2021/12/14 更新

写真a

タナカ ヒロヨシ
田中 啓祥
TANAKA Hiroyoshi
所属
医歯薬学域 助教
職名
助教
プロフィール
2013.3 東京大学 医学部 MD研究者育成プログラム(第2期)修了
2013.3 東京大学 医学部医学科 卒業、医師免許 取得
2013.4-2016.3 東京大学 大学院医学系研究科 病因・病理学専攻
2013.4-2016.3 武田科学振興財団 医学部博士課程奨学生
2016.4- 現職
2016.4- 国立病院機構 岡山医療センター 客員研究員
2019.6- preLighter (HP: https://prelights.biologists.com/profiles/hytanaka/)
2019 Mansfield-PhRMA Research Scholar (7th cohort)
外部リンク

学位

  • 医学士 ( 2013年3月   東京大学 )

研究キーワード

  • バイオマテリアル

  • ナノ医学

  • 線維化

  • 腫瘍生物学

  • 血管生物学

研究分野

  • ライフサイエンス / 細胞生物学

  • ナノテク・材料 / ナノバイオサイエンス

  • ライフサイエンス / 腫瘍生物学

  • ライフサイエンス / 実験病理学

学歴

  • 東京大学    

    - 2016年

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    国名: 日本国

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  • 東京大学   Faculty of Medicine   School of Medicine

    - 2013年

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    国名: 日本国

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経歴

  • - 岡山大学医歯薬学総合研究科 助教

    2016年

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  • - Assistant Professor,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University

    2016年

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所属学協会

 

論文

  • Modeling and analysis of disease microenvironments with 3D cell culture technology 招待 査読

    Hiroyoshi Y. Tanaka

    Yakugaku Zasshi   141 ( 5 )   647 - 653   2021年5月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(国際会議プロシーディングス)  

    Remarkable progress in our ability to analyze diseased tissue has revolutionized our understanding of disease. From a simplistic understanding of abnormalities in bulk tissue, there is now increasing recognition that the heterogeneous and dynamically evolving disease microenvironment plays a crucial role in disease pathogenesis and progression as well as in the determination of therapeutic response. The disease microenvironment consists of multiple cell types as well as the various factors that these cells secrete. There is now immense interest in treatment strategies that target or modify the abnormal disease microenvironment, and a deeper understanding of the mechanisms that drive the formation, maintenance, and progression of the disease microenvironment is thus necessary. The advent of 3-dimensional (3D) cell culture technology has made possible the reconstitution of the disease microenvironment to a previously unimaginable extent in vitro. As an intermediate between traditional in vitro models based on 2-dimensional (2D) cell culture and in vivo models, 3D models of disease enable the in vitro reconstitution of complex interactions within the disease microenvironment which were unamenable in 2D while simultaneously allowing the mechanistic analysis of these interactions that would be dificult to perform in vivo. This symposium review aims to highlight the promise of using 3D cell culture technology to model and analyze the disease microenvironment using pancreatic cancer as an example.

    DOI: 10.1248/yakushi.20-00219-4

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  • Heterotypic 3D pancreatic cancer model with tunable proportion of fibrotic elements 査読 国際誌

    Hiroyoshi Y. Tanaka, Tsuyoshi Kurihara, Takuya Nakazawa, Michiya Matsusaki, Atsushi Masamune, Mitsunobu R. Kano

    Biomaterials   251   120077 - 120077   2020年8月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Pancreatic ductal adenocarcinoma (PDAC) is an often lethal disease characterized by a dense, fibrotic stroma. However, the lack of relevant preclinical models that recapitulate the characteristic histopathology of human PDAC in vitro impedes the development of novel therapies. The amount of stromal elements differ largely within and between patients, but in vitro models of human PDAC often do not account for this heterogeneity. Indeed, analyses of human PDAC histopathology revealed that the proportion of stroma ranged from 40 to 80% across patients. We, therefore, generated a novel 3D model of human PDAC, consisting of co-cultured human PDAC tumor cells and fibroblasts/pancreatic stellate cells, in which the proportion of fibrotic elements can be tuned across the clinically observed range. Using this model, we analyzed the signaling pathways involved in the differentiation of myofibroblasts, a characteristic subpopulation of fibroblasts seen in PDAC. We show that both YAP and SMAD2/3 in fibroblasts are required for myofibroblastic differentiation and that both shared and distinct signaling pathways regulate the nuclear localization of these factors during this process. Our novel model will be useful in promoting the understanding of the complex mechanisms by which the fibrotic stroma develops and how it might be therapeutically targeted.

