2021/10/25 更新

写真a

コンドウ エイサク
近藤 英作
KONDO Eisaku
所属
教育研究院 医歯学系 医学系列 教授
医歯学総合研究科 分子細胞医学専攻 細胞機能 教授
職名
教授
外部リンク

学位

  • 医学博士 ( 1992年9月   岡山大学 )

研究キーワード

  • ホーミングペプチド

  • 分子病理学

  • 腫瘍生物学

  • 病理診断学

研究分野

  • ライフサイエンス / 人体病理学

  • ライフサイエンス / 実験病理学

  • ライフサイエンス / 腫瘍診断、治療学

経歴(researchmap)

  • 新潟大学医学部分子病理学(新潟大学大学院医歯学総合研究科分子細胞病理学分野)   教授

    2014年11月 - 現在

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  • 愛知県がんセンター(研究所腫瘍病理学部)   部長

    2009年11月 - 2014年10月

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  • Harvard Medical School   Department of Cell Biology   客員研究員

    1996年9月 - 1997年3月

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  • Harvard Medical School Dana-Farber Cancer Institute   ヒト・レトロウイルス学部門   リサーチフェロー

    1993年9月 - 1995年5月

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  • 岡山大学医学部病理学第二講座   助手~准教授

    1992年10月 - 2009年10月

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経歴

  • 新潟大学   医歯学総合研究科 分子細胞医学専攻 細胞機能   教授

    2014年11月 - 現在

学歴

  • 岡山大学大学院医学研究科病理系専攻 医学博士

    1992年9月

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  • 岡山大学医学部   医学科

    1988年3月

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所属学協会

  • 日本癌学会(評議員)

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  • 日本がん分子標的治療学会(評議員)

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  • 米国癌学会 (AACR active member)

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  • 日本病理学会(学術評議員)

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委員歴

  • 日本癌学会   評議員  

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    団体区分:学協会

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  • 日本がん分子標的治療学会   評議員  

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    団体区分:学協会

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  • 日本病理学会   学術評議員  

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    団体区分:学協会

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論文

  • PLOD2-driven IL-6/STAT3 signaling promotes the invasion and metastasis of oral squamous cell carcinoma via activation of integrin β1. 査読 国際誌

    Ken Saito, Ayaka Mitsui, I Wayan Sumardika, Yusuke Yokoyama, Masakiyo Sakaguchi, Eisaku Kondo

    International journal of oncology   58 ( 6 )   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We previously reported that high expression of procollagen‑lysine 2‑oxoglutarate 5‑dioxygenase 2 (PLOD2) leads to stabilization and plasma membrane translocation of integrin β1 to promote the invasion and metastasis of oral squamous cell carcinoma (SCC). The present study aimed to further understand the relationship between PLOD2‑integrin β1 signaling and the tumor microenvironment. This study provided further advanced insights indicating that elevated interleukin (IL)‑6 in the tumor microenvironment acts as a key molecule that triggers PLOD2‑integrin β1 axis‑derived acceleration of tumor invasion and metastasis. It was found using the dual‑luciferase reporter assay system that signal transducer and activator of transcription 3 (STAT3) activation by IL‑6 was essential for increasing the expression levels of PLOD2 through direct activation of the PLOD2 promoter in oral SCC, whereas IL‑6 stimulation did not contribute to integrin β1 expression or the subsequent maturation process towards a functional form on the plasma membrane. Furthermore, the expression of IL‑6 in oral SCC tissues was mainly observed in the tumor stroma. Finally, with double immunofluorescence staining, it was found that IL‑6 expression occurred in CD163‑positive M2 macrophages distributed around the tumor nest. These results combined with our previous results indicate that as IL‑6 significantly increases STAT3‑mediated PLOD2 promoter activity, IL‑6 released by M2‑type tumor‑associated macrophages is a crucial factor that promotes PLOD2‑integrin β1 axis‑enhanced invasion and metastasis of oral SCC cells.

    DOI: 10.3892/ijo.2021.5209

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  • Tumor-homing peptide and its utility for advanced cancer medicine. 査読 国際誌

    Eisaku Kondo, Hidekazu Iioka, Ken Saito

    Cancer science   2021年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cell-penetrating peptides, such as antibodies, have gained great attention as tools for the development of specific delivery systems for payloads, which might be applied as non-invasive carriers in vivo. Among these, tumor-homing peptides recently have been studied for use in tumor medicine. Tumor-homing peptides are oligopeptides, usually consisting of 30 or fewer amino acids that are efficiently and specifically incorporated into tumor cells, suggesting their potential use in establishing novel non-invasive tumor imaging systems for diagnostic and therapeutic applications. Here, we briefly introduce the biological characteristics of our tumor-homing peptides, focusing especially on those developed using a random peptide library constructed using mRNA display technology. The advantage of the tumor-homing peptides is their biological safety, given that these molecules do not show significant cytotoxicity against non-neoplastic cells; lack serious antigenicity, which alternatively might evoke unfavorable immune responses and inflammation in vivo; and are rapidly incorporated into target cells/tissues, with rates exceeding those seen for antibodies. Given their small size, tumor-homing peptides also are easy to modify and redesign. Based on these merits, tumor-homing peptides are expected to find wide application in various aspects of tumor medicine, including imaging diagnostics (eg, with dye-conjugated probes for direct visualization of invasive/metastatic tumor lesions in vivo) and therapeutics (eg, using peptide-drug conjugates [PDCs] for tumor targeting). Although further evidence will be required to demonstrate their practical utility, tumor-homing peptides are expected to show great potential as a next-generation bio-tool contributing to precision medicine for cancer patients.

    DOI: 10.1111/cas.14909

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  • PLOD2 Is Essential to Functional Activation of Integrin β1 for Invasion/Metastasis in Head and Neck Squamous Cell Carcinomas. 査読 国際誌

    Yushi Ueki, Ken Saito, Hidekazu Iioka, Izumi Sakamoto, Yasuhiro Kanda, Masakiyo Sakaguchi, Arata Horii, Eisaku Kondo

    iScience   23 ( 2 )   100850 - 100850   2020年2月

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    記述言語:英語  

    Identifying the specific functional regulator of integrin family molecules in cancer cells is critical because they are directly involved in tumor invasion and metastasis. Here we report high expression of PLOD2 in oropharyngeal squamous cell carcinomas (SCCs) and its critical role as a stabilizer of integrin β1, enabling integrin β1 to initiate tumor invasion/metastasis. Integrin β1 stabilized by PLOD2-mediated hydroxylation was recruited to the plasma membrane, its functional site, and accelerated tumor cell motility, leading to tumor metastasis in vivo, whereas loss of PLOD2 expression abrogated it. In accordance with molecular analysis, examination of oropharyngeal SCC tissues from patients corroborated PLOD2 expression associated with integrin β1 at the invasive front of tumor nests. PLOD2 is thus implicated as the key regulator of integrin β1 that prominently regulates tumor invasion and metastasis, and it provides important clues engendering novel therapeutics for these intractable cancers.

    DOI: 10.1016/j.isci.2020.100850

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  • PODXL1 promotes metastasis of the pancreatic ductal adenocarcinoma by activating the C5aR/C5a axis from the tumor microenvironment. 査読 国際誌

    Saito K, Iioka H, Maruyama S, Sumardika IW, Sakaguchi M, Kondo E

    Neoplasia (New York, N.Y.)   21 ( 12 )   1121 - 1132   2019年12月

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  • Crumbs3 is a critical factor that regulates invasion and metastasis of colon adenocarcinoma via the specific interaction with FGFR1. 査読 国際誌

    Iioka H, Saito K, Sakaguchi M, Tachibana T, Homma K, Kondo E

    International journal of cancer   145 ( 10 )   2740 - 2753   2019年11月

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    記述言語:英語  

    DOI: 10.1002/ijc.32336

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  • Crumbs3 regulates the expression of glycosphingolipids on the plasma membrane to promote colon cancer cell migration. 査読 国際誌

    Iioka H, Saito K, Kondo E

    Biochemical and biophysical research communications   519 ( 2 )   287 - 293   2019年11月

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  • Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts. 査読 国際誌

    Mitsui Y, Tomonobu N, Watanabe M, Kinoshita R, Sumardika IW, Youyi C, Murata H, Yamamoto KI, Sadahira T, Rodrigo AGH, Takamatsu H, Araki K, Yamauchi A, Yamamura M, Fujiwara H, Inoue Y, Futami J, Saito K, Iioka H, Kondo E, Nishibori M, Toyooka S, Yamamoto Y, Nasu Y, Sakaguchi M

    Oncology research   27 ( 8 )   945 - 956   2019年8月

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  • Newly developed anti-S100A8/A9 monoclonal antibody efficiently prevents lung tropic cancer metastasis. 査読 国際誌

    Rie Kinoshita, Hiroki Sato, Akira Yamauchi, Yuta Takahashi, Yusuke Inoue, I Wayan Sumardika, Youyi Chen, Nahoko Tomonobu, Kota Araki, Kazuhiko Shien, Shuta Tomida, Hidejiro Torigoe, Kei Namba, Eisuke Kurihara, Yusuke Ogoshi, Hitoshi Murata, Ken-Ichi Yamamoto, Junichiro Futami, Endy Widya Putranto, I Made Winarsa Ruma, Hiromasa Yamamoto, Junichi Soh, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

    International journal of cancer   145 ( 2 )   569 - 575   2019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)  

    The metastatic dissemination of cancer cells to remote areas of the body is the most problematic aspect in cancer patients. Among cancers, melanomas are notoriously difficult to treat due to their significantly high metastatic potential even during early stages. Hence, the establishment of advanced therapeutic approaches to regulate metastasis is required to overcome the melanoma disease. An accumulating mass of evidence has indicated a critical role of extracellular S100A8/A9 in melanoma distant metastasis. Lung S100A8/A9 is induced by melanoma cells from distant organs and it attracts these cells to its enriched lung environment since melanoma cells possess several receptors that sense the S100A8/A9 ligand. We hence aimed to develop a neutralizing antibody against S100A8/A9 that would efficiently block melanoma lung metastasis. Our protocol provided us with one prominent antibody, Ab45 that efficiently suppressed not only S100A8/A9-mediated melanoma mobility but also lung tropic melanoma metastasis in a mouse model. This prompted us to make chimeric Ab45, a chimera antibody consisting of mouse Ab45-Fab and human IgG2-Fc. Chimeric Ab45 also showed significant inhibition of the lung metastasis of melanoma. From these results, we have high hopes that the newly produced antibody will become a potential biological tool to block melanoma metastasis in future clinical settings.

    DOI: 10.1002/ijc.31982

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  • Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness. 査読 国際誌

    Youyi Chen, I Wayan Sumardika, Nahoko Tomonobu, Rie Kinoshita, Yusuke Inoue, Hidekazu Iioka, Yosuke Mitsui, Ken Saito, I Made Winarsa Ruma, Hiroki Sato, Akira Yamauchi, Hitoshi Murata, Ken-Ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Junichiro Futami, Miyoko Kubo, Endy Widya Putranto, Takashi Murakami, Ming Liu, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

    Neoplasia (New York, N.Y.)   21 ( 7 )   627 - 640   2019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)  

    Metastatic breast cancer is the leading cause of cancer-associated death in women. The progression of this fatal disease is associated with inflammatory responses that promote cancer cell growth and dissemination, eventually leading to a reduction of overall survival. However, the mechanism(s) of the inflammation-boosted cancer progression remains unclear. In this study, we found for the first time that an extracellular cytokine, S100A8/A9, accelerates breast cancer growth and metastasis upon binding to a cell surface receptor, melanoma cell adhesion molecule (MCAM). Our molecular analyses revealed an important role of ETS translocation variant 4 (ETV4), which is significantly activated in the region downstream of MCAM upon S100A8/A9 stimulation, in breast cancer progression in vitro as well as in vivo. The MCAM-mediated activation of ETV4 induced a mobile phenotype called epithelial-mesenchymal transition (EMT) in cells, since we found that ETV4 transcriptionally upregulates ZEB1, a strong EMT inducer, at a very high level. In contrast, downregulation of either MCAM or ETV4 repressed EMT, resulting in greatly weakened tumor growth and lung metastasis. Overall, our results revealed that ETV4 is a novel transcription factor regulated by the S100A8/A9-MCAM axis, which leads to EMT through ZEB1 and thereby to metastasis in breast cancer cells. Thus, therapeutic strategies based on our findings might improve patient outcomes.

    DOI: 10.1016/j.neo.2019.04.006

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  • Melanoma cell adhesion molecule is the driving force behind the dissemination of melanoma upon S100A8/A9 binding in the original skin lesion. 査読 国際誌

    Youyi Chen, I Wayan Sumardika, Nahoko Tomonobu, I Made Winarsa Ruma, Rie Kinoshita, Eisaku Kondo, Yusuke Inoue, Hiroki Sato, Akira Yamauchi, Hitoshi Murata, Ken-Ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Ming Liu, Junichiro Futami, Kaori Sasai, Hiroshi Katayama, Miyoko Kubo, Endy Widya Putranto, Toshihiko Hibino, Bei Sun, Masahiro Nishibori, Shinichi Toyooka, Masakiyo Sakaguchi

    Cancer letters   452   178 - 190   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Since metastasis accounts for the majority of cancer-associated deaths, studies on the mechanisms of metastasis are needed to establish innovative strategies for cancer treatment. We previously reported that melanoma cell adhesion molecule (MCAM) functions as a critical receptor for S100A8/A9, and binding of S100A8/A9 to MCAM results in the migration of melanoma cells to lung tissue. However, the critical role of MCAM in the original melanoma skin lesion is still not clear. In this study, we aimed to determine the importance of the S100A8/A9-MCAM axis in melanoma dissemination in a skin lesion as a critical early step for metastasis. Mechanistic studies revealed the downstream signaling of MCAM that signaled the induction of metastasis. S100A8/A9-MCAM binding activates mitogen-activated protein kinase kinase kinase 8 (MAP3K8), also termed TPL2, leading to strong activation of the transcription factor ETV4 and subsequent induction of matrix metalloproteinase-25 (MMP25), and finally to induction of melanoma lung tropic metastasis. Collectively, our results demonstrate a crucial role of the S100A8/A9-MCAM signaling axis in metastatic onset of melanoma cells and indicate that strategies targeting the identified pathway may be useful for the establishment of innovative anti-cancer therapies.

    DOI: 10.1016/j.canlet.2019.03.023

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  • Extracellular S100A11 Plays a Critical Role in Spread of the Fibroblast Population in Pancreatic Cancers. 査読 国際誌

    Takamatsu H, Yamamoto KI, Tomonobu N, Murata H, Inoue Y, Yamauchi A, Sumardika IW, Chen Y, Kinoshita R, Yamamura M, Fujiwara H, Mitsui Y, Araki K, Futami J, Saito K, Iioka H, Ruma IMW, Putranto EW, Nishibori M, Kondo E, Yamamoto Y, Toyooka S, Sakaguchi M

    Oncology research   27 ( 6 )   713 - 727   2019年6月

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  • exSSSRs (extracellular S100 soil sensor receptors)-Fc fusion proteins work as prominent decoys to S100A8/A9-induced lung tropic cancer metastasis. 査読 国際誌

    Rie Kinoshita, Hiroki Sato, Akira Yamauchi, Yuta Takahashi, Yusuke Inoue, I Wayan Sumardika, Youyi Chen, Nahoko Tomonobu, Kota Araki, Kazuhiko Shien, Shuta Tomida, Hidejiro Torigoe, Kei Namba, Eisuke Kurihara, Yusuke Ogoshi, Hitoshi Murata, Ken-Ichi Yamamoto, Junichiro Futami, Endy Widya Putranto, I Made Winarsa Ruma, Hiromasa Yamamoto, Junichi Soh, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

    International journal of cancer   144 ( 12 )   3138 - 3145   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Within the "seed and soil" theory of organ tropic cancer metastasis is a growing compilation of evidence that S100A8/A9 functions as a soil signal that attracts cancer cells to certain organs, which prove beneficial to their growth. S100A8/A9-sensing receptors including Toll-like receptor 4 (TLR4), advanced glycation end products (RAGE), and also important receptors we recently succeeded in identifying (EMMPRIN, NPTNβ, MCAM, and ALCAM) have the potential to become promising therapeutic targets. In our study, we prepared extracellular regions of these novel molecules and fused them to human IgG2-Fc to extend half-life expectancy, and we evaluated the anti-metastatic effects of the purified decoy proteins on metastatic cancer cells. The purified proteins markedly suppressed S100A8/A9-mediated lung tropic cancer metastasis. We hence expect that our novel biologics may become a prominent medicine to prevent cancer metastasis in clinical settings through cutting the linkage between "seed and soil".

    DOI: 10.1002/ijc.31945

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  • Neuroplastin-β mediates S100A8/A9-induced lung cancer disseminative progression. 査読 国際誌

    I Wayan Sumardika, Youyi Chen, Nahoko Tomonobu, Rie Kinoshita, I Made Winarsa Ruma, Hiroki Sato, Eisaku Kondo, Yusuke Inoue, Akira Yamauchi, Hitoshi Murata, Ken-Ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Junichiro Futami, Endy Widya Putranto, Toshihiko Hibino, Masahiro Nishibori, Shinichi Toyooka, Masakiyo Sakaguchi

    Molecular carcinogenesis   58 ( 6 )   980 - 995   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Compiling evidence indicates an unusual role of extracellular S100A8/A9 in cancer metastasis. S100A8/A9 secreted from either cancer cells or normal cells including epithelial and inflammatory cells stimulates cancer cells through S100A8/A9 sensor receptors in an autocrine or paracrine manner, leading to cancer cell metastatic progression. We previously reported a novel S100A8/A9 receptor, neuroplastin-β (NPTNβ), which plays a critical role in atopic dermatitis when it is highly activated in keratinocytes by an excess amount of extracellular S100A8/A9 in the inflammatory skin lesion. Interestingly, our expression profiling of NPTNβ showed significantly high expression levels in lung cancer cell lines in a consistent manner. We hence aimed to determine the significance of NPTNβ as an S100A8/A9 receptor in lung cancer. Our results showed that NPTNβ has strong ability to induce cancer-related cellular events, including anchorage-independent growth, motility and invasiveness, in lung cancer cells in response to extracellular S100A8/A9, eventually leading to the expression of a cancer disseminative phenotype in lung tissue in vivo. Mechanistic investigation revealed that binding of S100A8/A9 to NPTNβ mediates activation of NFIA and NFIB and following SPDEF transcription factors through orchestrated upstream signals from TRAF2 and RAS, which is linked to anchorage-independent growth, motility and invasiveness. Overall, our results indicate the importance of the S100A8/A9-NPTNβ axis in lung cancer disseminative progression and reveal a pivotal role of its newly identified downstream signaling, TRAF2/RAS-NFIA/NFIB-SPDEF, in linking to the aggressive development of lung cancers.

