, including bone and soft-tissue sarcomas. For targeting of telomerase-positive tumor cells, we developed OBP-301, a telomerase-specific replication-competent oncolytic adenovirus, in which the hTERT promoter regulates adenoviral E1 gene for tumor-specific viral replication. In this study, we present the diagnostic potential of green fluorescent protein (GFP)-expressing oncolytic adenovirus OBP-401 for assessing virotherapy sensitivity using bone and soft-tissue sarcomas. OBP-401-mediated GFP expression was significantly associated with the therapeutic efficacy of OBP-401 in human bone and soft-tissue sarcomas. In the tumor specimens from 68 patients, malignant and intermediate tumors demonstrated significantly higher expression levels of coxsackie and adenovirus receptor (CAR) and hTERT than benign tumors. OBP-401-mediated GFP expression was significantly increased in malignant and intermediate tumors with high expression levels of CAR and hTERT between 24 and 48 h after infection. Our results suggest that the OBP-401-based GFP expression system is a useful tool for predicting the therapeutic efficacy of oncolytic virotherapy on bone and soft-tissue sarcomas.

DOI： 10.1371/journal.pone.0298292

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Does primary tumor resection improve survival for patients with sarcomas of pelvic bones, sacrum, and coccyx who have metastasis at diagnosis ? 国際誌

Xianglin Hu, Tomohiro Fujiwara, Yangbai Sun, Wending Huang, Wangjun Yan

European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society 32 ( 12 ) 4362 - 4376 2023年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Recent studies demonstrated that primary tumor resection (PTR) improves survival of patients with metastatic bone sarcomas. However, it remains quite unclear regarding the role of PTR in the treatment of sarcomas of pelvic bones with synchronous metastasis at diagnosis. METHODS: Using the Surveillance, Epidemiology, and End Results Program, we enrolled a total of 385 patients with sarcomas of pelvic bones, sacrum, and coccyx who have metastasis at initial diagnosis, including 139 patients with osteosarcoma, 176 with Ewing sarcoma, and 70 with chondrosarcoma. Association between PTR and disease-specific survival (DSS) were investigated using the univariable and multivariable Cox regression models. Hazard ratio (HR) and 95% confidence interval (CI) were reported. Representative institutional PTR strategies and clinical outcomes for patients with metastatic pelvic sarcomas from our cancer center were displayed. RESULTS: The usage rate of PTR was 28.1% (39/139) in osteosarcoma, 13.6% (24/176) in Ewing sarcoma, and 41.4% (29/70) in chondrosarcoma with synchronous metastatic lesions. PTR was not associated with an improved DSS for metastatic pelvic osteosarcoma (HR = 0.686, 95% CI = 0.430 ~ 1.094, P = 0.113) and Ewing sarcoma (HR = 0.580, 95% CI = 0.291 ~ 1.154, P = 0.121). The use of PTR was associated with an improved DSS for metastatic pelvic chondrosarcoma (HR = 0.464, 95% CI = 0.225 ~ 0.954, P = 0.037). CONCLUSION: Primary lesion resection may provide a survival benefit for metastatic chondrosarcoma, but not for osteosarcoma and Ewing sarcoma of pelvic bones, sacrum, and coccyx. This population-based study recommends an active surgical intervention for metastatic chondrosarcoma while non-surgical treatment for metastatic osteosarcoma and Ewing sarcoma of the pelvis in terms of survival improvement.

DOI： 10.1007/s00586-023-07985-x

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【がん時代の整形外科必携! 骨転移診療アップデート】骨転移治療総論骨転移におけるロコモティブシンドローム

中田英二, 堅山佳美, 明崎禎輝, 濱田全紀, 藤原智洋, 国定俊之, 尾崎敏文

臨床整形外科 58 ( 12 ) 1431 - 1438 2023年12月

記述言語：日本語出版者・発行元：(株)医学書院

＜文献概要＞がんは高齢者に多いため,ロコモティブシンドロームが発生しやすい.がんの切除を行う患者の約9割は,ロコモを合併している.したがって,がん患者では,適切ながんロコモのスクリーニングが重要である.また,最近,がん治療は外来に移行しつつあり,がん患者が日常生活動作を維持することが求められ,がんロコモ予防に対する社会のニーズが増えている.したがって,各施設において,診療科横断的にがんロコモ予防に取り組む体制を構築することが重要である.