    DOI: 10.1016/j.biomaterials.2020.120077

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  • Pancreatic stellate cells derived from human pancreatic cancer demonstrate aberrant SPARC-dependent ECM remodeling in 3D engineered fibrotic tissue of clinically relevant thickness 査読 国際誌

    Hiroyoshi Y. Tanaka, Kentaro Kitahara, Naoki Sasaki, Natsumi Nakao, Kae Sato, Hirokazu Narita, Hiroshi Shimoda, Michiya Matsusaki, Hiroshi Nishihara, Atsushi Masamune, Mitsunobu R. Kano

    Biomaterials   192   355 - 367   2019年2月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Desmoplasia is a hallmark of pancreatic cancer and consists of fibrotic cells and secreted extracellular matrix (ECM) components. Various in vitro three-dimensional (3D) models of desmoplasia have been reported, but little is known about the relevant thickness of the engineered fibrotic tissue. We thus measured the thickness of fibrotic tissue in human pancreatic cancer, as defined by the distance from the blood vessel wall to tumor cells. We then generated a 3D fibrosis model with a thickness reaching the clinically observed range using pancreatic stellate cells (PSCs), the main cellular constituent of pancreatic cancer desmoplasia. Using this model, we found that Collagen fiber deposition was increased and Fibronectin fibril orientation drastically remodeled by PSCs, but not normal fibroblasts, in a manner dependent on Transforming Growth Factor (TGF)-β/Rho-Associated Kinase (ROCK) signaling and Matrix Metalloproteinase (MMP) activity. Finally, by targeting Secreted Protein, Acidic and Rich in Cysteine (SPARC) by siRNA, we found that SPARC expression in PSCs was necessary for ECM remodeling. Taken together, we developed a 3D fibrosis model of pancreatic cancer with a clinically relevant thickness and observed aberrant SPARC-dependent ECM remodeling in cancer-derived PSCs.

    DOI: 10.1016/j.biomaterials.2018.11.023

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  • Stromal barriers to nanomedicine penetration in the pancreatic tumor microenvironment 招待 査読

    Hiroyoshi Y. Tanaka, Mitsunobu R. Kano

    Cancer Science   109 ( 7 )   2085 - 2092   2018年7月

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    担当区分:筆頭著者  

    Pancreatic cancer is known for its dismal prognosis despite efforts to improve therapeutic outcome. Recently, cancer nanomedicine, application of nanotechnology to cancer diagnosis and treatment, has gained interest for treatment of pancreatic cancer. The enhanced permeability and retention (EPR) effect that promotes selective accumulation of nanometer-sized molecules within tumors is the theoretical rationale of treatment. However, it is clear that EPR may be insufficient in pancreatic cancer as a result of stromal barriers within the tumor microenvironment (TME). These limit intratumoral accumulation of macromolecules. The TME and stromal barriers inside it consist of various stromal cell types which interact both with each other and with tumor cells. We are only beginning to understand the complexities of the stromal barriers within the TME and its functional consequences for nanomedicine. Understanding the complex crosstalk between barrier stromal cells is challenging because of the difficulty of modeling pancreatic cancer TME. Here we provide an overview of stromal barriers within the TME. We also describe the preclinical models, both in vivo and in vitro, developed to study them. We furthermore discuss the critical gaps in our understanding, and how we might formulate a better strategy for using nanomedicine against pancreatic cancer.

    DOI: 10.1111/cas.13630

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  • がん微小環境における線維化とナノDDS 招待

    田中 啓祥, 狩野 光伸

    Drug Delivery System   36 ( 4 )   232 - 240   2021年9月

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    担当区分:筆頭著者   記述言語:日本語   出版者・発行元:日本DDS学会  

    Enhanced permeability and retention(EPR)効果により血管からがん組織内へと漏出したナノDDSは、多くの場合、間質障壁により妨げられ、腫瘍細胞へと到達することができない。間質障壁は、がん細胞と種々の「正常」な細胞の相互作用を通じて形成・維持される。こうした相互作用の場を「がん微小環境」という。がん微小環境中の線維化組織、すなわち主として異常な形質を獲得した線維芽細胞およびこれらの細胞により産生され過剰沈着している細胞外基質により構成される組織は、とりわけナノDDSの送達効率の重要な規定要因として知られる。本稿では、がん微小環境における線維化について概説した後、より効率的なナノDDS送達を実現するうえでの示唆について考察する。(著者抄録)