    DOI: 10.1002/mc.22987

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  • Identification of TRA-1-60-positive cells as a potent refractory population in follicular lymphomas. 査読 国際誌

    Takata K, Saito K, Maruyama S, Miyata-Takata T, Iioka H, Okuda S, Ling Y, Karube K, Miki Y, Maeda Y, Yoshino T, Steidl C, Kondo E

    Cancer Sci   110 ( 1 )   443 - 457   2019年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/cas.13870

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  • Visualizing the Rapid and Dynamic Elimination of Allogeneic T Cells in Secondary Lymphoid Organs. 査読 国際誌

    Kanda Y, Takeuchi A, Ozawa M, Kurosawa Y, Kawamura T, Bogdanova D, Iioka H, Kondo E, Kitazawa Y, Ueta H, Matsuno K, Kinashi T, Katakai T

    Journal of immunology (Baltimore, Md. : 1950)   201 ( 3 )   1062 - 1072   2018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)  

    DOI: 10.4049/jimmunol.1700219

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  • Embigin Promotes Prostate Cancer Progression by S100A4-Dependent and-Independent Mechanisms. 査読 国際誌

    Ruma IMW, Kinoshita R, Tomonobu N, Inoue Y, Kondo E, Yamauchi A, Sato H, Sumardika IW, Chen Y, Yamamoto KI, Murata H, Toyooka S, Nishibori M, Sakaguchi M

    Cancers   10 ( 7 )   2018年7月

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  • ß-1,3-galactosyl-O-glycosyl-glycoprotein ß-1,6-N-acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility. 査読 国際誌

    Sumardika IW, Youyi C, Kondo E, Inoue Y, Ruma IMW, Murata H, Kinoshita R, Yamamoto KI, Tomida S, Shien K, Satoh H, Yamauchi A, Futami J, Putranto EW, Hibino T, Toyooka S, Nishibori M, Sakaguchi M

    Oncology research   26 ( 3 )   431 - 444   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3727/096504017X15031557924123

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  • Design of peptide–dendrimer conjugates with tumor homing and antitumor effects 査読

    Chie Kojima, Ken Saito, Eisaku Kondo

    Research on Chemical Intermediates   44 ( 8 )   1 - 11   2018年1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:Springer Netherlands  

    Development of drug delivery systems for cancer therapy is a crucial issue. Previously, some peptides were designed as tumor homing cell-penetrating peptides with antitumor activities. In this study, dual function dendrimers with tumor targeting activities and antitumor effects were designed using the tumor targeting CPP44 peptide for acute myelogenous leukemia (AML) and the antitumor p16INK4a peptide. Two types of peptide–dendrimer conjugates were synthesized. One was a CPP44-linked p16INK4a peptide-conjugated dendrimer (tandem linked dendrimer) and the other was a dendrimer conjugated with separate CPP44 and p16INK4a peptides (parallel linked dendrimer). In addition, a peptide cathepsin B substrate was linked to the antitumor p16INK4a peptide to release it from the carriers. These peptide–dendrimer conjugates produced more effective antitumor effects than a CPP44-linked p16INK4a peptide. The parallel linked dendrimer showed less association with AML cells than the tandem linked dendrimer, but had greater antitumor effects. This suggested that both cellular uptake and antitumor peptide cleavage affected the antitumor activities of dual functional peptide-conjugated dendrimers.

    DOI: 10.1007/s11164-018-3280-9

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  • Stromal mesenchymal stem cells facilitate pancreatic cancer progression by regulating specific secretory molecules through mutual cellular interaction. 査読 国際誌

    Saito K, Sakaguchi M, Maruyama S, Iioka H, Putranto EW, Sumardika IW, Tomonobu N, Kawasaki T, Homma K, Kondo E

    Journal of Cancer   9 ( 16 )   2916 - 2929   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.7150/jca.24415

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  • Induction of Short NFATc1/αA Isoform Interferes with Peripheral B Cell Differentiation. 査読 国際誌

    Muhammad K, Rudolf R, Pham DAT, Klein-Hessling S, Takata K, Matsushita N, Ellenrieder V, Kondo E, Serfling E

    Frontiers in immunology   9   32 - 32   2018年

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  • Identification of a novel component leading to anti-tumor activity besides the major ingredient cordycepin in Cordyceps militaris extract 査読

    Takeharu Wada, I. Wayan Sumardika, Shingo Saito, I. Made Winarsa Ruma, Eisaku Kondo, Masami Shibukawa, Masakiyo Sakaguchi

    JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES   1061   209 - 219   2017年9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  

    In accordance with our previous study that was carried out to identify novel anti-tumor ingredients, chromatographic separation in combination with an anti-tumor activity assay was used for analysis of Cordyceps militaris extract in this study. Various modes of chromatography including reversed-phase, cation-exchange and anion exchange were used to separate components of Cordyceps militaris, which showed various chemical properties. Anti-tumor activity of each fraction was assessed by a Hoechst staining-based apoptosis assay using malignant melanoma MeWo cells. By these repeated approaches through chromatographic segregation and cell biological assay, we finally succeeded in identifying the target substance from a certain fraction that included neutral hydrophilic components using a pre-column and post-column chlorine adduct ionization LC APCI MS method. The target substance was a mono-carbohydrate, xylitol, that induced apoptotic cell death in MeWo cells but not in normal human OUMS-24 fibroblasts. This is the first study showing that Cordyceps militaris extract contains a large amount of xylitol. Thus, our results will contribute greatly to uncovering the mysterious multifunctional herbal drug Cordyceps militaris as an anti-tumor agent.

    DOI: 10.1016/j.jchromb.2017.07.022

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  • Differences in Urinary Renal Failure Biomarkers in Cancer Patients Initially Treated with Cisplatin. 査読 国際誌

    Maeda A, Ando H, Ura T, Muro K, Aoki M, Saito K, Kondo E, Takahashi S, Ito Y, Mizuno Y, Fujimura A

    Anticancer research   37 ( 9 )   5235 - 5239   2017年9月

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  • Association between ABCG2 and SLCO1B1 polymorphisms and adverse drug reactions to regorafenib: a preliminary study . 査読 国際誌

    Maeda A, Ando H, Ura T, Komori A, Hasegawa A, Taniguchi H, Kadowaki S, Muro K, Tajika M, Kobara M, Matsuzaki M, Hashimoto N, Maeda M, Kojima Y, Aoki M, Kondo E, Mizutani A, Fujimura A

    International journal of clinical pharmacology and therapeutics   55 ( 5 )   409 - 415   2017年5月

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    記述言語:英語  

    DOI: 10.5414/CP202788

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  • [Development of tumor-lineage homing peptide for their tailored application to diverse malignancies ]. 査読

    Saito K, Kondo E

    Seikagaku. The Journal of Japanese Biochemical Society   89 ( 1 )   44 - 50   2017年2月

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    記述言語:日本語  

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  • ß-1,3-galactosyl-O-glycosyl-glycoprotein ß-1,6-N-acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility. 査読

    Sumardika IW, Youyi C, Kondo E, Inoue Y, Ruma IMW, Murata H, Kinoshita R, Yamamoto KI, Tomida S, Shien K, Satoh H, Yamauchi A, Futami J, Putranto EW, Hibino T, Toyooka S, Nishibori M, Sakaguchi M

    Oncol Res   2017年

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  • Active Secretion of Dimerized S100A11 Induced by the Peroxisome in Mesothelioma Cells. 査読 国際誌

    Satomi Saho, Hiroki Satoh, Eisaku Kondo, Yusuke Inoue, Akira Yamauchi, Hitoshi Murata, Rie Kinoshita, Ken-Ichi Yamamoto, Junichiro Futami, Endy Widya Putranto, I Made Winarsa Ruma, I Wayan Sumardika, Chen Youyi, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Shuta Tomida, Yoshihiko Sakaguchi, Ken Saito, Hidekazu Iioka, Nam-Ho Huh, Shinichi Toyooka, Masakiyo Sakaguchi

    Cancer microenvironment : official journal of the International Cancer Microenvironment Society   9 ( 2-3 )   93 - 105   2016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)  

    S100A11, a small Ca2+ binding protein, acts extracellularly as a mediator of cancer progression. That raises the question of how a protein that lacks the classical secretory signal is able to be secreted outside cells without being damaged. Some insights into this question have been obtained, and there has been accumulating evidence indicating a pivotal role of a non-classical vesicle-mediated pathway using lysosomes or peroxisomes for the protein secretion. To obtain a more precise insight into the secretory mechanism of S100A11, we first screened representative cancer cells exhibiting significantly active secretion of S100A11. From the results of profiling, we turned our attention to aggressive cancer mesothelioma cells. In mesothelioma cells, we found that abundant dimeric S100A11 was produced selectively in the peroxisome after transportation of monomeric S100A11 through an interaction with PEX14, a peroxisome membrane protein, resulting in peroxisomal secretion of dimerized S100A11. In an extracellular environment in vitro, dimerized S100A11 promoted mesothelial cell invasion indirectly with the help of fibroblast cells. Overall, the results indicate that the peroxisome functions as an essential vesicle for the production of dimerized S100A11 and the subsequent secretion of the protein from mesothelioma cells and that peroxisome-mediated secretion of dimerized S100A11 might play a critical role in mesothelioma progression in a tumor microenvironment.

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  • Peptide-based tumor inhibitor encoding mitochondrial p14(ARF) is highly efficacious to diverse tumors. 査読 国際誌

    Ken Saito, Hidekazu Iioka, Chie Kojima, Mikako Ogawa, Eisaku Kondo

    Cancer science   107 ( 9 )   1290 - 301   2016年9月

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    記述言語:英語  

    p14(ARF) is one of the major tumor suppressors conventionally identified both as the mdm2-binding molecule restoring p53 function in the nucleus, and as a nucleophosmin-binding partner inside the nucleolous to stabilize ribosomal RNA. However, its recently reported mitochondrial localization has pointed to novel properties as a tumor suppressor. At the same time, functional peptides are gaining much attention in nanomedicine for their in vivo utility as non-invasive biologics. We previously reported the p14(ARF) -specific peptide that restored the sensitivity to gefitinib on the gefitinib-resistant lung cancer cells. Based on the information of this prototype peptide, here we generated the more powerful anti-tumor peptide "r9-CatB-p14 MIS," which comprises the minimal inhibitory sequence of the mitochondrial targeting p14(ARF) protein in combination with the proteolytic cleavage site for cathepsin B, which is activated in various tumor cells, fused with the nine-polyarginine-domain for cell penetration, and demonstrated its novel action of regulating mitochondrial function in accordance with localization of endogenous p14(ARF) . The p14 MIS peptide showed a potent tumor inhibiton in vitro and in vivo against not only lung cancer cells but also tumor cells of diverse lineages, via modulating mitochondrial membrane potential, with minimal cytotoxicity to non-neoplastic cells and tissues. Hence, this mitochondrially targeted p14 peptide agent provides a novel basis for non-invasive peptide-based antitumor therapeutics.

    DOI: 10.1111/cas.12991

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  • Regulation of B cell differentiation by the ubiquitin-binding protein TAX1BP1. 査読 国際誌

    Nobuko Matsushita, Midori Suzuki, Emi Ikebe, Shun Nagashima, Ryoko Inatome, Kenichi Asano, Masato Tanaka, Masayuki Matsushita, Eisaku Kondo, Hidekatsu Iha, Shigeru Yanagi

    Scientific reports   6   31266 - 31266   2016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)  

    Tax1-binding protein 1 (TAX1BP1) is a ubiquitin-binding protein that restricts nuclear factor-κB (NF-κB) activation and facilitates the termination of aberrant inflammation. However, its roles in B-cell activation and differentiation are poorly understood. To evaluate the function of TAX1BP1 in B cells, we established TAX1BP1-deficient DT40 B cells that are hyper-responsive to CD40-induced extracellular signal-regulated kinase (ERK) activation signaling, exhibit prolonged and exaggerated ERK phosphorylation and show enhanced B lymphocyte-induced maturation protein 1 (Blimp-1; a transcription factor inducing plasma cell differentiation) expression that is ERK-dependent. Furthermore, TAX1BP1-deficient cells exhibit significantly decreased surface IgM expression and increased IgM secretion. Moreover, TAX1BP1-deficient mice display reduced germinal center formation and antigen-specific antibody production. These findings show that TAX1BP1 restricts ERK activation and Blimp-1 expression and regulates germinal center formation.

    DOI: 10.1038/srep31266

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  • MCAM, as a novel receptor for S100A8/A9, mediates progression of malignant melanoma through prominent activation of NF-κB and ROS formation upon ligand binding. 査読

    Ruma IM, Putranto EW, Kondo E, Murata H, Watanabe M, Huang P, Kinoshita R, Futami J, Inoue Y, Yamauchi A, Sumardika IW, Youyi C, Yamamoto K, Nasu Y, Nishibori M, Hibino T, Sakaguchi M

    Clinical & experimental metastasis   33 ( 6 )   609 - 627   2016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)  

    DOI: 10.1007/s10585-016-9801-2

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  • GANP protein encoded on human chromosome 21/mouse chromosome 10 is associated with resistance to mammary tumor development. 査読 国際誌

    Kazuhiko Kuwahara, Mutsuko Yamamoto-Ibusuki, Zhenhuan Zhang, Suchada Phimsen, Naomi Gondo, Hiroko Yamashita, Toru Takeo, Naomi Nakagata, Daisuke Yamashita, Yoshimi Fukushima, Yutaka Yamamoto, Hiroji Iwata, Hideyuki Saya, Eisaku Kondo, Keitaro Matsuo, Motohiro Takeya, Hirotaka Iwase, Nobuo Sakaguchi

    Cancer science   107 ( 4 )   469 - 77   2016年4月

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    記述言語:英語  

    Human chromosome 21 is known to be associated with the high risk of hematological malignancy but with resistance to breast cancer in the study of Down syndrome. In human cancers, we previously observed the significant alterations of the protein expression encoded by the ganp/MCM3AP gene on human chromosome 21q22.3. Here, we investigated GANP protein alterations in human breast cancer samples (416 cases) at various stages by immunohistochemical analysis. This cohort study clearly showed that expression of GANP is significantly decreased in human breast cancer cases with poor prognosis as an independent risk factor (relapse-free survival, hazard ratio = 2.37, 95% confidence interval, 1.27-4.42, P = 0.007 [univariate analysis]; hazard ratio = 2.70, 95% confidence interval, 1.42-5.13, P = 0.002 [multivariate analysis]). To investigate whether the altered GANP expression is associated with mammary tumorigenesis, we created mutant mice that were conditionally deficient in the ganp/MCM3AP gene using wap-cre recombinase transgenic mice. Mammary gland tumors occurred at a very high incidence in female mammary gland-specific GANP-deficient mice after severe impairment of mammary gland development during pregnancy. Moreover, tumor development also occurred in female post parous GANP-heterodeficient mice. GANP has a significant role in the suppression of DNA damage caused by estrogen in human breast cancer cell lines. These results indicated that the GANP protein is associated with breast cancer resistance.

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  • Preferential HER2 expression in liver metastases and EGFR expression in peritoneal metastases in patients with advanced gastric cancer 査読

    Takuya Saito, Hayao Nakanishi, Yoshinari Mochizuki, Seiji Ito, Yuichi Ito, Kazunari Misawa, Yasushi Yatabe, Keigo Yamamichi, Eisaku Kondo

    GASTRIC CANCER   18 ( 4 )   711 - 719   2015年10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:SPRINGER  

    Despite recent clinical trials, the sensitivity and resistance of metastatic gastric cancer to anti-HER2 and anti-EGFR therapy are still unclear.
    To clarify the HER2 and EGFR expression status in the metastatic sites, we immunohistochemically compared HER2 and EGFR expression between primary and metastatic tumors from 52 gastric cancer patients with liver metastases and 85 patients with peritoneal metastases.
    The HER2 positivity rate of primary and metastatic tumors in patients with liver metastases, especially with intestinal-type histology (70.6 and 80.0 %, respectively), was significantly higher than in primary and metastatic tumors (22.4 and 16.4 %, respectively) in patients with peritoneal metastases. HER2 positivity of the primary tumor and liver metastases showed good concordance (87.5 %) in patients with liver metastases. In contrast, the EGFR positivity rate of metastatic tumors (70.1 %) in patients with peritoneal metastases was significantly higher than that of metastatic tumors (37.5 %) in patients with liver metastases. HER2 and EGFR expression tended to be mutually exclusive, and HER2/EGFR double-positive cases were rare in patients with liver or peritoneal metastases. In four such patients with HER2/EGFR double-positive primary tumors, the HER2- and EGFR-positive areas were separate, and corresponding liver metastasis was only positive for HER2 and peritoneal metastasis only positive for EGFR.
    These results indicate that HER2 and EGFR are preferentially expressed in the liver and peritoneal metastases, respectively, which would be potential targets for anti-HER2 and anti-EGFR molecular therapy in metastatic gastric cancer patients.

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    その他リンク: http://orcid.org/0000-0003-1788-559X

  • Identification of a novel cell-penetrating peptide targeting human glioblastoma cell lines as a cancer-homing transporter. 査読 国際誌

    Moritoshi Higa, Chiaki Katagiri, Chigusa Shimizu-Okabe, Tomoyuki Tsumuraya, Masanori Sunagawa, Mariko Nakamura, Shogo Ishiuchi, Chitoshi Takayama, Eisaku Kondo, Masayuki Matsushita

    Biochemical and biophysical research communications   457 ( 2 )   206 - 12   2015年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cell-penetrating peptides (CPPs) as a novel biomedical delivery system have been highly anticipated, since they can translocate across biological membranes and are capable of transporting their cargo inside live cells with minimal invasiveness. However, non-selective internalization in various cell types remains a challenge in the clinical application of CPPs, especially in cancer treatment. In this study, we attempted to identify novel cancer-homing CPPs to target glioblastoma multiforme (GBM), which is often refractory and resistant to treatment. We screened for CPPs showing affinity for the human GBM cell line, U87MG, from an mRNA display random peptide library. One of the candidate peptides which amino-acid sequence was obtained from the screening showed selective cell-penetrating activity in U87MG cells. Conjugation of the p16(INK4a) functional peptide to the GBM-selective CPP induced cellular apoptosis and reduced phosphorylated retinoblastoma protein levels. This indicates that the CPP was capable of delivering a therapeutic molecule into U87MG cells inducing apoptosis. These results suggest that the novel CPP identified in this study permeates with high affinity into GBM cells, revealing it to be a promising imaging and therapeutic tool in the treatment of glioblastoma.

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  • NF-kappa B factors control the induction of NFATc1 in B lymphocytes 査読

    Khalid Muhammad, Hani Alrefai, Ralf Marienfeld, Duong Anh Thuy Pham, Krisna Murti, Amiya K. Patra, Andris Avots, Valesca Bukur, Ugur Sahin, Eisaku Kondo, Stefan Klein-Hessling, Edgar Serfling

    EUROPEAN JOURNAL OF IMMUNOLOGY   44 ( 11 )   3392 - 3402   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:WILEY-BLACKWELL  

    In peripheral lymphocytes, the transcription factors (TFs) NF-B, NFAT, and AP-1 are the prime targets of signals that emerge from immune receptors. Upon activation, these TFs induce gene networks that orchestrate the growth, expansion, and effector function of peripheral lymphocytes. NFAT and NF-B factors share several properties, such as a similar mode of induction and architecture in their DNA-binding domain, and there is a subgroup of B-like DNA promoter motifs that are bound by both types of TFs. However, unlike NFAT and AP-1 factors that interact and collaborate in binding to DNA, NFAT, and NF-B seem neither to interact nor to collaborate. We show here that NF-B1/p50 and c-Rel, the most prominent NF-B proteins in BCR-induced splenic B cells, control the induction of NFATc1/A, a prominent short NFATc1 isoform. In part, this is mediated through two composite B/NFAT-binding sites in the inducible Nfatc1 P1 promoter that directs the induction of NFATc1/A by BCR signals. In concert with coreceptor signals that induce NF-B factors, BCR signaling induces a persistent generation of NFATc1/A. These data suggest a tight connection between NFATc1 and NF-B induction in B lymphocytes contributing to the effector function of peripheral B cells.