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01554&link_issn=&doc_id=20231129020009&doc_link_id=10.11477%2Fmf.1408202843&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1408202843&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

ヒトiPS細胞由来肢芽間葉系細胞から作製した軟骨組織体を用いた骨再生

中田英二, 佐藤浩平, 高尾知佳, 藤澤祐樹, 山田大祐, 上原健敬, 藤原智洋, 尾崎敏文, 宝田剛志

移植 58 ( 3 ) 293 - 293 2023年12月

Factors associated with survival in patients with clear cell sarcoma. 国際誌

Tomohiro Fujiwara, Toshiyuki Kunisada, Eiji Nakata, Toshiharu Mitsuhashi, Toshifumi Ozaki, Akira Kawai

The bone & joint journal 105-B ( 11 ) 1216 - 1225 2023年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: Clear cell sarcoma (CCS) of soft-tissue is a rare melanocytic subtype of mesenchymal malignancy. The aim of this study was to investigate the clinical and therapeutic factors associated with increased survival, stratified by clinical stage, in order to determine the optimal treatment. METHODS: The study was a retrospective analysis involving 117 patients with histologically confirmed CCS, between July 2016 and November 2017, who were enrolled in the Bone and Soft Tissue Tumour Registry in Japan. RESULTS: The five- and ten-year survival rates were 41% (95% confidence interval (CI) 29 to 52) and 37% (95% CI 25 to 49), respectively. On multivariable analysis, the size of the tumour of > 10 cm (p = 0.006), lymph node metastasis at the time of diagnosis (p < 0.001), distant metastases at the time of diagnosis (p < 0.001), and no surgery for the primary tumour (p = 0.019) were independently associated with a poor survival. For N0M0 CCS (n = 68), the development of distant metastases was an independent prognostic factor for survival (early (< 12 months), hazard ratio (HR) 116.78 (95% CI 11.69 to 1,166.50); p < 0.001; late (> 12 months), HR 14.79 (95% CI 1.66 to 131.63); p = 0.016); neoadjuvant/adjuvant chemotherapy (p = 0.895) and/or radiotherapy (p = 0.216) were not significantly associated with survival. The five-year cumulative incidence of local recurrence was 19% (95% CI 8 to 35) and the size of the tumour was significantly associated with an increased rate of local recurrence (p = 0.012). For N1M0 CCS (n = 18), the risk of mortality was significantly lower in patients who underwent surgery for both the primary tumour and lymph node metastases (HR 0.03 (95% CI 0.00 to 0.56); p = 0.020). For M1 CCS (n = 31), excision of the primary tumour was independently associated with better survival (HR 0.26 (95% CI 0.09 to 0.76); p = 0.013). There was no significant difference in survival between the different types of systemic treatment (p = 0.523). CONCLUSION: Complete excision of the primary tumour and lymph nodes is associated with a better survival in patients with CCS. Systemic treatment appears to provide limited benefits, demonstrating a pressing need for novel systemic agents.

DOI： 10.1302/0301-620X.105B11.BJJ-2022-0743.R3

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著明な疼痛を伴う椎間板発生の仙骨脊索腫の一例

藤原智洋, 魚谷弘二, 国定俊之, 中田英二, 小田孔明, 三澤治夫, 尾崎敏文

中国・四国整形外科学会雑誌 35 ( 3 ) 423 - 423 2023年11月

Advances in treatment of alveolar soft part sarcoma: an updated review. 国際誌

Tomohiro Fujiwara, Toshiyuki Kunisada, Eiji Nakata, Kenji Nishida, Hiroyuki Yanai, Tomoki Nakamura, Kazuhiro Tanaka, Toshifumi Ozaki

Japanese journal of clinical oncology 53 ( 11 ) 1009 - 1018 2023年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Alveolar soft part sarcoma is a rare neoplasm of uncertain histogenesis that belongs to a newly defined category of ultra-rare sarcomas. The neoplasm is characterized by a specific chromosomal translocation, der (17) t(X; 17)(p11.2;q25), that results in ASPSCR1-TFE3 gene fusion. The natural history of alveolar soft part sarcoma describes indolent behaviour with slow progression in deep soft tissues of the extremities, trunk and head/neck in adolescents and young adults. A high rate of detection of distant metastasis at presentation has been reported, and the most common metastatic sites in decreasing order of frequency are the lung, bone and brain. Complete surgical resection remains the standard treatment strategy, whereas radiotherapy is indicated for patients with inadequate surgical margins or unresectable tumours. Although alveolar soft part sarcoma is refractory to conventional doxorubicin-based chemotherapy, monotherapy or combination therapy using tyrosine kinase inhibitors and immune checkpoint inhibitors have provided antitumor activity and emerged as new treatment strategies. This article provides an overview of the current understanding of this ultra-rare sarcoma and recent advancements in treatments according to the clinical stage of alveolar soft part sarcoma.

DOI： 10.1093/jjco/hyad102

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テロメラーゼ依存性腫瘍融解アデノウイルスの骨・軟部腫瘍への応用を目指した蛍光タンパクによるウイルスの治療効果予測

魚谷弘二, 藤原智洋, 田澤大, 植田昌敬, 志渡澤央和, 小田孔明, 鉄永倫子, 三澤治夫, 中田英二, 国定俊之, 尾崎敏文

日本整形外科学会雑誌 97 ( 8 ) S1714 - S1714 2023年8月