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  • 三次元培養技術によるがん微小環境のin vitroでの再現とDDS研究への応用 招待

    田中 啓祥, 栗原 毅, 狩野 光伸

    Drug Delivery System   35 ( 5 )   445 - 447   2020年11月

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    担当区分:筆頭著者   記述言語:日本語   出版者・発行元:日本DDS学会  

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  • Antibiotic prescriptions for Japanese outpatients with acute respiratory tract infections (2013–2015): A retrospective Observational Study 査読 国際誌

    Toshihiro Koyama, Hideharu Hagiya, Yusuke Teratani, Yasuhisa Tatebe, Ayako Ohshima, Mayu Adachi, Tomoko Funahashi, Yoshito Zamami, Hiroyoshi Y. Tanaka, Ken Tasaka, Kazuaki Shinomiya, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Mitsunobu R. Kano

    Journal of Infection and Chemotherapy   26 ( 7 )   660 - 666   2020年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Objectives: Appropriate antibiotic prescriptions for outpatients with acute respiratory tract infections (ARTIs) are urgently needed in Japan. However, the empirical proof of this need is under-documented. Therefore, we aimed to determine antibiotic prescription rates, and the proportions of antibiotic classes prescribed for Japanese patients with ARTIs. Methods: We analysed health insurance claims data over 2013–2015 among Japanese patients aged <75 years and determined the following indicators: 1) visit rates for patients with ARTIs and antibiotic prescription rates per 1000 person-years, and 2) proportion of visits by antibiotic-prescribed patients with ARTIs. We defined broad-spectrum antibiotics using the WHO Anatomical Therapeutic Chemical classification 4 level codes. Results: Among 8.65 million visits due to ARTIs at 6859 hospitals and 62,024 physicians’ offices, the visit rate and antibiotic prescription rate per 1000 person-years were 990.6 (99% confidence interval [CI], 989.4–991.7) and 532.4 (99% CI, 531.6–533.3), respectively. The visit rates for patients aged 0–17, 18–59, and 60–74 years were 2410.0 (99% CI, 2407.2–2412.9), 683.6 (99% CI, 682.7–684.6), and 682.1 (99% CI, 678.2–686.0), and antibiotic prescription rates were 1093.3 (99% CI, 1091.4–1095.2), 434.1 (99% CI, 433.4–434.9), and 353.4 (99% CI, 350.7–356.1), respectively. The overall proportion of antibiotic prescriptions for ARTI visits was 52.7% and 91.3% of the antibiotics prescribed were broad-spectrum. Conclusions: Both the visit rates and antibiotic prescription rates for ARTIs were high in this Japanese cohort. The proportion of antibiotic prescriptions exceeded that recommended in the clinical guidelines. Thus, there might be a scope for reducing the current antibiotic prescription rate in Japan.

    DOI: 10.1016/j.jiac.2020.02.001

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  • 3D in vitro Model of Vascular Medial Thickening in Pulmonary Arterial Hypertension 査読

    Chiharu Morii, Hiroyoshi Y. Tanaka, Yasuhisa Izushi, Natsumi Nakao, Masaya Yamamoto, Hiromi Matsubara, Mitsunobu R. Kano, Aiko Ogawa

    Frontiers in Bioengineering and Biotechnology   8   2020年5月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In pulmonary arterial hypertension (PAH), excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) causes vascular medial thickening. Medial thickening is a histopathological hallmark of pulmonary vascular remodeling, the central disease process driving PAH progression. Pulmonary vascular remodeling causes stenosis and/or obstruction of small pulmonary arteries. This leads to increased pulmonary vascular resistance, elevated pulmonary arterial pressure, and ultimately right heart failure. To improve the survival of PAH patients, which remains at approximately 60% at 3 years after diagnosis, the development of novel PAH-targeted drugs is desired. To this end, a detailed understanding of the mechanisms underlying excessive PASMC proliferation and the medial thickening that ensues is necessary. However, a lack of in vitro models that recapitulate medial thickening impedes our deeper understanding of the pathogenetic mechanisms involved. In the present study, we applied 3-dimensional (3D) cell culture technology to develop a novel in vitro model of the pulmonary artery medial layer using human PAH patient-derived PASMCs. The addition of platelet-derived growth factor (PDGF)-BB, a mitogen known to promote excessive PASMC proliferation in PAH, resulted in increased thickness of the 3D-PAH media tissues. Conversely, administration of the PDGF receptor inhibitor imatinib or other clinical PAH drugs inhibited this medial thickening-inducing effect of PDGF-BB. Altogether, by using 3D cell culture technology, we report the generation of an in vitro model of medial thickening in PAH, which had hitherto not been successfully modeled in vitro. This model is potentially useful for assessing the ability of candidate PAH drugs to suppress medial thickening.