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  • Deficient HER3 expression in poorly-differentiated colorectal cancer cells enhances gefitinib sensitivity 査読

    Susumu Nakata, Harunari Tanaka, Yuichi Ito, Masayasu Hara, Mitsugu Fujita, Eisaku Kondo, Yukihide Kanemitsu, Yasushi Yatabe, Hayao Nakanishi

    INTERNATIONAL JOURNAL OF ONCOLOGY   45 ( 4 )   1583 - 1593   2014年10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:SPANDIDOS PUBL LTD  

    Poorly-differentiated colorectal cancers (PD-CRC) show high metastatic potential and poor prognosis. However, molecular characteristics of PD-CRC remain unknown to date, particularly in molecular targeting therapy for patients with PD-CRC. In this study, we examined the expression of EGFR, HERZ and HER3 in PD-CRC by immunohistochemical analysis of archived clinical specimens of primary tumors and investigated the sensitivity of PD-CRC cell lines to gefitinib, a tyrosine kinase inhibitor for EGFR in vitro. We found that HER3 expression of PD-CRC among members of the HER family was significantly lower than that of well to moderately differentiated CRC (WMD-CRC) and 37% of the PD cases showed a EGFR(+)/HER2(+)/HER3(-) expression pattern. COLM-5 cells, a PD-CRC-derived cell line, which exhibits EGFR(+)/HER2(+)/HER3(-) expression pattern and recapitulates the typical histology of PD-CRC in xenografted tumors, showed high gefitinib sensitivity both in vitro and in vivo, compared with WMD-CRC cell line (COLM-2). Treatment with gefitinib resulted in the upregulation of p27(Kip1)(10 expression and induction of G1 cell cycle arrest, concomitantly associated with inactivation of PI3K/Akt signaling in COLM-5 cells and marked inhibition of xenografted tumors in nude mice, but not evident in COLM-2 cells. Treatment with sodium butyrate, an HDAC inhibitor that induces differentiation, upregulated the expression of HER3 associated with enhancement of the PI3K/Akt signaling, attenuated gefitinib-mediated p27(Kip1) upregulation and reduced gefitinib sensitivity in COLM-5 cells in vitro. Furthermore, enforced expression of HER3 in COLM-5 cells resulted in significant resistance to gefitinib treatment both in vitro and in vivo. These findings suggest that deficient HER3 expression plays an important role in gefitinib sensitivity and that a malignant subset of PD with EGFR(+)/HER2(+)/HER3(-) phenotype is a potential candidate for a target of anti-EGFR molecular therapy such as gefitinib.

    DOI: 10.3892/ijo.2014.2538

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  • New whole-body multimodality imaging of gastric cancer peritoneal metastasis combining fluorescence imaging with ICG-labeled antibody and MRI in mice 査読

    Akihiro Ito, Yuichi Ito, Shigeru Matsushima, Daisuke Tsuchida, Mai Ogasawara, Junichi Hasegawa, Kazunari Misawa, Eisaku Kondo, Norio Kaneda, Hayao Nakanishi

    GASTRIC CANCER   17 ( 3 )   497 - 507   2014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)   出版者・発行元:SPRINGER  

    Peritoneal metastasis is the most frequent pattern of recurrence after curative surgery for gastric cancer. However, such a recurrence is difficult to detect by conventional computed tomography (CT) and magnetic resonance imaging (MRI) at an early stage. To improve the sensitivity and specificity of diagnostic imaging for peritoneal metastasis, we developed a new type of multimodality imaging combining fluorescence imaging with near-infrared fluorophore (NIR)-labeled antibodies and MRI.
    Dual optical imaging of peritoneal metastasis was carried out using luciferase-tagged gastric cancer cell lines and XenoLight CF750 or indocyanine green (ICG)-labeled anti-human epidermal growth factor receptor (EGFR) or CEA antibody as a probe in mice with Ivis in vivo imaging system.
    This whole-body fluorescent imaging system sensitively detected metastatic foci < 1 mm in diameter in the peritoneal cavity noninvasively. Fluorescence imaging proved to be specific because the fluorescence signal was abolished by blocking with excess unlabeled antibody. Although this fluorescence imaging had higher sensitivity for detection of small-sized peritoneal metastases than MRI, it proved difficult to accurately determine organ distribution of the metastasis. We thus developed a multimodality imaging system by the fusion of the three-dimensional fluorescence image with the MRI image and demonstrated its improved diagnostic accuracy over either method alone.
    The present results suggest that multimodality imaging consisting of fluorescence imaging with NIR-labeled EGFR or CEA antibody and MRI allows sensitive, specific, and anatomically accurate detection of peritoneal metastasis noninvasively at an early stage.

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  • Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells. 査読 国際誌

    I Made Winarsa Ruma, Endy Widya Putranto, Eisaku Kondo, Risayo Watanabe, Ken Saito, Yusuke Inoue, Ken-Ichi Yamamoto, Susumu Nakata, Masaji Kaihata, Hitoshi Murata, Masakiyo Sakaguchi

    International journal of oncology   45 ( 1 )   209 - 18   2014年7月

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    記述言語:英語  

    Angiogenesis is essential for tumor development and metastasis. Among several angiogenic factors, vascular endothelial growth factor receptor (VEGF) is important for tumor-derived angiogenesis and commonly overexpressed in solid tumors. Thus, many antitumor strategies targeting VEGF have been developed to inhibit cancer angiogenesis, offering insights into the successful treatment of solid cancers. However, there are a number of issues such as harmful effects on normal vascularity in clinical trials. Taking this into consideration, we employed Cordyceps militaris as an antitumor approach due to its biological safety in vivo. The herbal medicinal mushroom Cordyceps militaris has been reported to show potential anticancer properties including anti-angiogenic capacity; however, its concrete properties have yet to be fully demonstrated. In this study, we aimed to elucidate the biological role of Cordyceps militaris extract in tumor cells, especially in regulating angiogenesis and tumor growth of a human malignant melanoma cell line. We demonstrated that Cordyceps militaris extract remarkably suppressed tumor growth via induction of apoptotic cell death in culture that links to the abrogation of VEGF production in melanoma cells. This was followed by mitigation of Akt1 and GSK-3β activation, while p38α phosphorylation levels were increased. Extract treatment in mouse model xenografted with human melanoma cells resulted in a dramatic antitumor effect with down-regulation of VEGF expression. The results suggest that suppression of tumor growth by Cordyceps militaris extract is, at least, mediated by its anti-angiogenicity and apoptosis induction capacities. Cordyceps militaris extract may be a potent antitumor herbal drug for solid tumors.

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  • Coxsackie and adenovirus receptor is a critical regulator for the survival and growth of oral squamous carcinoma cells 査読

    K. Saito, M. Sakaguchi, H. Iioka, M. Matsui, H. Nakanishi, N. H. Huh, E. Kondo

    ONCOGENE   33 ( 10 )   1274 - 1286   2014年3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:NATURE PUBLISHING GROUP  

    Coxsackie and adenovirus receptor (CAR) is essential for adenovirus infection to target cells, and its constitutive expression in various cancerous and normal tissues has been reported. Recently, the biological role of CAR in human cancers of several different origins has been investigated with respect to tumor progression, metastasis and tumorigenesis. However, its biological function in tumor cells remains controversial. Here we report the critical role of CAR in growth regulation of oral squamous cell carcinomas (SCCs) in vitro and in vivo via the specific interaction with Rho-associated protein kinase (ROCK). Loss of endogenous CAR expression by knockdown using specific small interfering RNA (siRNA) against CAR facilitates growth suppression of SCC cells due to cell dissociation, followed by apoptosis. The consequent morphological reaction was reminiscent of anoikis, rather than epithelial-mesenchymal transition, and the dissociation of oral SCC cells was triggered not by lack of contact with extracellular matrix, but by loss of cell-to-cell contact caused by abnormal translocation of E-cadherin from surface membrane to cytoplasm. Immunoprecipitation assays of the CAR-transfected oral SCC cell line, HSC-2, with or without ROCK inhibitor (Y-27632) revealed that CAR directly associates with ROCK! and ROCKII, which results in inhibition of ROCK activity and contributes to maintenance of cell-to-cell adhesion for their growth and survival. Based on these findings, in vivo behavior of CAR-downregulated HSC-2 cells from siRNA knockdown was compared with that of normally CAR-expressing cells in intraperitoneally xenografted mouse models. The mice engrafted with CAR siRNA-pretreated HSC-2 cells showed poor formation of metastatic foci in contrast to those implanted with the control siRNA-pretreated cells. Thus, CAR substantially has an impact on growth and survival of oral SCC cells as a negative regulator of ROCK in vitro and in vivo.

    DOI: 10.1038/onc.2013.66

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  • Development of a New Rapid Isolation Device for Circulating Tumor Cells (CTCs) Using 3D Palladium Filter and Its Application for Genetic Analysis 査読

    Akiko Yusa, Makoto Toneri, Taisuke Masuda, Seiji Ito, Shuhei Yamamoto, Mina Okochi, Naoto Kondo, Hiroji Iwata, Yasushi Yatabe, Yoshiyuki Ichinosawa, Seichin Kinuta, Eisaku Kondo, Hiroyuki Honda, Fumihito Arai, Hayao Nakanishi

    PLOS ONE   9 ( 2 )   e88821   2014年2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:PUBLIC LIBRARY SCIENCE  

    Circulating tumor cells (CTCs) in the blood of patients with epithelial malignancies provide a promising and minimally invasive source for early detection of metastasis, monitoring of therapeutic effects and basic research addressing the mechanism of metastasis. In this study, we developed a new filtration-based, sensitive CTC isolation device. This device consists of a 3-dimensional (3D) palladium (Pd) filter with an 8 mu m-sized pore in the lower layer and a 30 mu m-sized pocket in the upper layer to trap CTCs on a filter micro-fabricated by precise lithography plus electroforming process. This is a simple pump-less device driven by gravity flow and can enrich CTCs from whole blood within 20 min. After on-device staining of CTCs for 30 min, the filter cassette was removed from the device, fixed in a cassette holder and set up on the upright fluorescence microscope. Enumeration and isolation of CTCs for subsequent genetic analysis from the beginning were completed within 1.5 hr and 2 hr, respectively. Cell spike experiments demonstrated that the recovery rate of tumor cells from blood by this Pd filter device was more than 85%. Single living tumor cells were efficiently isolated from these spiked tumor cells by a micromanipulator, and KRAS mutation, HER2 gene amplification and overexpression, for example, were successfully detected from such isolated single tumor cells. Sequential analysis of blood from mice bearing metastasis revealed that CTC increased with progression of metastasis. Furthermore, a significant increase in the number of CTCs from the blood of patients with metastatic breast cancer was observed compared with patients without metastasis and healthy volunteers. These results suggest that this new 3D Pd filter-based device would be a useful tool for the rapid, cost effective and sensitive detection, enumeration, isolation and genetic analysis of CTCs from peripheral blood in both preclinical and clinical settings.

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  • Lapatinib sensitivities of two novel trastuzumab-resistant HER2 gene-amplified gastric cancer cell lines. 査読

    Yukiko Oshima, Harunari Tanaka, Hiroki Murakami, Yuichi Ito, Tomomi Furuya, Eisaku Kondo, Yasuhiro Kodera, Hayao Nakanishi

    Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association   17 ( 3 )   450 - 62   2014年

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    記述言語:英語  

    BACKGROUND: Trastuzumab (Tmab) resistance is a major clinical problem to be resolved in patients with HER2-positive gastric cancers. However, in contrast to the situation for HER2-positive breast cancer lines, the Tmab-resistant gastric cancer preclinical models that are needed to develop a new therapy to overcome this problem are not yet available. METHODS: We developed three new cell lines from HER2 gene-amplified gastric cancer cell lines (GLM-1, GLM-4, NCI N-87) by a new in vivo selection method consisting of the repeated culture of small residual peritoneal metastasis but not subcutaneous tumor after Tmab treatment. We then evaluated the anti-tumor efficacy of lapatinib for these Tmab-resistant cells. RESULTS: We successfully isolated two Tmab-resistant cell lines (GLM1-HerR2(3), GLM4-HerR2) among the three tested cell lines. These resistant cells differed from the parental cells in their flat morphology and rapid growth in vitro, but HER2, P95HER2 expression, and Tmab binding were essentially the same for the parental and resistant cells. MUC4 expression was up- or downregulated depending on the cell line. These resistant cells were still sensitive to lapatinib, similar to the parental cells, in vitro. This growth inhibition of the Tmab-resistant cells by lapatinib was due to both G1 cell-cycle arrest and apoptosis induction via effective blockade of the PI3K/Akt and MAPK pathways. A preclinical study confirmed that the Tmab-resistant tumors are significantly susceptible to lapatinib. CONCLUSION: These results suggest that lapatinib has antitumor activity against the Tmab-resistant gastric cancer cell lines, and that these cell lines are useful for understanding the mechanism of Tmab resistance and for developing a new molecular therapy for Tmab-resistant HER2-positive gastric cancers.

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  • Establishment of new intraperitoneal paclitaxel-resistant gastric cancer cell lines and comprehensive gene expression analysis. 査読 国際誌

    Hiroki Murakami, Seiji Ito, Harunari Tanaka, Eisaku Kondo, Yasuhiro Kodera, Hayao Nakanishi

    Anticancer research   33 ( 10 )   4299 - 307   2013年10月

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    記述言語:英語  

    BACKGROUND: Intraperitoneal (i.p.) chemotherapy with paclitaxel is a potential therapeutic modality for patients with peritoneal metastasis of gastric cancer. To overcome paclitaxel resistance, which is a major clinical problem with this modality, prediction of i.p. paclitaxel resistance is critically important. MATERIALS AND METHODS: We developed three new i.p. paclitaxel-resistant cell lines from parental gastric cancer cell lines by an in vivo selection method using i.p. paclitaxel chemotherapy. With these cell lines, we performed gene expression profiling analysis to select up-regulated genes in i.p. paclitaxel-resistant cells and validated the genes with clinical samples. RESULTS: We successfully isolated nine up-regulated genes in i.p. paclitaxel-resistant cell lines compared with parental cells by microarray analysis, followed by confirmation with quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Among these, we identified four genes, namely kinesin family member-23 (KIF23), ERBB2 interacting protein (ERBB2IP), ATPase family, AAA domain containing-2 (ATAD2) and PHD finger protein (PHF19) as candidate genes for paclitaxel resistance after validation with clinical samples derived from responders and non-responders to paclitaxel treatment. CONCLUSION: These i.p. paclitaxel-resistant cell lines are ideal models for understanding the mechanism of resistance to i.p. paclitaxel and development of a new therapeutic modality. Four up-regulated genes may be potential new predictive markers for resistance to i.p. paclitaxel in patients with peritoneal metastasis of gastric cancer.

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  • Antitumor impact of p14ARF on gefitinib-resistant non-small cell lung cancers. 査読 国際誌

    Ken Saito, Nagio Takigawa, Naoko Ohtani, Hidekazu Iioka, Yuki Tomita, Ryuzo Ueda, Junya Fukuoka, Kazuhiko Kuwahara, Eiki Ichihara, Katsuyuki Kiura, Eisaku Kondo

    Molecular cancer therapeutics   12 ( 8 )   1616 - 28   2013年8月

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    記述言語:英語  

    Activation of the epidermal growth factor receptor (EGFR) has been observed in many malignant tumors and its constitutive signal transduction facilitates the proliferation of tumors. EGFR-tyrosine kinase inhibitors, such as gefitinib, are widely used as a molecular-targeting agent for the inactivation of EGFR signaling and show considerable therapeutic effect in non-small cell lung cancers harboring activating EGFR mutations. However, prolonged treatment inevitably produces tumors with additional gefitinib-resistant mutations in EGFR, which is a critical issue for current therapeutics. We aimed to characterize the distinct molecular response to gefitinib between the drug-resistant and drug-sensitive lung adenocarcinoma cells in order to learn about therapeutics based on the molecular information. From the quantitative PCR analysis, we found a specific increase in p14(ARF) expression in gefitinib-sensitive lung adenocarcinoma clones, which was absent in gefitinib-resistant clones. Moreover, mitochondria-targeted p14(ARF) triggered the most augmented apoptosis in both clones. We identified the amino acid residues spanning from 38 to 65 as a functional core of mitochondrial p14(ARF) (p14 38-65 a.a.), which reduced the mitochondrial membrane potential and caused caspase-9 activation. The synthesized peptide covering the p14 38-65 a.a. induced growth suppression of the gefitinib-resistant clones without affecting nonneoplastic cells. Notably, transduction of the minimized dose of the p14 38-65 peptide restored the response to gefitinib like that in the sensitive clones. These findings suggest that the region of p14(ARF) 38-65 a.a. is critical in the pharmacologic action of gefitinib against EGFR-mutated lung adenocarcinoma cells and has potential utility in the therapeutics of gefitinib-resistant cancers.

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  • Positive and negative regulation of podoplanin expression by TGF-β and histone deacetylase inhibitors in oral and pharyngeal squamous cell carcinoma cell lines. 査読 国際誌

    Mitsuhiko Ohta, Atsushi Abe, Fumi Ohno, Yasuhisa Hasegawa, Harunari Tanaka, Shinichiro Maseki, Eisaku Kondo, Kenichi Kurita, Hayao Nakanishi

    Oral oncology   49 ( 1 )   20 - 6   2013年1月

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    記述言語:英語  

    OBJECTIVES: Podoplanin, a transmembrane sialomucin-like glycoprotein, is known to express at high frequency in oral squamous cell carcinomas (OSCC) and possess metastasis-promoting activity such as increased invasion and platelet-aggregating activity. However, the regulatory mechanism of podoplanin expression in OSCC remains unknown. MATERIALS AND METHODS: In the present study, we investigated the podoplanin expression in both clinical specimens from total 80 patients (50 OSCC and 30 pharyngeal SCC) and in 4 OSCC cell lines in vitro. RESULTS: Immunohistochemical analysis of surgically resected specimens of OSCC revealed podoplanin expression in 70% of OSCC cases with localization primarily in the basal layer of squamous cancer nest and the expression was inversely correlated with squamous cell differentiation. In vitro analysis of OSCC cell lines revealed 36 that podoplanin expression was decreased in response to the squamous cell differentiation (Cytokeratin 10 expression as a marker) induced by treatment with histone deacetylase (HDAC) inhibitors such as sodium butyrate and trichostatin. Furthermore, transforming growth factor-β (TGF-β) significantly enhanced podoplanin expression in OSCC cell lines in line with increased phosphorylation of Smad2. A TGF-β type I receptor inhibitor (SB431542) significantly inhibited such induction of podoplanin expression by TGF-β at both the protein and mRNA level. However, in a subset of OSCC cell line, its expression was only weakly dependent on TGF-β and squamous differentiation. CONCLUSION: These results suggest that regulation of podoplanin is not simple, but in the majority of OSCC cell lines, its expression is positively and negatively regulated by TGF-β receptor/Smad signaling pathway and epigenetic mechanism leading to squamous differentiation, respectively.

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  • Establishment and characterization of novel gastric signet-ring cell and non signet-ring cell poorly differentiated adenocarcinoma cell lines with low and high malignant potential 査読

    Hiroki Murakami, Hayao Nakanishi, Harunari Tanaka, Seiji Ito, Kazunari Misawa, Yuuichi Ito, Yuzuru Ikehara, Eisaku Kondo, Yasuhiro Kodera

    GASTRIC CANCER   16 ( 1 )   74 - 83   2013年1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:SPRINGER  

    Background Poorly differentiated signet-ring cell carcinoma (SRCC) and non signet-ring cell carcinoma (NSRCC) are prevalent histological subtypes of gastric cancers with distinct morphological features. To date, however, the molecular basis of their growth, differentiation, and metastasis still remains unclear, because of the limitation of available cell lines.
    Methods In the present study, we established novel SRCC and NSRCC cell lines (designated GPM-2 and GPM-1) derived from the ascites of two individual gastric cancer patients with peritoneal metastasis.
    Results Immunohistochemical and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis revealed that GPM-2 cells showed both gastric and intestinal differentiation phenotypes (E-cadherin+/MUC5AC+/MUC6+/Villin+), and formed xenografted tumors with typical SRCC histology in nude mice. In contrast, GPM-1 cells only weakly expressed differentiation markers, showing a phenotype of E-cadherin(low) +/MUC2-/MUC5AC-/Villin (low) +. Characteristically, GPM-2 cells were found to highly express both membrane-bound mucin (MUC1/MUC4) and secreted mucin glycoproteins (MUC5AC/MUC6), whose expression is regulated by an epigenetic mechanism such as histone acetylation. GPM-2 cells also secreted a large amount of sTn antigen into the culture medium. These mucin profiles of GPM-2 cells are distinct from those of conventional SRCC cell lines (KATO III and HSC-39), which preferentially express intestinal MUC2/MUC4 as well as sLe(x) and sLe(A) antigens. In addition, GPM-2 cells showed a slow growth rate, and a lower metastatic potential than GPM-1 cells.
    Conclusions These results indicate that the cells of the new SRCC line, GPM-2 cells, are more differentiated and less aggressive than NSRCC-type GPM-1 cells, and would thus offer an excellent model for understanding the molecular mechanism underlying the growth, differentiation, and mucin production of an SRCC gastric cancer cell line.

