Faculty Profiles - KUNISADA Toshiyuki

Unidirectional porous hydroxyapatite (UDPHAp) was developed as a remarkable scaffold characterized by a distinct structure with unidirectional pores oriented in the horizontal direction and connected through interposes. We evaluated the radiographic changes, clinical outcomes, and complications following UDPHAp implantation for the treatment of bone tumors. Excellent bone formation within and around the implant was observed in all patients treated with intralesional resection and UDPHAp implantation for benign bone tumors. The absorption of UDPHAp and remodeling of the bone marrow space was observed in 45% of the patients at a mean of 17 months postoperatively and was significantly more common in younger patients. Preoperative cortical thinning was completely regenerated in 84% of patients at a mean of 10 months postoperatively. No complications related to the implanted UDPHAp were observed. In a pediatric patient with bone sarcoma, when the defect after fibular resection was filled with UDPHAp implants, radiography showed complete resorption of the implant and clear formation of cortex and marrow in the resected part of the fibula. The patient could walk well without crutches and participate in sports activities. UDPHAp is a useful bone graft substitute for the treatment of benign bone tumors, and the use of this material has a low complication rate. We also review and discuss the potential of UDPHAp as a bone graft substitute in the clinical setting of orthopedic surgery.

DOI： 10.3390/biomimetics9050294

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p53-Armed Oncolytic Virotherapy Improves Radiosensitivity in Soft-Tissue Sarcoma by Suppressing BCL-xL Expression.

Tadashi Komatsubara, Hiroshi Tazawa, Joe Hasei, Toshinori Omori, Kazuhisa Sugiu, Yusuke Mochizuki, Koji Demiya, Aki Yoshida, Tomohiro Fujiwara, Toshiyuki Kunisada, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

Acta medica Okayama 78 ( 2 ) 151 - 161 2024.4

Language：English Publishing type：Research paper (scientific journal)

Soft-tissue sarcoma (STS) is a heterogeneous group of rare tumors originating predominantly from the embryonic mesoderm. Despite the development of combined modalities including radiotherapy, STSs are often refractory to antitumor modalities, and novel strategies that improve the prognosis of STS patients are needed. We previously demonstrated the therapeutic potential of two telomerase-specific replication-competent oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, in human STS cells. Here, we demonstrate in vitro and in vivo antitumor effects of OBP-702 in combination with ionizing radiation against human STS cells (HT1080, NMS-2, SYO-1). OBP-702 synergistically promoted the antitumor effect of ionizing radiation in the STS cells by suppressing the expression of B-cell lymphoma-X large (BCL-xL) and enhancing ionizing radiation-induced apoptosis. The in vivo experiments demonstrated that this combination therapy significantly suppressed STS tumors' growth. Our results suggest that OBP-702 is a promising antitumor reagent for promoting the radiosensitivity of STS tumors.

DOI： 10.18926/AMO/66924

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PRRX1-TOP2A interaction is a malignancy-promoting factor in human malignant peripheral nerve sheath tumours. International journal

Shota Takihira, Daisuke Yamada, Tatsunori Osone, Tomoka Takao, Masakiyo Sakaguchi, Michiyuki Hakozaki, Takuto Itano, Eiji Nakata, Tomohiro Fujiwara, Toshiyuki Kunisada, Toshifumi Ozaki, Takeshi Takarada

British journal of cancer 2024.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Paired related-homeobox 1 (PRRX1) is a transcription factor in the regulation of developmental morphogenetic processes. There is growing evidence that PRRX1 is highly expressed in certain cancers and is critically involved in human survival prognosis. However, the molecular mechanism of PRRX1 in cancer malignancy remains to be elucidated. METHODS: PRRX1 expression in human Malignant peripheral nerve sheath tumours (MPNSTs) samples was detected immunohistochemically to evaluate survival prognosis. MPNST models with PRRX1 gene knockdown or overexpression were constructed in vitro and the phenotype of MPNST cells was evaluated. Bioinformatics analysis combined with co-immunoprecipitation, mass spectrometry, RNA-seq and structural prediction were used to identify proteins interacting with PRRX1. RESULTS: High expression of PRRX1 was associated with a poor prognosis for MPNST. PRRX1 knockdown suppressed the tumorigenic potential. PRRX1 overexpressed in MPNSTs directly interacts with topoisomerase 2 A (TOP2A) to cooperatively promote epithelial-mesenchymal transition and increase expression of tumour malignancy-related gene sets including mTORC1, KRAS and SRC signalling pathways. Etoposide, a TOP2A inhibitor used in the treatment of MPNST, may exhibit one of its anticancer effects by inhibiting the PRRX1-TOP2A interaction. CONCLUSION: Targeting the PRRX1-TOP2A interaction in malignant tumours with high PRRX1 expression might provide a novel tumour-selective therapeutic strategy.

DOI： 10.1038/s41416-024-02632-8

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

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

Cancer science 115 ( 3 ) 871 - 882 2024.3

Language：English Publishing type：Research paper (scientific journal)

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 2024.3

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 2024.3

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 2024.3

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 2024.3

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 2024.3

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 2024.2

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

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

Language：English Publishing type：Research paper (scientific journal)

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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【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 2023.12

Language：Japanese Publisher：(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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Other Link： 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

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