    DOI: 10.3389/fbioe.2020.00482

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  • In vivo rendezvous of small nucleic acid drugs with charge-matched block catiomers to target cancers 査読 国際誌

    Sumiyo Watanabe, Kotaro Hayashi, Kazuko Toh, Hyun Jin Kim, Xueying Liu, Hiroyuki Chaya, Shigeto Fukushima, Keisuke Katsushima, Yutaka Kondo, Satoshi Uchida, Satomi Ogura, Takahiro Nomoto, Hiroyasu Takemoto, Horacio Cabral, Hiroaki Kinoh, Hiroyoshi Y. Tanaka, Mitsunobu R. Kano, Yu Matsumoto, Hiroshi Fukuhara, Shunya Uchida, Masaomi Nangaku, Kensuke Osada, Nobuhiro Nishiyama, Kanjiro Miyata, Kazunori Kataoka

    Nature Communications   10 ( 1 )   1894 - 1894   2019年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Stabilisation of fragile oligonucleotides, typically small interfering RNA (siRNA), is one of the most critical issues for oligonucleotide therapeutics. Many previous studies encapsulated oligonucleotides into ~100-nm nanoparticles. However, such nanoparticles inevitably accumulate in liver and spleen. Further, some intractable cancers, e.g., tumours in pancreas and brain, have inherent barrier characteristics preventing the penetration of such nanoparticles into tumour microenvironments. Herein, we report an alternative approach to cancer-targeted oligonucleotide delivery using a Y-shaped block catiomer (YBC) with precisely regulated chain length. Notably, the number of positive charges in YBC is adjusted to match that of negative charges in each oligonucleotide strand (i.e., 20). The YBC rendezvouses with a single oligonucleotide in the bloodstream to generate a dynamic ion-pair, termed unit polyion complex (uPIC). Owing to both significant longevity in the bloodstream and appreciably small size (~18 nm), the uPIC efficiently delivers oligonucleotides into pancreatic tumour and brain tumour models, exerting significant antitumour activity.

    DOI: 10.1038/s41467-019-09856-w

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  • Oral anticoagulants usage in Japanese patients aged 18-74 years with non-valvular atrial fibrillation: A retrospective analysis based on insurance claims data 査読 国際誌

    Ayako Ohshima, Toshihiro Koyama, Aiko Ogawa, Yoshito Zamami, Hiroyoshi Y. Tanaka, Yoshihisa Kitamura, Toshiaki Sendo, Shiro Hinotsu, Michael W. Miller, Mitsunobu R. Kano

    Family Practice   36 ( 6 )   685 - 692   2019年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Oral anticoagulants use has increased rapidly, internationally. Here we look at risks and benefits, based on Japanese data, of therapy with low risk non-valvular atrial fibrillation patients. Objectives: Using a health insurance claims data set we assessed: (i) oral anticoagulants usage in Japan, and (ii) efficacy and safety of dabigatran compared with warfarin, in Japanese patients with non-valvular atrial fibrillation, aged 18-74 years. Methods: We identified 4380 non-valvular atrial fibrillation patients treated with anticoagulants between 1 January 2005, and 28 February 2014, and estimated the adjusted hazard ratio for stroke or systemic embolism, and any hemorrhagic event (Cox proportional hazards regression model with stabilized inverse probability treatment weighting). Results: The data included 101 989 anticoagulant prescriptions for 4380 patients, of which direct oral anticoagulants increased to 40.0% of the total by the end of the study. After applying exclusion criteria, 1536 new non-valvular atrial fibrillation patients were identified, including 1071 treated with warfarin and 465 with dabigatran. Mean ages were 56.11 ± 9.70 years for warfarin, and 55.80 ± 9.65 years for dabigatran. The adjusted hazard ratio (95% confidence interval), comparing dabigatran with warfarin, was 0.48 (0.25-0.91) for stroke or systemic embolism, and 0.91 (0.60-1.39) for any hemorrhage including intracranial and gastrointestinal. Conclusions: Number of patients prescribed direct oral anticoagulants steadily increased, and incidence of all-cause bleeding related to dabigatran was similar to warfarin, in our study population of younger non-valvular atrial fibrillation patients. Dabigatran, compared with warfarin, generally reduced risk of all-cause stroke and systemic embolism.