    DOI: 10.1007/s10120-012-0149-2

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  • Lineage-specific growth inhibition of NK cell lines by FOXO3 in association with Akt activation status. 査読 国際誌

    Kennosuke Karube, Shinobu Tsuzuki, Noriaki Yoshida, Kotaro Arita, Fang Liu, Eisaku Kondo, Young-Hyeh Ko, Koichi Ohshima, Shigeo Nakamura, Tomohiro Kinoshita, Masao Seto

    Experimental hematology   40 ( 12 )   1005 - 1015   2012年12月

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    記述言語:英語  

    FOXO3 and PRDM1 are located on 6q21, one of the most frequently deleted regions among natural killer (NK) cell neoplasms. We previously demonstrated that forced expression of each gene suppresses the proliferation of NK cell lines with the 6q deletion. In this study, the forced expression of FOXO3 or PRDM1 was performed in various cell lines to clarify these suppressive effects. Forced expression of PRDM1 suppressed the proliferation of not only NK cell lines, but also other broad lineage cell lines. On the other hand, forced expression of FOXO3 was only effective on NK cell lines. FOXO3 functions as a transcriptional factor when it is localized in nuclei. Akt is known to induce cytoplasmic localization of FOXO3 as a result of phosphorylation. Transduced FOXO3 was predominantly localized in nuclei of NK cell lines, while it was localized in the cytoplasm of all non-NK cell lines. NK cell lines showed significantly lower Akt activity compared to other lineage cell lines. The low Akt activity and nucleic localization of FOXO3 in NK cell neoplasms seemed to cause NK cell-specific suppression. These findings indicate the "functional lineage specificity" of FOXO3 and the possibility for NK cell-specific gene therapy with minimal unexpected effects.

    DOI: 10.1016/j.exphem.2012.08.005

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  • Tumour lineage-homing cell-penetrating peptides as anticancer molecular delivery systems. 査読 国際誌

    Eisaku Kondo, Ken Saito, Yuichi Tashiro, Kaeko Kamide, Shusei Uno, Tomoko Furuya, Masao Mashita, Kiichiro Nakajima, Tomoyuki Tsumuraya, Naoya Kobayashi, Masahiro Nishibori, Mitsune Tanimoto, Masayuki Matsushita

    Nature communications   3   951 - 951   2012年7月

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    記述言語:英語  

    Cell-penetrating peptides have gained attention owing to their promise in noninvasive delivery systems. Among the identified cell-penetrating peptides, the TAT peptide has been preferentially used for transduction into cells of diverse origins. However, this activity is nonselective between neoplastic and non-neoplastic cells. Here we describe artificial cell-penetrating peptides that are selectively and efficiently incorporated into human tumour cells, according to their lineage. Ten representative tumour lineage-homing cell-penetrating peptides were obtained by screening of a random peptide library constructed using messenger RNA display technology, and some of the isolates were further modified by amino-acid substitution. Their advantageous tumour cell-targeting ability is corroborated in an in vivo mouse model for imaging and growth suppression of metastatic xenoplant tumours. These cell-penetrating peptides are potentially useful for the efficient targeting of human neoplasms in a tumour origin-dependent manner, and provide a framework for the development of peptide-based anti-tumour technologies.

    DOI: 10.1038/ncomms1952

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  • Acquisition of EMT phenotype in the gefitinib-resistant cells of a head and neck squamous cell carcinoma cell line through Akt/GSK-3Β/snail signalling pathway 査読

    S. Maseki, K. Ijichi, H. Tanaka, M. Fujii, Y. Hasegawa, T. Ogawa, S. Murakami, E. Kondo, H. Nakanishi

    British Journal of Cancer   106 ( 6 )   1196 - 1204   2012年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Epithelial mesenchymal transition (EMT) is known to be associated with chemoresistance as well as increased invasion/metastasis. However, the relationship between EMT and resistance to an epidermal growth factor receptor (EGFR)-targeting drug in head and neck squamous cell carcinoma (HNSCC) remains unknown. In this study, we investigated the acquisition of EMT by gefitinib in HNSCC cell line (UMSCC81B). Methods: We isolated fibroblastoid variant (81B-Fb) from gefitinib-resistant UMSCC81B-GR3 cells obtained after increasing the doses of gefitinib treatment in vitro and examined EMT and its underlying mechanism.Result:81B-Fb cells exhibited fibroblast-like morphology, increased motility, loss of E-cadherin, acquisition of vimentin and snail expression. In 81B-Fb cells, downregulation of EGFR, which is mediated by increased ubiquitination, and activation of downstream protein kinase B (Akt), glycogen synthase kinase-beta (GSK-3Β) signalling and upregulation of snail expression were observed compared with UMSCC81B cells. LY294002, but not U0126, suppressed foetal bovine serum or heregulin-Β1-induced phosphorylation of Akt/GSK-3Β and snail expression together with the inhibition of 81B-Fb cell motility. Furthermore, forced expression of EGFR resulted in partial restoration of gefitinib sensitivity and reversal of EMT. Conclusion: These Results suggest that EMT in the gefitinib-resistant cells is mediated by the downregulation of EGFR and compensatory activation of Akt/GSK-3Β/snail pathway. © 2012 Cancer Research UK All rights reserved.

    DOI: 10.1038/bjc.2012.24

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  • TGF-β synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth. 査読 国際誌

    Makiko Fujii, Takeshi Toyoda, Hayao Nakanishi, Yasushi Yatabe, Ayuko Sato, Yasue Matsudaira, Hidemi Ito, Hideki Murakami, Yutaka Kondo, Eisaku Kondo, Toyoaki Hida, Tohru Tsujimura, Hirotaka Osada, Yoshitaka Sekido

    The Journal of experimental medicine   209 ( 3 )   479 - 94   2012年3月

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    記述言語:英語  

    Malignant mesothelioma (MM) is an incurable malignancy that is caused by exposure to asbestos and is accompanied by severe fibrosis. Because MM is usually diagnosed at an advanced stage and clinical identification of early lesions is difficult, its molecular pathogenesis has not been completely elucidated. Nearly 75% of MM cases have inactivating mutations in the NF2 (neurofibromatosis type 2; Merlin) gene or in downstream signaling molecules of the Hippo signaling cascade, which negatively regulates the transcription factor Yes-associated protein (YAP). In this study, we demonstrate a functional interaction between the Hippo and TGF-β pathways in regulating connective tissue growth factor (CTGF). Expression of CTGF in MM cells was induced by the formation of a YAP-TEAD4-Smad3-p300 complex on the CTGF promoter. Knocking down CTGF expression in MM cells prolonged the survival of xenografted mice, and a significant association was seen between CTGF expression and extracellular matrix deposition in MM xenografts and in patient tissue specimens. We further suggest that CTGF may influence the malignancy of mesothelioma because of the different histological expression patterns observed in human MM tissues. These data suggest that CTGF is an important modulator of MM growth and pathology and represents a novel therapeutic target for this disease.

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  • Certain protein transducing agents convert translocated proteins into cell killers. 査読 国際誌

    Siergiej Tcherniuk, Anne-Laure Fiser, Madiha Derouazi, Bertrand Toussaint, Yan Wang, Izabela Wojtal, Eisaku Kondo, Ewa Szolajska, Jadwiga Chroboczek

    Acta biochimica Polonica   59 ( 3 )   433 - 9   2012年

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    記述言語:英語  

    The majority of proteins are unable to translocate into the cell interior. Hence for peptide- and protein-based therapeutics a direct intracytoplasmic delivery with the aid of transducing agents is an attractive approach. We wanted to deliver to the cell interior a putatively cytotoxic protein VPg. Protein transduction was achieved in vitro with three different commercial products. However, in our hands, delivery of various control proteins without known deleterious effects, as well as of protein VPg, always induced cell death. Finally, we used a novel transducing peptide Wr-T, which was not toxic to cultured cells, even in a quite large range of concentrations. Most importantly, control protein delivered to cells in culture did not display any toxicity while VPg protein exerted a strong cytotoxic effect. These data show that results obtained with cell-penetrating agents should be interpreted with caution.

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  • A new molecular targeted therapeutic approach for renal cell carcinoma with a p16 functional peptide using a novel transporter system. 査読 国際誌

    Kenji Zennami, Kazuhiro Yoshikawa, Eisaku Kondo, Kogenta Nakamura, Yoshiaki Upsilonamada, Marco A De Velasco, Motoyoshi Tanaka, Hirotsugu Uemura, Toru Shimazui, Hideyuki Akaza, Shinsuke Saga, Ryuzo Ueda, Nobuaki Honda

    Oncology reports   26 ( 2 )   327 - 33   2011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)  

    Molecular targeting agents have become formidable anticancer weapons showing much promise against refractory tumors and functional peptides and are among the more desirable of these nanobio-tools. Intracellular delivery of multiple functional peptides forms the basis for a potent, non-invasive mode of delivery, providing distinctive therapeutic advantages. We examine the growth suppression efficiency of human renal cell carcinoma (RCC) by single-peptide targeting. We simultaneously introduced p16INK4a tumor suppressor peptides by Wr-T-mediated peptide delivery. Wr-T-mediated transport of p16INK4a functional peptide into 10 RCC lines, lacking expression of the p16INK4a molecule, reversed the specific loss of p16 function, thereby drastically inhibiting tumor growth in all but 3 lines by >95% within the first 96 h. In vivo analysis using SK-RC-7 RCC xenografts in nude mice demonstrated tumor growth inhibition by the p16INK4a peptide alone, however, inoculation of Wr-T and the p16INK4a functional peptide mixture, via the heart resulted in complete tumor regression. Thus, restoration of tumor suppressor function with Wr-T peptide delivery represents a powerful approach, with mechanistic implications for the development of efficacious molecular targeting therapeutics against intractable RCC.

    DOI: 10.3892/or.2011.1290

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  • MicroRNA 130 family regulates the hypoxia response signal through the P-body protein DDX6 査読

    Ken Saito, Eisaku Kondo, Masayuki Matsushita

    Nucleic Acids Research   39 ( 14 )   6086 - 6099   2011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)  

    The transcription factor HIF-1α (hypoxia inducible factor 1α) has an essential role in the maintenance of oxygen homeostasis in metazoans. HIF-1α expression and activity in the hypoxic response is regulated at the translation and post-translational levels. However, the mechanism and modulator of HIF-1α translation during hypoxia is not fully understood. We found that HIF-1α expression during hypoxia was upregulated by the microRNA 130 (miR-130) family. Levels of the miR-130 family are elevated under hypoxia, and their target is DDX6 mRNA, which is a component of the P-bodies. Furthermore, we found that a decrease of DDX6 expression by the miR-130 family enhanced the translation of HIF-1α in an internal ribosome entry site element-dependent manner. These results reveal a new HIF-1α translational mechanism and a role for P-bodies in hypoxic stress. © 2011 The Author(s).

    DOI: 10.1093/nar/gkr194

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  • MicroRNA 130 family regulates the hypoxia response signal through the P-body protein DDX6. 査読

    Saito K, Kondo E, Matsushita M

    Nucleic acids research   39 ( 14 )   6086 - 6099   2011年8月

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    出版者・発行元:14  

    DOI: 10.1093/nar/gkr194

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  • Potent anti-tumor killing activity of the multifunctional Treg cell line HOZOT against human tumors with diverse origins. 査読 国際誌

    Toshiya Inoue, Yuichi Tashiro, Makoto Takeuchi, Takeshi Otani, Kazue Tsuji-Takayama, Ayumi Okochi, Yuriko Mukae, Mayuko Koreishi, Fumiyuki Yamasaki, Hiromi Kumon, Shuji Nakamura, Masayoshi Kibata, Eisaku Kondo

    International journal of oncology   38 ( 5 )   1299 - 306   2011年5月

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    記述言語:英語  

    The T cell line HOZOT has a unique FOXP3+CD4+ CD8+CD25+ phenotype, exhibits suppressive activity in allogeneic mixed lymphocyte reactions (MLR), and produces IL-10, defining HOZOT as regulatory T cells (Tregs). Interestingly, in addition to possessing a suppressive Treg ability, HOZOT was also found to show cytotoxicity against certain representative human cancer cell types. In order to disclose the range of anti-tumor activity by HOZOT, we screened it by using a panel of twenty human tumor cell lines with different origins. Consequently, HOZOT showed potent cytocidal effects against a wide spectrum of neoplastic cells including carcinomas, sarcomas, mesotheliomas and glioblastomas except for hematopoietic malignancies. Its anti-tumor activity was strong enough with an E:T ratio of 4:1, which is considered to be more effective than that by conventional CTLs. Furthermore, an in vivo representative mouse tumor model by implanting human colon adenocarcinoma cells revealed that adoptive transfer of HOZOT almost completely eradicated disseminated lesions on peritoneum, markedly reduced metastases in lung and liver, and dramatically decreased bloody ascites caused by peritoneal carcinomatosis. Treatment of the tumor model mice by HOZOT with an E:T ratio of 2:1 even indicated the prolongation of their survival, although not reaching obvious statistical significance. In vitro blocking experiments using antibodies and inhibitors suggested that the cytotoxic mechanism of HOZOT against tumors is different from conventional cytotoxic cells such as CTL, NK or NKT cells. Altogether, our studies demonstrated the potent killing activity of HOZOT against a broad range of human malignancies, which indicates that HOZOT is a powerful tool in immunotherapy for advanced stage tumors.

    DOI: 10.3892/ijo.2011.962

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  • NFATc1 affects mouse splenic B cell function by controlling the calcineurin--NFAT signaling network. 査読 国際誌

    Sankar Bhattacharyya, Jolly Deb, Amiya K Patra, Duong Anh Thuy Pham, Wen Chen, Martin Vaeth, Friederike Berberich-Siebelt, Stefan Klein-Hessling, Edward D Lamperti, Kurt Reifenberg, Julia Jellusova, Astrid Schweizer, Lars Nitschke, Ellen Leich, Andreas Rosenwald, Cornelia Brunner, Swen Engelmann, Ursula Bommhardt, Andris Avots, Martin R Müller, Eisaku Kondo, Edgar Serfling

    The Journal of experimental medicine   208 ( 4 )   823 - 39   2011年4月

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    記述言語:英語  

    By studying mice in which the Nfatc1 gene was inactivated in bone marrow, spleen, or germinal center B cells, we show that NFATc1 supports the proliferation and suppresses the activation-induced cell death of splenic B cells upon B cell receptor (BCR) stimulation. BCR triggering leads to expression of NFATc1/αA, a short isoform of NFATc1, in splenic B cells. NFATc1 ablation impaired Ig class switch to IgG3 induced by T cell-independent type II antigens, as well as IgG3(+) plasmablast formation. Mice bearing NFATc1(-/-) B cells harbor twofold more interleukin 10-producing B cells. NFATc1(-/-) B cells suppress the synthesis of interferon-γ by T cells in vitro, and these mice exhibit a mild clinical course of experimental autoimmune encephalomyelitis. In large part, the defective functions of NFATc1(-/-) B cells are caused by decreased BCR-induced Ca(2+) flux and calcineurin (Cn) activation. By affecting CD22, Rcan1, CnA, and NFATc1/αA expression, NFATc1 controls the Ca(2+)-dependent Cn-NFAT signaling network and, thereby, the fate of splenic B cells upon BCR stimulation.

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  • miR-155, a Modulator of FOXO3a Protein Expression, Is Underexpressed and Cannot Be Upregulated by Stimulation of HOZOT, a Line of Multifunctional Treg. 査読 国際誌

    Mayuko Yamamoto, Eisaku Kondo, Makoto Takeuchi, Akira Harashima, Takeshi Otani, Kazue Tsuji-Takayama, Fumiyuki Yamasaki, Hiromi Kumon, Masayoshi Kibata, Shuji Nakamura

    PloS one   6 ( 2 )   e16841   2011年2月

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    記述言語:英語  

    MicroRNAs (miRNAs) play important roles in regulating post-transcriptional gene repression in a variety of immunological processes. In particular, much attention has been focused on their roles in regulatory T (Treg) cells which are crucial for maintaining peripheral tolerance and controlling T cell responses. Recently, we established a novel type of human Treg cell line, termed HOZOT, multifunctional cells exhibiting a CD4(+)CD8(+) phenotype. In this study, we performed miRNA profiling to identify signature miRNAs of HOZOT, and therein identified miR-155. Although miR-155 has also been characterized as a signature miRNA for FOXP3(+) natural Treg (nTreg) cells, it was expressed quite differently in HOZOT cells. Under both stimulatory and non-stimulatory conditions, miR-155 expression remained at low levels in HOZOT, while its expression in nTreg and conventional T cells remarkably increased after stimulation. We next searched candidate target genes of miR-155 through bioinformatics, and identified FOXO3a, a negative regulator of Akt signaling, as a miR-155 target gene. Further studies by gain- and loss-of-function experiments supported a role for miR-155 in the regulation of FOXO3a protein expression in conventional T and HOZOT cells.

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  • Critical Role of Pcid2 in B Cell Survival through the Regulation of MAD2 Expression 査読

    Teruo Nakaya, Kazuhiko Kuwahara, Kazutaka Ohta, Masahiro Kitabatake, Teppei Toda, Naoki Takeda, Tokio Tani, Eisaku Kondo, Nobuo Sakaguchi

    JOURNAL OF IMMUNOLOGY   185 ( 9 )   5180 - 5187   2010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:AMER ASSOC IMMUNOLOGISTS  

    The mitotic checkpoint is essential for maintaining genomic stability in differentiating B cells undergoing genetic alterations of the Ig gene. In this study, using real-time RT-PCR and in situ RNA hybridization, we demonstrated that MAD2 mRNA export is selectively regulated by Pcid2/Thp1. Pcid2 small interfering RNA induced a cell-cycle abnormality with increased apoptosis and polyploidy, as previously observed in MAD2-knockdown cells. Pcid2 small interfering RNA reduced MAD2 expression, but not the expression of other cell-cycle checkpoint proteins, such as MAD1 and BUBR1, or the cell-cycle-associated proteins, cyclin A, cyclin B1, and cyclin-dependent kinase 1. In mouse B lineage cells, Pcid2 transcripts appeared in a stage-dependent manner at high levels in bone marrow pre-B and immature B cells, and in spleen transitional 1 and follicular B cells, but at lower levels in pro-B, transitional 2, and marginal zone B cells, suggesting a stage-dependent requirement for MAD2 regulation. Cd19-cre-derived targeting of the Pcid2 gene induced a mature B cell deficiency in mice. These findings indicate that Pcid2 is essential for B cell survival through the regulation of MAD2 expression during B cell differentiation. The Journal of Immunology, 2010, 185: 5180-5187.