    DOI: 10.1093/fampra/cmz016

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  • Pattern of antibiotic prescriptions for outpatients with acute respiratory tract infections in Japan, 2013-15: A retrospective observational study 査読

    Yusuke Teratani, Hideharu Hagiya, Toshihiro Koyama, Mayu Adachi, Ayako Ohshima, Yoshito Zamami, Hiroyoshi Y. Tanaka, Yasuhisa Tatebe, Ken Tasaka, Naoko Mikami, Kazuaki Shinomiya, Yoshihisa Kitamura, Mitsunobu R. Kano, Shiro Hinotsu, Toshiaki Sendo

    Family Practice   36 ( 4 )   402 - 409   2019年8月

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    掲載種別:研究論文(学術雑誌)  

    Background: In this age of antimicrobial resistance, unnecessary use of antibiotics to treat non-bacterial acute respiratory tract infections (ARTIs) and inappropriate use of antibiotics in treating bacterial ARTIs are public health concerns. Purpose: Our aim is to identify the pattern of oral antibiotic prescriptions for outpatients with ARTIs in Japan. Methods: We analysed health insurance claims data of patients (aged ≤74 years) from 2013 to 2015, to determine the pattern of antibiotic prescriptions for outpatient ARTIs and calculated the proportion of each antibiotic. Results: Data on 4.6 million antibiotic prescriptions among 1559394 outpatients with ARTIs were analysed. The most commonly prescribed classes of antibiotics included cephalosporins (41.9%), macrolides (32.8%) and fluoroquinolones (14.7%). The proportion of first-, second- and third-generation cephalosporins was 1.0%, 1.7% and 97.3%, respectively. Fluoroquinolones accounted for a quarter of the prescriptions for ARTIs in patients aged >20 years. In contrast, penicillins accounted for just 8.0% of the total number of antibiotic prescriptions for ARTIs. Conclusions: According to clinical guidelines, penicillins are first-line antibiotics against ARTIs. However, third-generation cephalosporins, macrolides and fluoroquinolones are more frequently prescribed in Japan. Although we could not assess the extent to which appropriate antibiotics are selected, our results support the necessity of improving antibiotic choices in the treatment of ARTIs.

    DOI: 10.1093/fampra/cmy094

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  • Stroma Nanotechnologyを応用したDrug Delivery System 招待

    田中 啓祥, 狩野 光伸

    肝・胆・膵   75 ( 4 )   805 - 809   2017年10月

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    担当区分:筆頭著者   記述言語:日本語   出版者・発行元:(株)アークメディア  

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  • Desmoplastic Reaction in 3D-Pancreatic Cancer Tissues Suppresses Molecular Permeability 査読 国際誌

    Michiya Matsusaki, Misaki Komeda, Simona Mura, Hiroyoshi Y. Tanaka, Mitsunobu R. Kano, Patrick Couvreur, Mitsuru Akashi

    Advanced Healthcare Materials   6 ( 15 )   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    The survival rate of pancreatic ductal adenocarcinoma is still the lowest among all types of cancers, primarily as a consequence of an important desmoplastic reaction. Although the presence of thick stromal tissues in pancreatic tumors has been reported, in vivo animal studies do not enable a clear understanding of the crosstalk between cancer cells and fibroblasts. Accordingly, this paper reports the design and characterization of an in vitro pancreatic cancer–stromal 3D-tissue model, which enhances the understanding of the interactions between cancer cells and fibroblasts and their influence on the secretion of extracellular matrix (ECM). 3D-tissue models comprising fibroblasts and pancreatic cancer cells (MiaPaCa-2 cell line) or colon cancer cells (HT29 cell line, used as a control) show decreased molecular permeability with increased cancer cell ratios. The 3D-MiaPaCa-2 tissues display an increase in the secretion of collagen as a function of the cancer cell ratio, whereas 3D-HT29 tissues do not show a significant difference. Notably, the secretion of ECM proteins from single fibroblasts in 3D-tissue models containing 90% MiaPaCa-2 cells is ten times higher than that under 10% cancer cell conditions. In vitro pancreatic cancer 3D-tissues will be a valuable tool to obtain information on the interactions between cancer and stromal cells.

    DOI: 10.1002/adhm.201700057

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  • Regulation of endothelial Fas expression as a mechanism of promotion of vascular integrity by mural cells in tumors 査読 国際誌

    Ryosuke Kamei, Hiroyoshi Y. Tanaka, Takao Kawano, Chiharu Morii, Sayaka Tanaka, Hiroshi Nishihara, Caname Iwata, Mitsunobu R. Kano

    Cancer Science   108 ( 5 )   1080 - 1088   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    Angiogenesis is a multi-step process that culminates in vascular maturation whereby nascent vessels stabilize to become functional, and mural cells play an essential role in this process. Recent studies have shown that mural cells in tumors also promote and maintain vascular integrity, with wide-reaching clinical implications including the regulation of tumor growth, metastases, and drug delivery. Various regulatory signaling pathways have been hitherto implicated, but whether regulation of Fas-dependent apoptotic mechanisms is involved has not yet been fully investigated. We first compared endothelial FAS staining in human pancreatic ductal adenocarcinomas and colon carcinomas and show that the latter, characterized by lower mural cell coverage of tumor vasculature, demonstrated higher expression of FAS than the former. Next, in an in vitro coculture system of MS-1 and 10T1/2 cells as endothelial and mural cells respectively, we show that mural cells decreased endothelial Fas expression. Then, in an in vivo model in which C26 colon carcinoma cells were inoculated together with MS-1 cells alone or with the further addition of 10T1/2 cells, we demonstrate that mural cells prevented hemorrhage. Finally, knockdown of endothelial Fas sufficiently recapitulated the protection against hemorrhage seen with the addition of mural cells. These results together suggest that regulation of endothelial Fas signaling is involved in the promotion of vascular integrity by mural cells in tumors.

    DOI: 10.1111/cas.13216

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  • Increased fibrosis and impaired intratumoral accumulation of macromolecules in a murine model of pancreatic cancer co-administered with FGF-2 査読 国際誌

    Satoshi Sakai, Caname Iwata, Hiroyoshi Y. Tanaka, Horacio Cabral, Yasuyuki Morishita, Kohei Miyazono, Mitsunobu R. Kano

    Journal of Controlled Release   230   109 - 115   2016年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Pancreatic cancer is notorious for its poor prognosis. The histopathologic characteristic of pancreatic ductal adenocarcinoma (PDAC), which is the most common type of pancreatic cancer, is fibrosis within tumor tissue. Although fibrosis within tumor tissue is thought to impede drug therapy by interfering with the intratumoral accumulation of anti-tumor drugs, this hypothesis has yet to be proven directly in preclinical models. Here, we evaluated the effect of enhanced fibrosis on intratumoral accumulation of macromolecular drugs by increasing fibrosis in a murine tumor model of subcutaneously xenografted BxPC-3, a human PDAC cell line. When fibroblast growth factor-2 (FGF-2) was co-administered upon BxPC-3 inoculation, stromal fibrotic area was increased and was characterized by augmented murine collagen accumulation compared to inoculation of BxPC-3 alone, which correlated with increased monocyte/macrophage contents in the tumor tissues. We further discovered that the intratumoral accumulation of intravenously administrated fluorescein isothiocyanate-dextran of 2,000,000 Da (2 MDa) was significantly reduced in the FGF-2 co-administered tumors despite unaltered hyaluronan accumulation and pericyte coverage of the tumor neovasculature and increased lymphangiogenesis. Finally, we found that FGF-2 co-administered tumors are more refractory to macromolecular drug therapy using nab-paclitaxel (Abraxane). The model established and analyzed in this study, characterized by increased fibrotic component, provides a preclinical animal model suited to predict the intratumoral accumulation of macromolecular drugs and to evaluate the efficacy of drugs targeting the tumor stroma.

    DOI: 10.1016/j.jconrel.2016.04.007

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  • Secretions from placenta, after hypoxia/reoxygenation, can damage developing neurones of brain under experimental conditions 査読 国際誌

    Daniel J. Curtis, Aman Sood, Tom J. Phillips, Akihiro Nishiguchi, Veron H.L. Leinster, Christopher Coyle, Lizeth Lacharme-Lora, Oliver Beaumont, Helena Kemp, Roberta Goodall, Leila Cornes, Michele Giugliano, Rocco A. Barone, Michiya Matsusaki, Mitsuru Akashi, Hiroyoshi Y. Tanaka, Mitsunobu Kano, Jennifer McGarvey, Nagaraj D. Halemani, Katja Simon, Robert Keehan, William Ind, Tracey Masters, Simon Grant, Sharan Athwal, Gavin Collett, Dionne Tannetta, Ian L. Sargent, Emma Scull-Brown, Xun Liu, Kristian Aquilina, Nicki Cohen, Jon D. Lane, Marianne Thoresen, Jon Hanley, Andrew Randall, C. Patrick Case