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  • Targeted delivery of oligomannose-coated liposome to the omental micrometastasis by peritoneal macrophages from patients with gastric cancer 査読

    Makoto Matsui, Yoshitaka Shimizu, Yasuhiro Kodera, Eisaku Kondo, Yuzuru Ikehara, Hayao Nakanishi

    CANCER SCIENCE   101 ( 7 )   1670 - 1677   2010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)   出版者・発行元:WILEY-BLACKWELL  

    We recently developed a novel drug delivery system (DDS) using oligomannose-coated liposomes (OMLs), which are effectively taken up by mouse peritoneal macrophages to carry anticancer drugs to omental milky spots known as initial metastatic sites in the peritoneal cavity in mice. However, the feasibility of the clinical application of this DDS to gastric cancer patients remains essentially unknown. In the present study, we investigated whether human peripheral blood monocytes (PBMs) and human peritoneal macrophages (PEMs) could successfully uptake OMLs and deliver them to the micrometastatic foci in the mouse omentum and resected omentum from cancer patients ex vivo. When OMLs were incubated with the PBMs from four healthy volunteers in vitro, an average 88% of CD14-positive PBMs, most of which also express CD206, took up OMLs, and this uptake was significantly inhibited by alpha-methylmannoside. In the experiment using PEMs obtained from peritoneal washes of five gastric cancer patients, the average uptake rate (63%) of OML by CD14-positive PEMs was somewhat lower than that of PBMs, but in three advanced gastric cancer patients the uptake rate of OMLs was 76% which was comparable to that of mouse PEMs. Oligomannose-coated liposome (OML)-incorporated PBMs and PEMs were successfully accumulated at the micrometastatic foci at the omentum formed after intraperitoneal injection of GFP-tagged gastric cancer cells into mice. Furthermore, OML-incorporated PBMs substantially accumulated to tumor foci in the surgically resected human omentum ex vivo. These results suggest that OMLs using human monocytes/macrophages as a cellular vehicle have the potential to target peritoneal micrometastasis in the omentum of gastric cancer patients. (Cancer Sci 2010).

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  • Germinal center-associated nuclear protein (GANP) is involved in mRNA export of Shugoshin-1 required for centromere cohesion and in sister-chromatid exchange 査読

    Nobukazu Okamoto, Kazuhiko Kuwahara, Kazutaka Ohta, Masahiro Kitabatake, Katsumasa Takagi, Hiroshi Mizuta, Eisaku Kondo, Nobuo Sakaguchi

    GENES TO CELLS   15 ( 5 )   471 - 483   2010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:WILEY-BLACKWELL  

    Germinal center-associated nuclear protein (GANP) is a 210-kDa protein that is upregulated in rapidly proliferating B cells. GANP contains regions for RNA-primase and minichromosome maintenance 3 (MCM3)-associated activities, as well as a Sac3-homology region, which is associated with mRNA export in yeast. Here, we examined the role of GANP in mRNA export and cell proliferation in mammalian cells. The ganp small interfering RNA (siRNA) induced cell-cycle arrest at the G2/M-phase, but increased abnormal chromosome alignment of metaphase chromosomes and cell apoptosis in HeLa cells. These changes were not associated with either the abnormality of the spindle assembly checkpoint or the expression level of cohesin. ganp siRNA disrupted the assembly and localization of cohesin at the centromeres in metaphase cells, which is a quite similar phenotype caused by Shugoshin-1 (Sgo1) siRNA-treatment, which was reported previously. ganp siRNA did induce a selective decrease in Sgo1 transcript levels in the cytoplasm, resulting in a lack of cohesin at the centromeres in metaphase and premature separation of the sister chromatids at mitosis. GANP lacking the Sac3-homology region caused the dominant-negative effect with similar abnormalities and impaired mRNA export. Thus, human GANP is critically involved in cell proliferation at the mitotic phase through its selective support of Sgo1 mRNA export.

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  • Intramuscular transplantation of engineered hepatic tissue constructs corrects acute and chronic liver failure in mice. 査読 国際誌

    Nalu Navarro-Alvarez, Alejandro Soto-Gutierrez, Yong Chen, Jose Caballero-Corbalan, Wael Hassan, Satoru Kobayashi, Yoshitaka Kondo, Masaya Iwamuro, Kazuhide Yamamoto, Eisaku Kondo, Noriaki Tanaka, Ira J Fox, Naoya Kobayashi

    Journal of hepatology   52 ( 2 )   211 - 9   2010年2月

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    記述言語:英語  

    BACKGROUND & AIMS: Transplantation of isolated hepatocytes holds great promise as an alternative to whole organ liver transplantation. For treatment of liver failure, access to the portal circulation has significant risks and intrahepatic hepatocyte engraftment is poor. In advanced cirrhosis, transplantation into an extrahepatic site is necessary and intrasplenic engraftment is short-lived. Strategies that allow repeated extrahepatic infusion of hepatocytes could improve the efficacy and safety of hepatocyte transplantation for the treatment of liver failure. METHODS: A non-immunogenic self-assembling peptide nanofiber (SAPNF) was developed as a three-dimensional scaffold and combined with growth factors derived from a conditionally immortalized human hepatocyte cell line to engineer a hepatic tissue graft that would allow hepatocyte engraftment outside the liver. RESULTS: The hepatic tissue constructs maintained hepatocyte-specific gene expression and functionality in vitro. When transplanted into skeletal muscle as an extrahepatic site for engraftment, the engineered hepatic grafts provided life-saving support in models of acute, fulminant, and chronic liver failure that recapitulates these clinical diseases. CONCLUSIONS: SAPNF-engineered hepatic constructs engrafted and functioned as hepatic tissues within the muscle to provide life-sustaining liver support. These engineered tissue constructs contained no animal products that would limit their development as a therapeutic approach.

    DOI: 10.1016/j.jhep.2009.11.019

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  • Hepatic differentiation of mouse iPS cells in vitro. 査読 国際誌

    Masaya Iwamuro, Toshiyuki Komaki, Yasuhiro Kubota, Masayuki Seita, Hironobu Kawamoto, Takeshi Yuasa, Javed M Shahid, Reham A R A Hassan, Wael A R A Hassan, Shuhei Nakaji, Yuriko Nishikawa, Eisaku Kondo, Kazuhide Yamamoto, Ira J Fox, Naoya Kobayashi

    Cell transplantation   19 ( 6 )   841 - 7   2010年

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    記述言語:英語  

    Induced pluripotent stem (iPS) cells are pluripotent and are able to unlimitedly proliferate in vitro. This technical breakthrough in creating iPS cells from somatic cells has noteworthy implications for overcoming the immunological rejection and the ethical issues associated with the derivation of embryonic stem cells from embryos. In the current work, we present an efficient hepatic differentiation of mouse iPS cells in vitro. iPS cells were cultured free floating to induce the formation of embryoid bodies (EB) for 5 days. EB were transferred to a gelatin-coated plate and treated with 100 ng/ml activin A and 100 ng/ml basic fibroblast growth factor (bFGF) for 3 days to induce definitive endoderm. Cells were further cultured for 8 days with 100 ng/ml hepatocyte growth factor (HGF) to generate hepatocytes. Characterization was performed by RT-PCR assay. Functional analysis for albumin secretion and ammonia removal was also carried out. iPS cell-derived hepatocyte-like cells (iPS-Heps) were obtained at the end of the differentiation program. Expression levels of a gestational hepatocyte gene and lineage-specific hepatic genes intensified in iPS-Heps. The production of albumin increased in a time-dependent manner. iPS-Heps were capable of metabolizing ammonia. We present here instant hepatic differentiation of mouse iPS cells using combined 3-day treatments of activin A and bFGF with subsequent 8-day HGF. Our study will be an important step to generate hepatocytes from human iPS cells as a new source for liver-targeted cell therapies.

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  • Comparative analysis of endoderm formation efficiency between mouse ES cells and iPS cells. 査読 国際誌

    Masaya Iwamuro, Toshiyuki Komaki, Yasuhiro Kubota, Masayuki Seita, Hironobu Kawamoto, Takeshi Yuasa, Javed M Shahid, Reham A R A Hassan, Wael A R A Hassan, Shuhei Nakaji, Yuriko Nishikawa, Eisaku Kondo, Kazuhide Yamamoto, Naoya Kobayashi

    Cell transplantation   19 ( 6 )   831 - 9   2010年

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    記述言語:英語  

    Definitive endoderm (DE) derived from stem cells holds potential to differentiate into hepatocytes. Stem cell therapy using those cells has potential for a treatment of liver disease. To date, various ways of inducing hepatocytes from embryonic stem (ES) cells have been reported by researchers. However, it has not been proved enough that induced pluripotent stem (iPS) cells behave in the same manner as ES cells in endoderm differentiation. The purpose of this study was to establish an efficient method to induce DE from iPS cells, through comparatively analyzing the efficacy of endoderm formation from mouse ES cells. Furthermore, the efficiency of a serum-free medium in the differentiation into DE was investigated. Mouse ES cells and iPS cells were floated in culture medium for 2 or 5 days and embryoid bodies (EB) were formed. Subsequently, DE was induced with 100 ng/ml activin A and 100 ng/ml basic fibroblast growth factor (bFGF). RT-PCR and real-time PCR analyses were carried out at each step to determine the gene expression of EB markers. The difference in cellular proliferation between serum-containing and serum-free media was examined by an MTS assay in EB and DE induction. iPS cells showed the paralleled mRNA expression to ES cells in each step of differentiation into EB, but the levels of expression of Sox17 and Foxa2 were relatively higher in ES cell-derived DE, whereas Cxcr4 expression was higher in iPS cell-derived DE. The utilization of serum-free medium for iPS cells showed significantly favorable cellular proliferation during EB formation and subsequent DE induction. Forming EB for 5 days and subsequently DE induction with activin A and bFGF with serum-free medium was an appropriate protocol in iPS cells. This may represent an important step for generating hepatocytes from iPS cells for the development of cell therapy.

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  • Treatment of acute liver failure in mice by hepatocyte xenotransplantation. 査読 国際誌

    Tsuyoshi Yamamoto, Nalú Navarro-Alvarez, Alejandro Soto-Gutierrez, Takeshi Yuasa, Masaya Iwamuro, Yasuhiro Kubota, Masayuki Seita, Hironobu Kawamoto, Shahid M Javed, Eisaku Kondo, Hirofumi Noguchi, Satoru Kobayashi, Shuhei Nakaji, Naoya Kobayashi

    Cell transplantation   19 ( 6 )   799 - 806   2010年

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    記述言語:英語  

    Liver diseases still have a high mortality even though liver transplantation has become a standard treatment. Currently, hepatocyte transplantation has been proposed as another promising strategy. One limitation is the availability of human livers as a source of hepatocytes. Because of an unlimited supply, the use of porcine hepatocytes might address this problem. Regardless of the source, once isolated hepatocytes lose specific functionality due to the loss of the natural microenvironment. For this reason, we tested the ability of a self-assembling peptide nanofiber (SAPNF) to provide a provisional three-dimensional (3D) support to interact with cells to control their function in vivo. Isolated porcine hepatocytes were embedded in SAPNF, or collagen type I and transplanted by direct injection into the splenic pulp of SCID mice suffering from acute liver failure (ALF) by 90% hepatectomy. SAPNF porcine hepatocyte transplantation produced engraftment that was far superior to that obtained using collagen and prolonged the survival of mice with ALF, in contrast with controls. An ultrastructural evaluation using transmission electron microscopy indicated extensive cell-cell communication and preservation of hepatocyte architecture. The transplanted SAPNF hepatocytes showed higher expression of albumin and PAS and lower apoptotic events assessed by TUNEL staining. Hepatocytes culture in a truly 3D network allows in vivo maintaining of differentiated functions, and once transplanted between widely divergent species can function to correct acute liver failure in mice and prolong their survival.

    DOI: 10.3727/096368910X508915

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  • Characteristics of CD133(+) human colon cancer SW620 cells. 査読 国際誌

    Hironobu Kawamoto, Takeshi Yuasa, Yasuhiro Kubota, Masayuki Seita, Hiromi Sasamoto, Javed M Shahid, Takahiro Hayashi, Hiroyuki Nakahara, Reham Hassan, Masaya Iwamuro, Eisaku Kondo, Shuhei Nakaji, Noriaki Tanaka, Naoya Kobayashi

    Cell transplantation   19 ( 6 )   857 - 64   2010年

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    記述言語:英語  

    Worldwide, colorectal cancer is the third most common type of cancer affecting both sexes. It has been proposed that a small subset of cancer cells (cancer stem cells) within each tumor is able to initiate tumor growth. In 2007, two research groups simultaneously identified a colon cancer stem cell population in human tumors by the use of CD133 expression. In the present study, we used a human colon cancer cell line, SW620, to analyze the cancer stem cell-like characteristics of CD133(+) cells in vitro and in vivo. In vitro, CD133(+) SW620 cells had a higher proliferative capacity, were more irradiation- and chemotherapy-resistant, and had a higher expression of β-catenin compared with CD133(-) cells. Injections of either CD133(+) or CD133(-) cells into the skin or rectal mucosa of NOD/SCID mice led to tumors; however, injection of CD133(+) cells resulted in the formation of larger tumors. Tumors derived from injections of CD133(-) cells did not contain any CD133(+) cells, whereas tumors derived from injections of CD133(+) cells did contain CD133(+) cells, suggesting self-renewing capability. However, the proportion of CD133(+) cells in the newly formed tumors in vivo was lower than the proportion of CD133(+) cells in vitro. In conclusion, the human colon cancer cell line, SW620, contains both CD133(+) and CD133(-) phenotypes, and the CD133(+) phenotype has characteristics consistent with those of cancer stem cells.

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  • Isolation and propagation of a human CD133(-) colon tumor-derived cell line with tumorigenic and angiogenic properties. 査読 国際誌

    Nalú Navarro-Alvarez, Eisaku Kondo, Hironobu Kawamoto, Wael Hassan, Takeshi Yuasa, Yasuhiro Kubota, Masayuki Seita, Hiroyuki Nakahara, Takahiro Hayashi, Yuriko Nishikawa, Reham A R A Hassan, Shahid M Javed, Hirofumi Noguchi, Shinichi Matsumoto, Shuhei Nakaji, Noriaki Tanaka, Naoya Kobayashi, Alejandro Soto-Gutierrez

    Cell transplantation   19 ( 6 )   865 - 77   2010年

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    記述言語:英語  

    It has been proposed in human colorectal cancers (CRC) a minority subset of cancer cells within tumors able to initiate tumor growth, defined as cancer stem cells (CSC). Solid human primary colonic and its ovarian metastatic cancer tissues were collected from fresh surgical samples and subsequent xenografts were established in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. The resulting tumors were disaggregated into single-cell suspensions and a CD133(-) cell line (NANK) was newly established and analyzed by flow cytometry. Surface markers of progenitor cells were immunophenotypically analyzed, and expression of stem cell and cancer-related genes was characterized. Secreted angiogenesis-associated molecules were investigated by proteomic array technology. Finally, different numbers of NANK were implanted and their tumor-initiating properties were investigated in NOD/SCID mice. Intraperitoneal injection of NANK in NOD/SCID mice induced tumors with developing progressive peritoneal dissemination and ascites. NANK cells maintained a differentiated phenotype and reproduced the full morphologic and phenotypic heterogeneity of their parental lesions. Noticeably, NANK lacked the expression of conventional CSC markers CD133 and CD44, self-renewal genes Oct-4 and Nanog, but showed the expression of an important gastrointestinal development marker CDX-2 and BMI-1 that is essential in regulating the proliferative activity of normal and leukemic stem cells. In addition, NANK secreted high amounts of important angiogenic cytokines. These results provide a novel and extensive model in human CSC for studying the generation and maintenance of phenotypic heterogeneity in CRC.

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  • Frequent downregulation or loss of CD79a expression in plasma cell myelomas: potential clue for diagnosis. 査読 国際誌

    Takehiro Tanaka, Kouichi Ichimura, Yasuharu Sato, Katsuyoshi Takata, Toshiaki Morito, Maiko Tamura, Eisaku Kondo, Nobuya Ohara, Hiroyuki Yanai, Masaharu Sakai, Satoru Takahashi, Tadashi Yoshino

    Pathology international   59 ( 11 )   804 - 8   2009年11月

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    記述言語:英語  

    Plasma cell myeloma is a frequent hematogeneous disorder that occurs mainly in older people. Not only bone marrow smears but also clots and/or biopsied specimens are often taken for confirmation of pathological diagnosis. Some specimens show sheet-like plasma cell proliferation associated with immunoglobulin monotype on immunohistology, which readily leads to diagnosis, but many samples do not clearly show light-chain restriction. The aim of the present study was therefore to examine CD79a expression because some samples had reduced expression or none at all. The immunoreactivity of CD79a was categorized into three groups: positive, weakly positive and negative, compared with scattering non-neoplastic plasma cells in the same specimen. Out of 100 specimens of plasma cell myeloma, 48% were positive for CD79a, 15% were weakly positive, and 37% were negative. In contrast, overexpression of cyclinD1 was detected in 26% of examined samples. CD79a-negative cases had a significantly lower percentage of positive staining for cyclinD1 than CD79a-positive or weakly positive cases. Clinicopathological data showed that CD79a-negative expression was associated with decreased platelet numbers in patients. The present study indicates that downregulation or loss of CD79a and/or overexpression of cyclin D1, observed in 59% of neoplastic plasma cell samples, could provide a strong diagnostic clue without regard to the results of immunoglobulin light-chain restriction.

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  • Bone repair by transplantation of hTERT-immortalized human mesenchymal stem cells in mice. 査読 国際誌

    Hiroyuki Nakahara, Haruo Misawa, Takahiro Hayashi, Eisaku Kondo, Takeshi Yuasa, Yasuhiro Kubota, Masayuki Seita, Hironobu Kawamoto, Wael A R A Hassan, Reham A R A Hassan, Shahid M Javed, Masato Tanaka, Hirosuke Endo, Hirofumi Noguchi, Shinichi Matsumoto, Katsuyoshi Takata, Yuichi Tashiro, Shuhei Nakaji, Toshifumi Ozaki, Naoya Kobayashi

    Transplantation   88 ( 3 )   346 - 53   2009年8月

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    記述言語:英語  

    BACKGROUND: Human mesenchymal stem cells (hMSCs) are multipotent stem cells found in the adult bone marrow that have the capacity to differentiate into various mesenchymal cell types. The hMSCs may provide a potential therapy to restore damaged tissues or organs of mesenchymal origin; however, a drawback is their limited life span in vitro. METHODS: We immortalized normal hMSCs with retrovirally transmitted human telomerase reverse transcriptase cDNA. One of the immortalized clones (YKNK-12) was established, and the biological characteristics were investigated in vitro and in vivo. RESULTS: YKNK-12 cells were capable of differentiating adipocytes, osetoblasts, and chondrocytes. Osteogenically differentiated YKNK-12 cells produced significant levels of growth factors BMP4, BMP6, FGF6, FGF7, transforming growth factor-beta1, and transforming growth factor-beta3.. Microcomputer tomography T and soft X-ray assays showed an excellent calvarial bone healing in mice after transplantation of osteogenically differentiated YKNK-12 cells. These cells expressed human-specific osteocalcin and increased the gene expression of runt-related transcription factor 2, alkaline phosphatase, osteocalcin, and osterix in the bone regenerating area. YKNK-12 cell transplant corrected the bone defect without inducing any adverse effects. CONCLUSIONS: We conclude that hMSCs immortalized by transduction with human telomerase reverse transcriptase may provide an unlimited source of cells for therapeutic use in bone regeneration.

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  • Duodenal and nodal follicular lymphomas are distinct: the former lacks activation-induced cytidine deaminase and follicular dendritic cells despite ongoing somatic hypermutations. 査読 国際誌

    Katsuyoshi Takata, Yasuharu Sato, Naoya Nakamura, Yara Yukie Kikuti, Koichi Ichimura, Takehiro Tanaka, Toshiaki Morito, Maiko Tamura, Takashi Oka, Eisaku Kondo, Hiroyuki Okada, Akira Tari, Tadashi Yoshino

    Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc   22 ( 7 )   940 - 9   2009年7月

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    記述言語:英語  

    Although most follicular lymphomas are believed to be of nodal origin, they sometimes originate from the duodenum. We have reported that the latter differ from nodal follicular lymphomas in having lower clinical stages and uniformly low histological grades, along with variable region of immunoglobulin heavy chain gene (VH) usage that is more similar to mucosa-associated lymphoid tissue (MALT) lymphomas. Little is known, however, about whether they possess other characteristics of nodal follicular lymphomas, particularly ongoing mutations with follicular dendritic cells. We examined 17 cases for which PCR identified the monoclonal bands of the immunoglobulin gene. The duodenal cases showed ongoing mutations, but they lacked activation-induced cytidine deaminase (AID) expression, a statistically significant difference from the nodal cases (P<0.001), and their follicular dendritic cell networks were disrupted. Moreover, not only were VH deviations observed but also they used very restricted VH genes. Although the mechanisms of ongoing mutation without AID and follicular dendritic cell were not clarified, restricted VH usage strongly suggested that antigen stimulation was involved, and that was similar to MALT lymphomas. In conclusion, duodenal follicular lymphomas were shown to be unique, in that they had ongoing hypermutations such as nodal cases, but the mechanisms involved in the hypermutation were quite different; furthermore, restricted VH usage suggested a strong similarity to the antigen-dependent origin of MALT lymphomas.

    DOI: 10.1038/modpathol.2009.51

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  • Ectopic localization of FOXO3a protein in Lewy bodies in Lewy body dementia and Parkinson's disease 査読

    Bo Su, Haihua Liu, Xinglong Wang, Shu G. Chen, Sandra L. Siedlak, Eisaku Kondo, Raymond Choi, Atsushi Takeda, Rudy J. Castellani, George Perry, Mark A. Smith, Xiongwei Zhu, Hyoung-Gon Lee

    Molecular Neurodegeneration   4 ( 1 )   2009年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Lewy bodies and Lewy neurites constitute the cardinal neuropathological features of both Parkinson's disease (PD) and Lewy body dementia (LBD). Whereas α-synuclein has been found to be the major component of the Lewy body, the mechanisms by which neurons degenerate, as well as basic mechanisms involved in the formation of α-synuclein-related inclusions, remain obscure. We have suggested previously that potential mechanisms are likely to leave a "molecular signature" or protein adduct within the Lewy body, and have found examples of such signatures in previous studies. In this study, we demonstrate increased FOXO3 in association with Lewy bodies and Lewy neurites in LBD and PD brain tissue. Since FOXO proteins are involved in several pathways responsible for the regulation of cell death, cell proliferation, and cell metabolism, the ectopic localization of FOXO3 to Lewy bodies provides evidence that aberrations in basic cellular biochemistry may contribute to inclusion formation, which is likely more complex than a simple "gain of function" toxicity as is commonly opined. In light of the known interaction of FOXO3 and 14-3-3, basic protein-protein interaction between these proteins and α-synuclein may be key. © 2009 Su et al
    licensee BioMed Central Ltd.

    DOI: 10.1186/1750-1326-4-32

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  • Synchronous pulmonary MALT lymphoma and pulmonary adenocarcinoma after metachronous gastric MALT lymphoma and gastric adenocarcinoma. 査読 国際誌

    Eiki Ichihara, Masahiro Tabata, Nagio Takigawa, Yumiko Sato, Eisaku Kondo, Motoi Aoe, Katsuyuki Kiura, Mitsune Tanimoto

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   3 ( 11 )   1362 - 3   2008年11月

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  • Induction of lung adenocarcinoma in transgenic mice expressing activated EGFR driven by the SP-C promoter. 査読 国際誌

    Kadoaki Ohashi, Kammei Rai, Yoshiro Fujiwara, Masahiro Osawa, Seiki Hirano, Katsuyoshi Takata, Eisaku Kondo, Tadashi Yoshino, Minoru Takata, Mitsune Tanimoto, Katsuyuki Kiura

    Cancer science   99 ( 9 )   1747 - 53   2008年9月

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    記述言語:英語  

    To investigate the role of an activating epidermal growth factor receptor (EGFR) mutation in lung cancer, we generated transgenic mice expressing the delE748-A752 mutant version of mouse EGFR driven by the SP-C promoter, which is equivalent to the delE746-A750 mutation found in lung cancer patients. Strikingly, the mice invariably developed multifocal lung adenocarcinomas of varying sizes at between 5 and 6 weeks of age, and they died from tumor progression approximately 2 months later if left untreated. Daily oral administration of the EGFR tyrosine kinase inhibitor (TKI) gefitinib (5 mg/kg/day) reduced the total and phosphorylation levels of EGFR to those in wild-type mouse lung tissue; in addition, it abrogated tumor growth within 1 week and prolonged survival to >30 weeks. Interestingly, phosphorylated ErbB2, ErbB3, and thyroid transcriptional factor-1 increased in the transgenic mice compared with those in wild-type mice. They might play some roles in tumors progression in the transgenic mice. This model will be useful for studying the mechanisms of carcinogenesis, chemoprevention, and acquired resistance to EGFR TKIs in lung cancer patients carrying activating EGFR mutations.

    DOI: 10.1111/j.1349-7006.2008.00875.x

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  • Ocular adnexal IgG4-related disease has uniform clinicopathology. 査読 国際誌

    Yasuharu Sato, Koh-ichi Ohshima, Kouichi Ichimura, Masakazu Sato, Ichiro Yamadori, Takehiro Tanaka, Katsuyoshi Takata, Toshiaki Morito, Eisaku Kondo, Tadashi Yoshino

    Pathology international   58 ( 8 )   465 - 70   2008年8月

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    記述言語:英語  

    IgG4-related disease is a recently proposed clinical entity with several unique clinicopathological features. Ocular adnexal IgG4-related disease, however, has not well been clarified. The purpose of the present study was to examine 21 patients (10 men, 11 women; age range, 39-86 years) with ocular adnexal IgG4-related disease. In 17 out of 21 patients (81%), the lacrimal glands were involved and bilateral lacrimal gland swelling was frequently observed (n = 12; 70.6%). In contrast, the conjunctiva was not involved in any of the patient. Histology was uniform with marked lymphoplasmacytic infiltration admixed with dense fibrosis, similar to previous reports of IgG4-related disease. Immunostaining detected numerous aggregates of IgG4-positive plasma cells. Serum IgG4 was higher than normal in 10 of the 13 patients tested, although it was measured after treatment in almost all cases. Interestingly, immunoglobulin heavy chain gene rearrangement was detected in two of 17 patients (12%) examined. The present results show that ocular adnexal IgG4-related disease has uniform clinicopathology: that is, disease involving the bilateral lacrimal glands with lymphoid hyperplasia and fibrosis, but not the conjunctiva. And presence of immunoglobulin heavy chain gene rearrangement suggests the possibility of B-cell lymphoma arising in a background of IgG4-related chronic inflammation.

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  • Potent synergy of dual antitumor peptides for growth suppression of human glioblastoma cell lines. 査読 国際誌

    Eisaku Kondo, Takehiro Tanaka, Takayoshi Miyake, Tomotsugu Ichikawa, Masahiko Hirai, Masaki Adachi, Kazuhiro Yoshikawa, Koichi Ichimura, Nobuya Ohara, Akiyoshi Moriwaki, Isao Date, Ryuzo Ueda, Tadashi Yoshino

    Molecular cancer therapeutics   7 ( 6 )   1461 - 71   2008年6月

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    Molecular targeting agents have become formidable anticancer weapons, which show much promise against the refractory tumors. Functional peptides are among the more desirable of these nanobio-tools. Intracellular delivery of multiple functional peptides forms a basis for potent, non-invasive mode of delivery, providing distinctive therapeutic advantages. Here, we examine growth suppression efficiency of human glioblastomas by dual-peptide targeting. We did simultaneous introduction of two tumor suppressor peptides (p14(ARF) and p16(INK4a) or p16(INK4a) and p21(CIP1) functional peptides) compared with single-peptide introduction using Wr-T-mediated peptide delivery. Wr-T-mediated transport of both p14(ARF) and p16(INK4a) functional peptides (p14-1C and p16-MIS, respectively) into human glioblastoma cell line, U87DeltaEGFR, reversed specific loss of p14 and p16 function, thereby drastically inhibiting tumor growth by >95% within the first 72 h, whereas the growth inhibition was approximately 40% by p14 or p16 single-peptide introduction. Additionally, the combination of p16 and p21(CIP1) (p21-S154A) peptides dramatically suppressed the growth of glioblastoma line Gli36DeltaEGFR, which carries a missense mutation in p53, by >97% after 120 h. Significantly, our murine brain tumor model for dual-peptide delivery showed a substantial average survival enhancement (P < 0.0001) for peptide-treated mice. Wr-T-mediated dual molecular targeting using antitumor peptides is highly effective against growth of aggressive glioblastoma cells in comparison with single molecule targeting. Thus, jointly restoring multiple tumor suppressor functions by Wr-T-peptide delivery represents a powerful approach, with mechanistic implications for development of efficacious molecular targeting therapeutics against intractable human malignancies.

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  • Duodenal follicular lymphomas share common characteristics with mucosa-associated lymphoid tissue lymphomas 査読

    Y. Sato, K. Ichimura, T. Tanaka, K. Takata, T. Morito, H. Sato, Y. Sato, E. Kondo, H. Yanai, N. Ohara, T. Oka, Tadashi Yoshino

    Journal of Clinical Pathology   61 ( 3 )   377 - 381   2008年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Follicular lymphomas occasionally arise in the extra-nodal organs and are frequently found in the duodenum. They are often localised tumours with multiple polyps around the ampulla of Vater. Aims: To examine a IgH/bcl-2 hybrid gene and VH gene to investigate the nature of the lymphoma cells and how they differ from nodal follicular lymphomas and MALT lymphomas. Methods: Of 40 patients reported previously, 35 with duodenal follicular lymphoma were studied in detail with respect to clinicopathological characteristics. Results: 37/40 patients were in clinical stage I (n = 30) or stage II (n = 7). Clonal immunoglobulin gene rearrangement was detected in 53.3% of examined cases, and rearrangement of IgH/bcl-2 gene at the major break point was detected in 27% of cases. Three of 8 examined cases were VH4 (38%)
    2 out of them were VH4-34. As VH4 deviation is one of the common characteristics of MALT lymphomas and 2/3 were identical, duodenal follicular lymphomas have a similar aetiology to MALT lymphomas. Clinical course was also similar to that of MALT lymphomas. Conclusions: Results suggest that duodenal follicular lymphomas have intermediate characteristics of MALT lymphomas and nodal follicular lymphomas.

    DOI: 10.1136/jcp.2007.049825

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  • Epigenetic changes and suppression of the nuclear factor of activated T cell 1 (NFATC1) promoter in human lymphomas with defects in immunoreceptor signaling. 査読 国際誌

    Askar Akimzhanov, Laszlo Krenacs, Timm Schlegel, Stefan Klein-Hessling, Enikö Bagdi, Eva Stelkovics, Eisaku Kondo, Sergei Chuvpilo, Philipp Wilke, Andris Avots, Stefan Gattenlöhner, Hans-Konrad Müller-Hermelink, Alois Palmetshofer, Edgar Serfling

    The American journal of pathology   172 ( 1 )   215 - 24   2008年1月

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    記述言語:英語  

    The nuclear factor of activated T cell 1 (Nfatc1) locus is a common insertion site for murine tumorigenic retroviruses, suggesting a role of transcription factor NFATc1 in lymphomagenesis. Although NFATc1 is expressed in most human primary lymphocytes and mature human T- and B-cell neoplasms, we show by histochemical stainings that NFATc1 expression is suppressed in anaplastic large cell lymphomas and classical Hodgkin's lymphomas (HLs). In HL cell lines, NFATc1 silencing correlated with a decrease in histone H3 acetylation, H3-K4 trimethylation, and Sp1 factor binding but with an increase in HP1 binding to the NFATC1 P1 promoter. Together with DNA hypermethylation of the NFATC1 P1 promoter, which we detected in all anaplastic large cell lymphoma and many HL lines, these observations reflect typical signs of transcriptional silencing. In several lymphoma lines, methylation of NFATC1 promoter DNA resulted in a "window of hypomethylation," which is flanked by Sp1-binding sites. Together with the under-representation of Sp1 at the NFATC1 P1 promoter in HL cells, this suggests that Sp1 factors can protect P1 DNA methylation in a directional manner. Blocking immunoreceptor signaling led to NFATC1 P1 promoter silencing and to a decrease in H3 acetylation and H3-K4 methylation but not DNA methylation. This shows that histone modifications precede the DNA methylation in NFATC1 promoter silencing.

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  • Expression of apoptosis regulators in germinal centers and germinal center-derived B-cell lymphomas: insight into B-cell lymphomagenesis. 査読 国際誌

    Eisaku Kondo, Tadashi Yoshino

    Pathology international   57 ( 7 )   391 - 7   2007年7月

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    記述言語:英語  

    Germinal centers (GC) are unique sites in peripheral lymphoid tissue where clonal selection of B cells takes place in response to stimulation by various antigens. To select a proper B-cell clone for antibody-mediated immunity, multiple apoptotic signals synchronize in the GC, both in negative and positive selection pathways. At the same time, GC have been known to be a major source of B-cell lymphomas including follicular and Burkitt's, and also some diffuse large B-cell lymphomas. Therefore, uncovering the biological characteristics of GC would greatly contribute to understanding lymphomagenesis, or progression of B-cell lymphomas of GC origin. Herein the authors briefly explain the expression and pathophysiological significance of apoptosis regulators in GC, focusing particularly on Bcl-2, Fas (CD95) and a transcription factor, nuclear factor of activated T cells, which seems to play a critical role in regulating cellular dynamics of GC B cells via B-cell antigen receptor. The expression of these molecules is then compared with that of the neoplastic counterpart B-cell lymphomas in order to consider lymphomagenesis of GC origin. In conclusion, follicular lymphoma closely reflected characteristics of GC among these B-cell lymphomas, although it acquires strong expression of apoptosis-resistant gene, bcl-2.

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  • Deviated VH4 immunoglobulin gene usage is found among thyroid mucosa-associated lymphoid tissue lymphomas, similar to the usage at other sites, but is not found in thyroid diffuse large B-cell lymphomas. 査読 国際誌

    Yumiko Sato, Naoya Nakamura, Satoko Nakamura, Sumie Sakugawa, Koichi Ichimura, Takehiro Tanaka, Nobuya Ohara, Takeshi Oka, Eisaku Kondo, Tadashi Yoshino

    Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc   19 ( 12 )   1578 - 84   2006年12月

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    記述言語:英語  

    It remains unclear whether or not diffuse large B-cell lymphomas of extranodal sites arise from mucosa-associated lymphoid tissue (MALT) lymphomas. We studied the clinicopathological features of MALT lymphoma and diffuse large B-cell lymphoma in the thyroid gland, with special reference to VH usage of immunoglobulin gene rearrangement, to clarify the relationships between these two types of lymphomas. In addition, t(11; 18) (q21; q21) translocation was examined by multiplex reverse transcription-polymerase chain reaction. We examined 58 patients with primary thyroid lymphoma: 31 (male seven and female 24) with MALT lymphoma and 27 (male three and female 24) with diffuse large B-cell lymphoma. Interestingly, the sequence of VH genes revealed that the two subtypes differed significantly in their use of the VH4 family (P < 0.05). Of the seven MALT lymphomas, three used the VH4 family and the other four used the VH3 family, whereas eight out of nine diffuse large B-cell lymphoma used the VH3 family, one used the VH1 family, and none used the VH4 family. It was also interesting that, in one diffuse large B-cell lymphoma patient with MALT lymphoma, the diffuse large B-cell lymphoma component used the VH3 family and the MALT lymphoma component used the VH4 family. These data imply that, in a subset of cases, these two subtypes do not share a common origin and that at least some diffuse large B-cell lymphomas have a de novo origin. No t(11; 18) (q21; q21) was detected in thyroid lymphomas, which are different from MALT lymphoma of the stomach, lungs, large intestine and ocular adnexa. This strongly indicated that the presence of t(11; 18) (q21; q21) in MALT lymphoma is organ-specific.

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  • Follicular lymphoma frequently originates in the salivary gland. 査読 国際誌

    Satoko Nakamura, Koichi Ichimura, Yumiko Sato, Shigeo Nakamura, Hirokazu Nakamine, Hiroshi Inagaki, Yoshito Sadahira, Koichi Ohshima, Sumie Sakugawa, Eisaku Kondo, Hiroyuki Yanai, Nobuya Ohara, Tadashi Yoshino

    Pathology international   56 ( 10 )   576 - 83   2006年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The aim of the present study was to examine the clinicopathological presentations of follicular lymphomas (FL) of the salivary glands, as compared to mucosa-associated lymphoid tissue (MALT) lymphomas. A total of 27 primary salivary gland lymphomas were examined: 6 FL (five, grade 1; one, grade 2); 19 MALT lymphomas; and two diffuse large B-cell lymphomas. The FL patients ranged in age from 24 to 73 years, with a mean of 49 years, which was younger than that of MALT patients (mean: 64 years; P < 0.05). Four of the six FL arose from the submandibular gland, which was the origin of only five out of a total of 19 MALT lymphomas. One FL patient was in clinical stage (CS) IE, two in CS IIE, and two in CS III and IV. As regards the MALT lymphoma patients, 13 (68%) were in CS IE and five (26%) in CS IIE. None of the FL patients had clinical diagnosis of autoimmune disease but eight MALT lymphoma patients had autoimmune disease. The present study found a relatively high incidence of FL in the salivary glands. The observed differences in age of onset, background of autoimmune disease, and lesion site suggests that the pathogenesis of FL may differ from that of MALT lymphoma.

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  • Bcl-2 phosphorylation in the BH4 domain precedes caspase-3 activation and cell death after neonatal cerebral hypoxic-ischemic injury. 査読 国際誌

    Ulrika Hallin, Eisaku Kondo, Yasuhiko Ozaki, Henrik Hagberg, Futoshi Shibasaki, Klas Blomgren

    Neurobiology of disease   21 ( 3 )   478 - 86   2006年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To date, there are very few in vivo studies addressing the role of Bcl-2 phosphorylation. In a model of neonatal hypoxic-ischemic (HI) brain injury, we characterized the spatial and temporal phosphorylation of Bcl-2 at serine-24 (PS24-Bcl-2), using a site-specific antibody. Very few cells positive for PS24-Bcl-2 were found in control animals, but the number increased during reperfusion in all investigated brain areas in the ipsilateral hemisphere after HI, particularly in the border region between intact and damaged tissue. The highest numbers were encountered 24 h post-HI. Phosphorylation of Bcl-2 at serine-24 coincided with cytochrome c release after hypoxia-ischemia and preceded caspase-3 activation. Injured neurons displayed a predominantly nuclear, but also mitochondrial, localization of PS24-Bcl-2 immunoreactivity. In conclusion, phosphorylation of Bcl-2 at serine 24 was induced by hypoxia-ischemia, presumably resulting in loss of its anti-apoptotic function.

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  • p27(Kip1) is detected on most gastric MALT lymphomas, but not large cell lymphomas. 査読

    Hiaki Sato, Yumiko Sato, Koichi Ichimura, Takashi Oka, Eisaku Kondo, Takehiro Tanaka, Takami Kondo, Nobuya Ohara, Kiyoshi Takahashi, Tadashi Yoshino

    Journal of clinical and experimental hematopathology : JCEH   46 ( 1 )   25 - 30   2006年3月

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    記述言語:英語  

    We investigated the relationship of gastric mucosa-associated lymphoid tissue (MALT) lymphoma tumorigenesis to Helicobacter pylori infection, the t (11;18) translocation, and alterations in cell cycle regulators. We sought to assess the implications of altered expression of p27(Kip1), a cyclin-dependent kinase inhibitor, on high-grade transformation and responsiveness to eradication therapy. We used immunohistochemistry to examine p27(Kip1), p53, and Ki-67 expression in 23 MALT lymphomas, five diffuse large B-cell lymphomas (DLBCLs), and four DLBCLs with associated MALT lymphoma. All of the MALT lymphomas were positive for p27(Kip1) expression and negative for p53 with a low Ki-67 index, regardless of the sensitivity of these cells to eradication. All DLBCLs were negative for p27(Kip1) and positive for p53, exhibiting a high Ki-67 index. In DLBCLs with MALT lymphoma, p27(Kip1) expression was absent from both the MALT and large cells components. In all of these lymphomas, the MALT components were negative for p53 and displayed a low Ki-67 index, while the large cell components were positive for p53 with a high Ki-67 index. The expression patterns of the DLBCLs differed significantly from those of the MALT lymphomas. p27(Kip1) was not detected in either component of DLBCL with MALT lymphoma, suggesting that decreased expression of p27(Kip1) in the MALT component may be related to high-grade transformation. Thus, p27(Kip1) expression in morphological MALT lymphomas could be useful tool to predict high-grade transformation to DLBCL.