    Experimental Neurology   261   386 - 395   2014年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Some psychiatric diseases in children and young adults are thought to originate from adverse exposures during foetal life, including hypoxia and hypoxia/reoxygenation. The mechanism is not understood. Several authors have emphasised that the placenta is likely to play an important role as the key interface between mother and foetus. Here we have explored whether a first trimester human placenta or model barrier of primary human cytotrophoblasts might secrete factors, in response to hypoxia or hypoxia/reoxygenation, that could damage neurones. We find that the secretions in conditioned media caused an increase of [Ca ] and mitochondrial free radicals and a decrease of dendritic lengths, branching complexity, spine density and synaptic activity in dissociated neurones from embryonic rat cerebral cortex. There was altered staining of glutamate and GABA receptors. We identify glutamate as an active factor within the conditioned media and demonstrate a specific release of glutamate from the placenta/cytotrophoblast barriers invitro after hypoxia or hypoxia/reoxygenation. Injection of conditioned media into developing brains of P4 rats reduced the numerical density of parvalbumin-containing neurones in cortex, hippocampus and reticular nucleus, reduced immunostaining of glutamate receptors and altered cellular turnover. These results show that the placenta is able to release factors, in response to altered oxygen, that can damage developing neurones under experimental conditions. © 2014 Elsevier Inc. 2+ i

    DOI: 10.1016/j.expneurol.2014.05.003

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書籍等出版物

  • Cancer Drug Delivery Systems Based on the Tumor Microenvironment

    ( 担当: 分担執筆 ,  範囲: Chapter 4 Stromal barriers within the tumor microenvironment and obstacles to nanomedicine)

    Springer Nature  2019年 

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  • DDS先端技術の製材への応用開発(共著)

    技術情報協会  2017年  ( ISBN:9784861046

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講演・口頭発表等

  • 線維化量を制御可能なヒト膵がん微小環境の三次元培養モデルの確立・解析とナノDDS研究への応用

    田中 啓祥, 狩野 光伸

    日本DDS学会学術集会プログラム予稿集  2021年6月  日本DDS学会

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    開催年月日: 2021年6月

    記述言語:日本語  

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  • 線維化量を自在に可変なヒト膵がん微小環境の三次元培養モデルの確立および解析

    田中 啓祥, 正宗 淳, 狩野 光伸

    第79回日本癌学会学術総会  2020年10月3日 

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    開催年月日: 2020年10月1日 - 2020年10月3日

    記述言語:英語   会議種別:口頭発表(一般)  

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  • 膵臓がん線維化組織の3D培養モデルを利用したナノ薬剤送達効率の解析

    田中 啓祥, 狩野 光伸

    日本DDS学会学術集会プログラム予稿集  2020年8月  日本DDS学会

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    開催年月日: 2020年8月

    記述言語:日本語  

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  • 次世代医工薬学に基づく"細胞編集"-バイオマテリアルを活かした細胞機能制御- 立体培養法を利用した疾患微小環境モデルの開発と病態解析

    田中 啓祥

    日本薬学会年会要旨集  2020年3月  (公社)日本薬学会

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    開催年月日: 2020年3月

    記述言語:日本語  

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  • 立体培養法による組織微小環境モデルの開発および疾患研究への応用

    田中啓祥, 狩野光伸, 狩野光伸

    日本化学会春季年会講演予稿集(CD-ROM)  2020年 

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    開催年月日: 2020年

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  • ヒト膵がん由来膵星状細胞を用いた三次元膵がん線維化モデルの構築ならびに異常ECM改築の機序の解析(Pancreatic stellate cells from human pancreatic cancer show aberrant ECM remodeling in 3D engineered fibrotic tissue)

    田中 啓祥, 西原 広史, 正宗 淳, 狩野 光伸

    日本癌学会総会記事  2019年9月  日本癌学会

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    開催年月日: 2019年9月

    記述言語:英語  

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  • Developing experimental models to analyze the behavior of Nano-DDSs within biological systems

    Mitsunobu R Kano, Hiroyoshi Y Tanaka

    Cancer science  2018年 

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    開催年月日: 2018年

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  • 膵臓がんにおいてナノ薬剤送達の障壁となる線維化組織の立体培養法によるモデル化および解析