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  • A tumor-suppressor function for NFATc3 in T-cell lymphomagenesis by murine leukemia virus. 査読 国際誌

    Sys Zoffmann Glud, Annette Balle Sørensen, Mindaugas Andrulis, Bruce Wang, Eisaku Kondo, Randi Jessen, Laszlo Krenacs, Eva Stelkovics, Matthias Wabl, Edgar Serfling, Alois Palmetshofer, Finn Skou Pedersen

    Blood   106 ( 10 )   3546 - 52   2005年11月

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    記述言語:英語  

    Nuclear factor of activated T cell (NFAT) transcription factors play a central role in differentiation, activation, and elimination of lymphocytes. We here report on the finding of provirus integration into the Nfatc3 locus in T-cell lymphomas induced by the murine lymphomagenic retrovirus SL3-3 and show that NFATc3 expression is repressed in these lymphomas. The provirus insertions are positioned close to the Nfatc3 promoter or a putative polyadenylated RNA (polyA) region. Furthermore, we demonstrate that NFATc3-deficient mice infected with SL3-3 develop T-cell lymphomas faster and with higher frequencies than wild-type mice or NFATc2-deficient mice. These results identify NFATc3 as a tumor suppressor for the development of murine T-cell lymphomas induced by the retrovirus SL3-3.

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  • Expression of phosphorylated Ser70 of Bcl-2 correlates with malignancy in human colorectal neoplasms. 査読 国際誌

    Eisaku Kondo, Takayoshi Miyake, Masao Shibata, Toshikazu Kimura, Hiromi Iwagaki, Shin-Ichi Nakamura, Takehiro Tanaka, Nobuya Ohara, Koichi Ichimura, Takashi Oka, Hiroyuki Yanai, Futoshi Shibasaki, Tadashi Yoshino

    Clinical cancer research : an official journal of the American Association for Cancer Research   11 ( 20 )   7255 - 63   2005年10月

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    記述言語:英語  

    PURPOSE: Bcl-2 is a model apoptosis suppressor postulated to promote tumorigenesis. Recently, it has been reported that Bcl-2 undergoes phosphoregulation of its Ser70 to substantially alter its molecular function. Previous studies further suggest that such phospho-Bcl-2 regulation may influence tumor progression in colorectal and other cancers; however, phosphorylation status of the Ser70 of Bcl-2 (pSer70) in vivo in tumors remains obscure. To elucidate this question that may suggest the biological role, we molecularly screened a panel of human colorectal adenomas and adenocarcinomas for endogenous expression of pSer70 Bcl-2. EXPERIMENTAL DESIGN: An antibody specific against pSer70 Bcl-2 was generated for thorough immunohistochemical examination of paraffin-embedded tumor specimens, allowing detection of the endogenously expressed antigen among a range of Bcl-2-positive colorectal neoplasms, including 75 tubular adenomas, 114 adenocarcinomas, and 15 cases of cancer in adenomas. RESULTS: Loss of pSer70 Bcl-2 expression was observed in adenocarcinomas in a differentiation-dependent manner (positivities: well differentiated 63%, moderately differentiated 52%, and poorly differentiated 12%), whereas tubular adenomas maintained their expression (positivity 88%). Interestingly, an inverse correlation was found between expression of pSer70 Bcl-2 and Ki-67 antigen in those cases of cancer in adenoma (P < 0.01). It was further observed that loss of pSer70 Bcl-2 expression was associated with significantly shorter survival (P < 0.05) and correlated with clinical stages and lymph node metastasis (P < 0.05 and P < 0.05, respectively). CONCLUSIONS: Loss of pSer70 Bcl-2 expression is closely linked to biological aggressiveness in colorectal tumors and represents a statistically significant molecular index for prognosis of patients with these tumors.

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  • Highly efficient delivery of p16 antitumor peptide into aggressive leukemia/lymphoma cells using a novel transporter system. 査読 国際誌

    Eisaku Kondo, Masao Seto, Kazuhiro Yoshikawa, Tadashi Yoshino

    Molecular cancer therapeutics   3 ( 12 )   1623 - 30   2004年12月

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    記述言語:英語  

    Molecular targeting of hematopoietic malignancies has been generally hindered by technological obstacles to gene delivery in the neoplastic cells. The development of peptide delivery systems based on protein transduction domains has recently gained attention as a means of potentially overcoming these impediments. Here, we present a novel peptide transporter system that increases the efficiency of peptide delivery more than 10 times compared with the previous methods. The transporter, Wr-T, has an enlarged hydrophobic pocket consisting of triple tryptophan-rich domains fused with nine d-enantiomer polyarginines (r9) via Gly-Pro-Gly spacer, which serves to augment delivery of a cargo peptide. Wr-T-mediated transport of p16(INK4a) functional peptide dramatically inhibits growth of highly aggressive leukemia/lymphomas by up to 80% through restoration of p16 function. The Wr-T system thus represents a highly effective approach to cargo peptide delivery with the potential for substantially developing p16 peptide-based therapy for hematopoietic malignancies.

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  • Expression and intracellular localization of FKHRL1 in mammary gland neoplasms. 査読

    Gui-Shan Jin, Eisaku Kondo, Takayoshi Miyake, Masao Shibata, Takako Takashima, Yi-Xuan Liu, Kazuhiko Hayashi, Tadaatsu Akagi, Tadashi Yoshino

    Acta medica Okayama   58 ( 4 )   197 - 205   2004年8月

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    記述言語:英語  

    FKHRL1 (FOXO3a), a member of the Forkhead family of genes, has been considered to be involved in the development of breast tumors; however, the in vivo expression and activation status of FKHRL1 in breast tumors still remains unclear. We immunohistochemically demonstrated the expression and intracellular localization of FKHRL1 in human breast tumors by the novel anti-FKHRL1 antibody which is available for formalin-fixed paraffin-embedded specimens. In a total of 51 cases of benign tumors, FKHRL1 was diffusely expressed in all cases, and its intracellular localization was revealed to be cytoplasmic (inactive form) in 94% of cases of intraductal papillomas (16/17) and 91% cases of fibroadenomas (31/34), with a similar pattern to normal glandular epithelium. In invasive ductal carcinomas, 83% of the cases (93/112) diffusely expressed FKHRL1; however, unlike benign tumors, 71% of the cases (66/93) showed the nuclear-targeted, active form of FKHRL1. Moreover, activated FKHRL1 was predominantly observed in scirrhous (29/36, 81% of the cases) and papillotubular (30/38, 79% of the cases) subtypes, compared to the solid-tubular subtype (7/19, 37% of the cases). Furthermore, the cases with nuclear-targeted FKHRL1 showed a tendency to have lymph nodal metastasis with statistical significance (P < 0.0001). Thus, the activation of FKHRL1 seems to be recognized as one of the specific features of invasive ductal carcinoma of the breast.

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  • Rabbit model for human EBV-associated hemophagocytic syndrome (HPS): Sequential autopsy analysis and characterization of IL-2-dependent cell lines established from Herpesvirus papio-induced fatal rabbit lymphoproliferative diseases with HPS 査読

    Kazuhiko Hayashi, Zaishun Jin, Sachiyo Onoda, Hiromasa Joko, Norihiro Teramoto, Nobuya Ohara, Wakako Oda, Takehiro Tanaka, Yi-Xuan Liu, Tirtha Raj Koirala, Takashi Oka, Eisaku Kondo, Tadashi Yoshino, Kiyoshi Takahashi, Tadaatsu Akagi

    American Journal of Pathology   162 ( 5 )   1721 - 1736   2003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:American Society for Investigative Pathology Inc.  

    Epstein-Barr virus-associated hemophagocytic syndrome (EBV-AHS) is often associated with fatal infectious mononucleosis or T-cell lymphoproliferative diseases (LPD). To elucidate the true nature of fatal LPD observed in Herpesvirus, papio (HVP)-induced rabbit hemophagocytosis, reactive or neoplastic, we analyzed sequential development of HVP-induced rabbit LPD and their cell lines. All of the seven Japanese White rabbits inoculated intravenously with HVP died of fatal LPD 18 to 27 days after inoculation. LPD was also accompanied by hemophagocytic syndrome (HPS) in five of these seven rabbits. Sequential autopsy revealed splenomegaly and swollen lymph nodes, often accompanied by bleeding, which developed in the last week. Atypical lymphoid cells infiltrated many organs with a "starry sky" pattern, frequently involving the spleen, lymph nodes, and liver. HVP-small RNA-1 expression in these lymphoid cells was clearly demonstrated by a newly developed in situ hybridization (ISH) system. HVP-ISH of immunomagnetically purified lymphoid cells from spleen or lymph nodes revealed HVP-EBER1+ cells in each CD4+, CD8+, or CD79a+ fraction. Hemophagocytic histiocytosis was observed in the lymph nodes, spleen, bone marrow, and thymus. HVP-DNA was detected in the tissues and peripheral blood from the infected rabbits by PCR or Southern blot analysis. Clonality analysis of HVP-induced LPD by Southern blotting with TCR gene probe revealed polyclonal bands, suggesting polyclonal proliferation. Six IL-2-dependent rabbit T-cell lines were established from transplanted scid mouse tumors from LPD. These showed latency type I/II HVP infection and had normal karyotypes except for one line, and three of them showed tumorigenicity in nude mice. These data suggest that HVP-induced fatal LPD in rabbits is reactive polyclonally in nature.

    DOI: 10.1016/S0002-9440(10)64306-4

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  • NF-ATc2 induces apoptosis in Burkitt's lymphoma cells through signaling via the B cell antigen receptor. 査読 国際誌

    Eisaku Kondo, Akira Harashima, Takami Takabatake, Hideo Takahashi, Yoshinobu Matsuo, Tadashi Yoshino, Kunzo Orita, Tadaatsu Akagi

    European journal of immunology   33 ( 1 )   1 - 11   2003年1月

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    記述言語:英語  

    Cross-linking of the B cell antigen receptor (BCR) with an anti-IgM antibody has been shown to induce dramatic apoptosis in type I Burkitt's lymphoma (BL) cells. However, the apoptotic mechanism triggered via BCR remains unknown. Here we reports a mechanism of BCR ligation-induced apoptosis involving protein phosphatase calcineurin and its specific substrate, transcriptional factor NF-AT. In response to BCR cross-linking, endogenous calcineurin was rapidly activated, and this facilitated nuclear translocation of NF-ATc2, a subtype of NF-AT members. Interestingly, nuclear-imported NF-ATc2 functioned pro-apoptotically in BL cells. The effect of NF-ATc2 was efficiently blocked with FK506, which prevented its nuclear translocation through inactivation of calcineurin. In addition, TR3 induction during BCR cross-linking was reduced by FK506 and the VIVIT peptide, which is a highly selective inhibitor for NF-AT. This strongly suggests that activation of NF-ATc2 by calcineurin is essential for TR3 recruitment, and that TR3 can be considered as a candidate for death effector in BCR-mediated apoptosis. Therefore, NF-ATc2 plays a crucial role in BCR-mediated apoptosis in type IBL, providing greater insight into unique BL characteristics through BCR signaling.

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  • Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas. 査読 国際誌

    Takashi Oka, Mamoru Ouchida, Maho Koyama, Yoichiro Ogama, Shinichi Takada, Yoko Nakatani, Takehiro Tanaka, Tadashi Yoshino, Kazuhiko Hayashi, Nobuya Ohara, Eisaku Kondo, Kiyoshi Takahashi, Junjiro Tsuchiyama, Mitsune Tanimoto, Kenji Shimizu, Tadaatsu Akagi

    Cancer research   62 ( 22 )   6390 - 4   2002年11月

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    記述言語:英語  

    High-frequent silencing of hematopoietic cell-specific protein-tyrosine phosphatase SHP1 gene by promoter methylation was detected in various kinds of leukemias and lymphomas, as well as in many hematopoietic cell lines, which is supported by our previous observation of strong decrease of SHP1 mRNA and protein. The promoter methylation of the SHP1 gene was clearly correlated with the clinical stage. Loss of heterozygosity with microsatellite markers near the SHP1 gene was shown in 79% of informative acute lymphoblastic leukemia cases. These results suggest that functional loss of SHP1 is associated with the pathogenesis of leukemias/lymphomas.

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  • Prostaglandin E2 inhibits IL-18-induced ICAM-1 and B7.2 expression through EP2/EP4 receptors in human peripheral blood mononuclear cells 査読

    Hideo K. Takahashi, Hiromi Iwagaki, Tadashi Yoshino, Shuji Mori, Toshihiko Morichika, Hideyuki Itoh, Minori Yokoyama, Shinichiro Kubo, Eisaku Kondo, Tadaatsu Akagi, Noriaki Tanaka, Masahiro Nishibori

    Journal of Immunology   168 ( 9 )   4446 - 4454   2002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:American Association of Immunologists  

    Costimulatory molecules play important roles in immune responses. In the present study we investigated the effects of PGE2 on the expression of ICAM-1, B7.1, and B7.2 on monocytes in IL-18-stimulated PBMC using FACS analysis. Addition of PGE2 to PBMC inhibited ICAM-1 and B7.2 expression elicited by IL-18 in a concentration-dependent manner. We examined the involvement of four subtypes of PGE2 receptors, EP1, EP2, EP3, and EP4, in the modulatory effect of PGE2, on ICAM-1 and B7.2 expression elicited by IL-18, using subtype-specific agonists. ONO-AE1-259-01 (EP2R agonist) inhibited IL-18-elicited ICAM-1 and B7.2 expression in a concentration-dependent manner with a potency slightly less than that of PGE2, while ONO-AE1-329 (EP4R agonist) was much less potent than PGE2. The EP2/EP4R agonist 11-deoxy-PGE1-mimicked the effect of PGE2 with the same potency. ONO-D1-004 (EP1R agonist) and ONO-AE-248 (EP3R agonist) showed no effect on IL-18-elicited ICAM-1 or B7.2 expression. These results indicated that EP2 and EP4Rs were involved in the action of PGE2. Dibutyryl cAMP and forskolin down-regulated ICAM-1 and B7.2 expression in IL-18-stimulated monocytes. As EP2 and EP4Rs are coupled to adenylate cyclase, we suggest that PGE2 down-regulates IL-18-induced ICAM-1 and B7.2 expression in monocytes via EP2 and EP4Rs by cAMP-dependent signaling pathways. The fact that anti-B7.2 as well as anti-ICAM-1 Ab inhibited IL-18-induced cytokine production implies that PGE2 may modulate the immune response through regulation of the expression of particular adhesion molecules on monocytes via EP2 and EP4Rs.

    DOI: 10.4049/jimmunol.168.9.4446

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  • IL-18-induced expression of intercellular adhesion molecule-1 in human monocytes: Involvement in IL-12 and IFN-γ production in PBMC 査読

    Atsushi Yoshida, Hideo Kohka Takahashi, Masahiro Nishibori, Hiromi Iwagaki, Tadashi Yoshino, Toshihiko Morichika, Minori Yokoyama, Eisaku Kondo, Tadaatsu Akagi, Noriaki Tanaka

    Cellular Immunology   210 ( 2 )   106 - 115   2001年6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.  

    IL-18 time- and concentration-dependently upregulated the expression of intercellular adhesion molecule-1 (ICAM-1) in a monocyte population in human PBMC as determined by FACS analysis while the expression of CD11a, CD18, CD29, CD44, and CD62L in monocytes and that of ICAM-1, CD11a, CD18, CD29, CD44, and CD62L in T cells was not influenced by IL-18. IL-18 in the same concentration range stimulated the production of IL-12, TNF-α, and IFN-γ in culture of PBMC
    however, IL-18-induced expression of ICAM-1 in monocytes was not inhibited by anti-IL-12, anti-TNF-α, or anti-IFN-γ Ab, suggesting the independence of the upregulating effect of IL-18 on endogenous IL-12, TNF-α, and IFN-γ production. IL-18 also induced the aggregation of PBMC, which was prevented by anti-ICAM-1 and anti-LFA-1 Abs. On the other hand, anti-ICAM-1 and anti-LFA-1 Abs inhibited IL-18-induced production of three cytokines, IL-12, IFN-γ and TNF-α, by 60 and 40%, respectively. These results strongly suggested that the IL-18-induced upregulation of ICAM-1 and the subsequent adhesive interaction through ICAM-1 on monocytes and LFA-1 on T/NK cells generate an additional stimulatory signaling as well as an efficient paracrine environment for the IL-18-initiated cytokine cascade. © 2001 Academic Press.

    DOI: 10.1006/cimm.2001.1811

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  • Reduction of hematopoietic cell-specific tyrosine phosphatase SHP-1 gene expression in natural killer cell lymphoma and various types of lymphomas/leukemias: Combination Analysis with cDNA expression array and tissue microarray 査読

    Takashi Oka, Tadashi Yoshino, Kazuhiko Hayashi, Nobuya Ohara, Tohru Nakanishi, Yuichiro Yamaai, A. Hiraki, Chiharu Aoki Aoki Sogawa, Eisaku Kondo, N. Teramoto, Kiyoshi Takahashi, Junjiro Tsuchiyama, Tadaatsu Akagi

    American Journal of Pathology   159 ( 4 )   1495 - 1505   2001年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To investigate the lymphomagenesis of NK/T lymphoma, we comprehensively and systematically analyzed the expression pattern of the human NK/T cell line (NK-YS) genome by cDNA expression array and tissue microarray. We detected significant changes in the gene expression of NK-YS cell line: an increase in 18 and a decrease in 20 genes compared to normal NK cells or peripheral blood mononuclear cells. Among these genes, we found a strong decrease in hematopoietic cell specific protein-tyrosine-phosphatase SH-PTP1 (SHP1) mRNA by cDNA expression array and reverse transcriptase-polymerase chain reaction. Further analysis with standard immunohistochemistry and tissue microarray, which used 207 paraffin-embedded specimens of various kinds of malignant lymphomas, showed that 100% of NK/T lymphoma specimens and more than 95% of various types of malignant lymphoma were negative for SHP1 protein expression. On the other hand, SHP1 protein was strongly expressed in the mantle zone and interfollicular zone lymphocytes in reactive lymphoid hyperplasia specimens. In addition, various kinds of hematopoietic cell lines, particularly the highly aggressive lymphoma/leukemia lines, lacked SHP1 expression in vitro, suggesting that loss of SHP1 expression may be related to not only malignant transformation, but also tumor cell aggressiveness. SHP1 expression could not be induced in either of two NK/T cell lines by phorbol ester, suggesting that genetic impairment or modification with methylation of SHP1 DNA could be one of the critical events in the pathogenesis of NK/T lymphoma. This evidence strongly suggests that loss of SHP1 gene expression plays an important role in multistep tumorigenesis, possibly as an anti-oncogene in the wide range of lymphomas/leukemias as well as NK/T lymphomas. © 2001 American Society forInvestigative Pathology.