    田中 啓祥, 狩野 光伸

    日本DDS学会学術集会プログラム予稿集  2019年6月 

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    記述言語:日本語  

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  • 疾患環境の理解とDDS 膵がんにおける組織構築の特徴とナノ薬剤の活用法を考える

    狩野 光伸, 田中 啓祥

    日本DDS学会学術集会プログラム予稿集  2018年5月 

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    記述言語:日本語  

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  • バイオマテリアルによるがん研究の展開(学際ネットワーク) ナノDDS研究のためのモデル開発

    狩野 光伸, 田中 啓祥

    日本癌学会総会記事  2017年9月 

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    記述言語:英語  

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  • 肺高血圧症症例由来の肺血管細胞を用いた血管モデルの構築

    久永 なつみ, 小川 愛子, 田中 啓祥, 狩野 光伸, 松原 広己

    血管  2017年1月 

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    記述言語:日本語  

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  • 膠芽腫幹細胞様細胞はFGF/FGFRシグナルを介し腫瘍血管の漏出性を減少させる

    田中 啓祥, 狩野 光伸

    日本癌学会総会記事  2016年10月 

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    記述言語:英語  

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  • Glioblastoma Stem-Like Cells Promote Barrier Integrity of Tumor Vasculature via FGF/FGFR Signaling

    The 75th Annual Meeting of the Japanese Cancer Association  2016年 

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受賞

  • 第三回日本バイオマテリアル学会中四国シンポジウム 優秀発表賞

    2015年  

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    受賞国:日本国

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共同研究・競争的資金等の研究

  • 立体培養法を用いた膵がん間質線維化における細胞とECMの異常配向獲得の機序解析

    研究課題/領域番号:20K16989  2020年04月 - 2023年03月

    日本学術振興会  科学研究費助成事業 若手研究  若手研究

    田中 啓祥

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

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  • 三次元培養法による膵がん微小環境の解析および治療標的の探索

    2019年 - 2020年

    川崎医学・医療福祉学振興会  令和元年度 川崎医学・医療福祉学振興会 教育研究助成 

    田中啓祥

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    担当区分:研究代表者 

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担当授業科目

  • 薬学基本実習 (2021年度) 1~3学期  - その他6~9

  • 薬学基本実習 (2021年度) 1~3学期  - その他6~9

  • 薬学基礎実習Ⅲ (2021年度) 第2学期  - その他6~9

  • 薬学基礎実習Ⅲ (2021年度) 第2学期  - その他6~9

  • 薬学基礎実習Ⅲ (2021年度) 第2学期  - その他6~9

  • 薬学基礎実習Ⅲ (2021年度) 第2学期  - その他6~9

  • 薬物治療学1 (2021年度) 第1学期  - 水1~2

  • 薬物治療学1 (2021年度) 第1学期  - 水1~2

  • 薬物治療学2 (2021年度) 第2学期  - 水1~2

  • 薬物治療学2 (2021年度) 第2学期  - 水1~2

  • 薬物治療学3 (2021年度) 第1学期  - 水3~4

  • 薬物治療学3 (2021年度) 第1学期  - 水3~4

  • 薬物治療学4 (2021年度) 第2学期  - 水3~4

  • 薬物治療学4 (2021年度) 第2学期  - 水3~4

  • 薬学基本実習 (2020年度) 特別  - その他

  • 薬学基本実習 (2020年度) 特別  - その他

  • 薬学基礎実習Ⅲ (2020年度) 第2学期  - その他

  • 薬学基礎実習Ⅲ (2020年度) 第2学期  - その他

  • 薬物治療学1 (2020年度) 第1学期  - 水1,水2

  • 薬物治療学1 (2020年度) 第1学期  - 水1,水2

  • 薬物治療学2 (2020年度) 第2学期  - 水1,水2

  • 薬物治療学2 (2020年度) 第2学期  - 水1,水2

  • 薬物治療学3 (2020年度) 第1学期  - 水3,水4

  • 薬物治療学3 (2020年度) 第1学期  - 水3,水4

  • 薬物治療学4 (2020年度) 第2学期  - 水3,水4

  • 薬物治療学4 (2020年度) 第2学期  - 水3,水4

  • 薬物治療学I (2020年度) 1・2学期  - 水1,水2

  • 薬物治療学II (2020年度) 1・2学期  - 水3,水4

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