    DOI: 10.1016/S0002-9440(10)62535-7

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  • Clinical, histopathological, and immunogenetic analysis of ocular adnexal lymphoproliferative disorders: Characterization of MALT lymphoma and reactive lymphoid hyperplasia 査読

    Tomohiko Mannami, Tadashi Yoshino, Koichi Oshima, Sumie Takase, Eisaku Kondo, Nobuya Ohara, Hideki Nakagawa, Hiroshi Ohtsuki, Mine Harada, Tadaatsu Akagi

    Modern Pathology   14 ( 7 )   641 - 649   2001年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Malignant lymphomas and reactive lymphoi hyperplasia (RLH) in the ocular adnexa are sometimes difficult to differentiate morphologically and have often been categorized together as a lymphoproliferative disorder. Immunogenotypic characters of these diseases have not yet been well clarified. This study included 76 cases of ocular adnexal lymphoproliferative disorders. These consisted of 52 cases of malignant lymphoma (43 primary and secondary), 22 of RLH, and 2 borderline cases. There were slightly more male than female subjects. Diagnoses were based on morphology and immunophenotypic characteristics. Clonalities were detected by means of polymerase chain reaction (PCR), an immunoglobulin heavy-chain variable region (VH) genes were sequenced in 10 cases of mucosa-associated lymphoid tissue (MALT) lymphoma. MAL lymphoma constituted 86% (37 cases) of the primary lymphomas. MALT lymphomas were more indolent, more rarely disseminated, and had a lower death rate than the other primary lymphomas. Two patients exhibited coexistence of MALT and diffuse large B-cell lymphoma. The average age of patients with RLH was 5.5 years younger than that of those with MALT lymphoma. One of the cases of RLH later progressed to malignant lymphoma. B-cell clonality was detected by PCR in 57%, 55%, and 0% o primary lymphomas, MALT lymphomas and RLHs respectively. Sequencing of VH genes revealed that the VH3 family was the most commonly expressed germline VH family (70%) and that DP-63, DP-54 and DP-47 genes were frequently found in the MALT lymphomas examined. PCR analysis wa useful for differentiation between MALT lymphoma and RLH. Sequence analysis of VH genes showed that an autoimmune mechanism may be involved in the lymphomagenesis of ocular adnexal MALT lymphoma.

    DOI: 10.1038/modpathol.3880366

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  • An animal model for human EBV-associated hemophagocytic syndrome: Herpesvirus papio frequently induces fatal lymphoproliferative disorders with hemophagocytic syndrome in rabbits 査読

    Kazuhiko Hayashi, Nobuya Ohara, Norihiro Teramoto, Sachiyo Onoda, Hong-Li Chen, Takashi Oka, Eisaku Kondo, Tadashi Yoshino, Kiyoshi Takahashi, John Yates, Tadaatsu Akagi

    American Journal of Pathology   158 ( 4 )   1533 - 1542   2001年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Epstein-Barr virus-associated hemophagocytic syndrome (EBV-AHS) is often associated with fatal infectious mononucleosis. However, the animal model for EBV-AHS has not been developed. We reported the first animal model for EBV-AHS using rabbits infected with EBV-related herpesvirus of baboon (HVP). Eleven of 13 (85%) rabbits inoculated intravenously with HVP-producing cells developed fatal lymphopro-liferative disorders (LPD) between 22 and 105 days after inoculation. LPD was also accompanied by hemophagocytic syndrome (HPS) in nine of these 11 rabbits. The peroral spray of cell-free HVP induced the virus infection with increased anti-EBV-viral capsid antigen-IgG titers in three of five rabbits, and two of these three infected rabbits died of LPD with HPS. Autopsy revealed hepatosplenomegaly and swollen lymph nodes. Atypical lymphoid T cells expressing EBV-encoded small RNA-1 infiltrated diffusely in many organs, frequently involving the lymph nodes, spleen, and liver. Hemophagocytic histiocytosis was observed in the lymph nodes, spleen, bone marrow, and thymus. HVP-DNA was detected in the tissues and peripheral blood from the infected rabbits by polymerase chain reaction or Southern blot analysis. Reverse transcriptase-polymerase chain reaction revealed both HVP-EBNA1 and HVP-EBNA2 transcripts, suggesting latency type III infection. These data indicate that the high rate of rabbit LPD with HPS induction is caused by HVP. This system is useful for studying the pathogenesis, prevention, and treatment of human EBV-AHS.

    DOI: 10.1016/S0002-9440(10)64104-1

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  • Clinicopathological features of gastric mucosa associated lymphoid tissue (MALT) lymphomas: High grade transformation and comparison with diffuse large B cell lymphomas without MALT lymphoma features 査読

    Tadashi Yoshino, Kunihiro Omonishi, Keita Kobayashi, Tomohiko Mannami, Hiroyuki Okada, Motowo Mizuno, Ichiro Yamadori, Eisaku Kondo, Tadaatsu Akagi

    Journal of Clinical Pathology   53 ( 3 )   187 - 190   2000年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Aims - To investigate the clinicopathological differences among gastric low grade MALT lymphomas (low MALT), large B cell lymphomas with low grade components (secondary high grade MALT lymphomas, high MALT), and diffuse large B cell lymphomas without low grade features (primary high grade MALT lymphomas, DLL). Methods - Clinicopathological and morphological characters of 126 gastric lymphoma cases were studied: 82 cases of low MALT lymphoma including 40 that were surgically resected, 17 cases of high MALT lymphoma including 13 surgically resected, and 27 cases of DLL including 12 surgically resected. Results - Age ranges were as follows: low MALT lymphoma, 34 to 85 years (mean 59.9)
    high MALT lymphoma, 53 to 88 years (mean 68.5)
    DLL, 29 to 83 years (mean 62.3). The average age for low and high MALT lymphomas was significantly different (p &lt
    0.05), but there were no differences in other comparisons. There was a female predominance of low MALT lymphoma patients (female to male ratio, 47/35), while for high MALT patients the ratio was almost even (8/9), and for DLL patients there was a male predominance (11/16). Examination of surgically resected material showed that MALT lymphomas had a wider distribution in the gastric wall than DLL. Conclusions - The findings suggest that at least some of the high grade gastric lymphomas, especially in patients younger than the fifth decade, do not originate from high grade transformation of low MALT lymphomas. It seems to take about one decade at least for high grade transformation of low MALT lymphomas.

    DOI: 10.1136/jcp.53.3.187

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  • Comparison of two methods of staining apoptotic cells of leukemia cell lines: Terminal deoxynucleotidyl transferase and DNA polymerase I reactions 査読

    Ichiro Yamadori, Tadashi Yoshino, Eisaku Kondo, Liu Cao, Tadaatsu Akagi, Yoshinobu Matsuo, Jun Minowada

    Journal of Histochemistry and Cytochemistry   46 ( 1 )   85 - 90   1998年

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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:Histochemical Society Inc.  

    We compared two methods to stain apoptotic cells, one using terminal deoxynucleotidyl transferase (TDT), the other DNA polymerase I, using leukemia cell lines treated with anti-Fas monoclonal antibody (MAb). Both TDT and polymerase I strongly reacted with fragmented nuclei of apoptotic MOLT- 16 and Jurkat cells, but only polymerase I strongly reacted with nonfragmented nuclei of early apoptotic cells. Anti-Fas MAb-treated MOLT-4 cells showed morphological changes corresponding to early apoptosis and were strongly positive for polymerase I only. MOLT-16 and Jurkat cells treated with anti-Fas MAb and inhibitors of endonuclease and poly(ADP-ribose) polymerase showed the morphology of early apoptosis but were not strongly stained by TDT. Because DNA polymerase I has nick-translation activity, it is possible that DNA polymerase I reaction is positive in early apoptotic cells by detecting single-strand DNA cleavage, which occurs before extensive oligonucleosomal DNA cleavage and late morphological changes of apoptosis in leukemia cell lines. Although TDT is widely used to stain apoptotic cells, DNA polymerase I may be more applicable in special cases of apoptosis, in which cells undergo single-strand rather than double-strand DNA breaks. However, the procedure has limitations, such as the necessity to use cell smears for comparison with the TDT reaction.

    DOI: 10.1177/002215549804600111

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  • Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and Bcl-2. 査読 国際誌

    F Shibasaki, E Kondo, T Akagi, F McKeon

    Nature   386 ( 6626 )   728 - 31   1997年4月

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    記述言語:英語  

    It is not known how the protein Bcl-2 inhibits cell death induced by calcium signalling and growth-factor withdrawal. Here we report that Bcl-2 forms a tight complex with calcineurin, resulting in the targeting of calcineurin to Bcl-2 sites on cytoplasmic membranes, and show that this interaction is dependent on the BH4 domain of Bcl-2. Calcineurin bound to Bcl-2 is an active phosphatase but is unable to promote the nuclear translocation of NF-AT, a transcription-factor required for induction of interleukin-2 expression, suggesting a mechanism by which Bcl-2 suppresses NF-AT activity. We also show that Bax, a pro-apoptotic member of the Bcl-2 family, interferes with interactions between calcineurin and Bcl-2. We propose that the ability of Bcl-2 to block NF-AT signalling is due to the sequestering of active calcineurin to the same domain of Bcl-2 which associates with Rad-1 (ref. 5), and that calcineurin may act in Bcl-2-regulated functions.

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  • Binding of human leukocytes to fibronectin is augmented by an anti-CD44 mAb (TL-1) and blocked by another anti-CD44 mAb (Hermes-3) but not by anti-VLA-4/VLA-5 mAbs 査読

    Liu Cao, Tadashi Yoshino, Nobuhiro Kawasaki, Hiroyuki Yanai, Kunimitsu Kawahara, Eisaku Kondo, Kunihiro Omonishi, Kiyoshi Takahashi, Tadaatsu Akagi

    Immunobiology   196 ( 5 )   504 - 512   1996年

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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 GmbH  

    Fibronectin (FN) forms meshworks in extracellular spaces, and it plays an important role in cellular trafficking. Lymphoid cells are activated by binding to FN of the VLA-4 and VLA-5 receptors. CD44 also acts as a receptor of FN, but the mechanism and physiologic regulation of their binding are poorly understood. We have developed an anti-CD44 monoclonal antibody (mAb) (TL-1) in which lymphoid cells are activated and form homotypic cell aggregation. In this study, we found that the adhesion of GEM, HSB2, and LAD lymphoid cells to FN was augmented by TL-1 treatment and was apparently blocked by another anti-CD44 mAb (Hermes-3), but TL-1 Fab' fragments treatment did not induce FN-binding. A similar phenomenon is reported in the binding of the CD44 molecule to HA. This augmentation was not inhibited by the CS1 and RGD peptides of FN or by anti-VLA-4 and -VLA-5 mAbs
    it was energy-dependent and associated with cytoplasmic actin filaments. Tl-1 treatment did not alter the cell surface expression of CD44 molecules. These findings above suggested that activated and/or altered cell surface distribution of CD44 molecules via a conformational change augmented the avidity of its binding to FN, which may be similar to lymphocyte-hyaluronate and lymphocyte-endothelial cell binding. As the Hermes-3 binding site is also involved in the interaction between lymphocytes and endothelial cells, activation of lymphocytes via CD44 molecules may facilitate the binding of lymphocytes to endothelial cells, extravasation, and migration to inflammatory sites rich in FN.

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  • Metastatic potential of lymphoma/leukemia cell lines in SCID mice is closely related to expression of CD44 査読

    Nobuhiro Kawasaki, Yoshinobu Matsuo, Tadashi Yoshino, Hiroyuki Yanai, Takashi Oka, Norihiro Teramoto, Cao Liu, Eisaku Kondo, Jun Minowada, Tadaatsu Akagi

    Japanese Journal of Cancer Research   87 ( 10 )   1070 - 1077   1996年

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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:Japanese Cancer Association  

    To investigate whether the lymphocyte homing receptors, adhesion molecules regulating normal lymphocyte traffic, influence the dissemination of lymphoma cells, 24 lymphoma/leukemia cell lines were inoculated into SCID mice subcutaneously, and the correlation between the expression of the adhesion molecules and the metastatic potential of the cell lines was examined. Among the six adhesion molecules examined (LFA-1, ICAM-1, CLA, VLA-4, L-selectin and CD44), L-selectin increased the incidence of lymph node metastasis, and CD44 expression was related to both lymph node and organ (hematogenous) metastasis. A monoclonal antibody to the standard form of CD44 (CD44s), Hermes-3, inhibited the local growth and remote metastasis of CD44+ cell lines. Thus, it is concluded that at least CD44s expression is important in both lymphatic and hematogenous metastasis.

    DOI: 10.1111/j.1349-7006.1996.tb03112.x

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  • The p6gag domain of human immunodeficiency virus type 1 is sufficient for the incorporation of Vpr into heterologous viral particles. 査読 国際誌

    E Kondo, F Mammano, E A Cohen, H G Göttlinger

    Journal of virology   69 ( 5 )   2759 - 64   1995年5月

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    記述言語:英語  

    The vpr gene of human immunodeficiency virus type 1 (HIV-1) encodes a virion-associated regulatory protein. Mutagenesis has shown that the virion association of Vpr requires sequences near the C terminus of the HIV-1 Gag polyprotein Pr55gag. To investigate whether Vpr incorporation is mediated by a specific domain of Pr55gag, we examined the ability of chimeric HIV-1/Moloney murine leukemia virus (MLV) Gag polyproteins to direct the incorporation of Vpr. Vpr expressed in trans did not associate with particles formed by the authentic MLV Gag polyprotein or with particles formed by chimeric Gag polyproteins that had the matrix (MA) or capsid (CA) domain of MLV precisely replaced by the corresponding domain of HIV-1HXB2. By contrast, Vpr was efficiently incorporated upon replacement of the C-terminal nucleocapsid (NC) domain of the MLV Gag polyprotein with HIV-1 p15 sequences. Vpr was also efficiently incorporated into particles formed by a MLV Gag polyprotein that had the HIV-1 p6 domain fused to its C terminus. Furthermore, a deletion analysis revealed that a conserved region near the C terminus of the p6 domain is essential for Vpr incorporation, whereas sequences downstream of the conserved region are dispensable. These results show that a virion association motif for Vpr is located within residues 1 to 46 of p6.

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  • Correlation between the number of apoptotic cells and expression of the apoptosis‐related antigens Fas, Ley and bcl‐2 protein in non‐Hodgkin's lymphomas 査読

    Mohammad Aftabuddin, Ichiro Yamadori, Tadashi Yoshino, Eisaku Kondo, Tadaatsu Akagi

    Pathology International   45 ( 6 )   422 - 429   1995年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The relationship between the number of apoptotic cells and the expression of apoptosis‐related antigens was examined In 56 cases of non‐Hodgkin's lymphomas and in 10 cases of reactive hyperplastic lymph nodes (RHL). Apoptosis was visually quantified by the in situ end‐labeling (ISEL) method, and the expression of Fas, Ley antigens and bcl‐2 protein was examined by Immunohistochemistry. The expression of Ley antigen was observed in germinal centers of RHL and 45% of non‐Hodgkin's lymphomas. The apoptotic cell count (AC) in follicular lymphomas was significantly less than that in diffuse lymphomas. The distribution pattern of apoptotic cells In follicular lymphomas was inverse to that in RHL. In follicular lymphomas, AC was lower in follicles than in inter‐follicular areas. In contrast, AC was higher in follicles than in Interfollicular areas in RHL. Ley antigen‐positive lymphomas showed a significantly higher AC than the negative cases. The Fas antigen‐positive lymphomas showed a higher AC than the negative cases. However, AC in bcl‐2 protein‐positive and negative cases was not significantly different. These results suggest that Ley and Fas antigens appear to be involved in the apoptotic tendency of tumor cells in non‐Hodgkin's lymphomas, whereas bcl‐2 does not necessarily. © 1995 Cambridge Philosophical Society

    DOI: 10.1111/j.1440-1827.1995.tb03479.x

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  • Ligation of HLA class II molecules promotes sensitivity to CD95 (Fas antigen, APO‐1)‐mediated apoptosis 査読

    Tadashi Yoshino, Liu Cao, Ritsuo Nishiuchi, Yoshinobu Matsuo, Ichiro Yamadori, Eisaku Kondo, Norihiro Teramoto, Kazuhiko Hayashi, Kiyoshi Takahashi, Nobuhiro Kamikawaji, Tadaatsu Akagi

    European Journal of Immunology   25 ( 8 )   2190 - 2194   1995年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    CD95 (Fas antigen/APO‐1) is up‐regulated in activated lymphocytes, and monoclonal antibody (mAb) to CD95 induces apoptosis. HLA class II molecules play a key role in antigen presentation, ligation of which induces signal transduction. We examined 18 lymphoid cell lines (15 B cell and 3 T cell lines) to investigate the effects of ligation of HLA class II molecules on CD95‐mediated apoptosis. All of the five immature B cell lines were sensitive to anti‐CD95 mAb, and ligation of HLA class II molecules promoted CD95‐mediated apoptosis. In seven B‐blastoid cell lines, two Burkitt lines were resistant to anti‐CD95 mAb in spite of high expression of CD95. In three of five non‐Burkitt B‐blastoid lines, CD95‐mediated apoptosis was augmented by treatment with anti‐HLA class II mAb, while the other two lines lacking CD95 were resistant to anti‐CD95 mAb. Three plasmacytic cell lines showed CD95‐mediated apoptosis, but enhancement by anti‐HLA class II mAb was slight in one cell line and was not observed in the other two lines. Out of three HLA class II antigen‐positive T cell lines, CD95‐mediated apoptosis was observed to some degree in one cell line but was not promoted by the treatment with anti‐HLA class II mAb, and the other two cell lines were resistant to anti‐CD95 mAb. Ligation of HLA class II molecules did not alter CD95 expression in the five cell lines examined, except Su‐DHL‐4 originated from a follicular lymphoma, which showed slight up‐regulation. Taken together, ligation of HLA class II molecules apparently promotes CD95‐mediated apoptosis in immature B cells and non‐Burkitt B blasts. These findings highlight the role of HLA class II molecules in CD95‐mediated apoptosis, which may facilitate rapid clearance of functionally useless cells from the immune system and might be involved in negative selection of B cells. Copyright © 1995 WILEY‐VCH Verlag GmbH &amp
    Co. KGaA, Weinheim

    DOI: 10.1002/eji.1830250811

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  • EXPRESSION OF BCL-2 PROTEIN AND FAS ANTIGEN IN NON-HODGKINS-LYMPHOMAS 査読

    E KONDO, T YOSHINO, YAMADORI, I, Y MATSUO, N KAWASAKI, J MINOWADA, T AKAGI

    AMERICAN JOURNAL OF PATHOLOGY   145 ( 2 )   330 - 337   1994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:AMER SOC INVESTIGATIVE PATHOLOGY, INC  

    Expression of Bcl-2 protein and Fas antigens was analyzed in 12 cases of follicular lymphoma and 32 cases of diffuse lymphoma, including 22 B-cell and 10 T-cell lymphomas. It was shown that 75% of follicular lymphomas had clear expression of both Bcl-2 protein and Fas antigen. Thus, follicular lymphomas may have a growth advantage due to their high expression of Bcl-2 protein, which tended to impede apoptosis mediated by Fas antigen On the other hand, diffuse lymphomas showed various patterns; 28% were double positive, 16% were only Bcl-2 protein-positive, 28% were only Fas antigen-positive, and 28% were double negative or equivocal. Cytocidal assay of seven leukemia/lymphoma cell lines using anti-human Fas monoclonal antibody revealed that overexpression of Bcl-2 protein tended to impede apoptosis mediated by Fas antigen. However, this inhibitory effect of Bcl-2 protein was incomplete and its effect might be dependent upon cell type

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  • Inverse expression of bcl-2 protein and Fas antigen in lymphoblasts in peripheral lymph nodes and activated peripheral blood T and B lymphocytes 査読

    Tadashi Yoshino, Eisaku Kondo, Liu Cao, Kiyoshi Takahashi, Kazuhiko Hayashi, Shintaro Nomura, Tadaatsu Akagi

    Blood   83 ( 7 )   1856 - 1861   1994年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To examine the regulatory mechanism of apoptosis in lymphoid cells, expression of both bcl-2 protein and Fas antigen was investigated in reactive lymph nodes, in resting lymphocytes from peripheral blood (PBLs), and in PBLs stimulated with pokeweed mitogen, interleukin-4 (IL-4) + anti-IgM antibody, IL-2 + anti-CD3 antibody, phytohemagglutinin + phorbol myristate acetate using immunohistochemistry and flow cytometry. Germinal center cells expressed a large amount of Fas antigen, which is associated with the induction of apoptosis in lymphoid cell lines, in contrast to the lack of bcl-2 protein as an apoptosis inhibitor. On the other hand, mantle zone lymphocytes expressed a high level of bcl-2 protein and less Fas antigen. This inverse expression of bcl-2 protein and Fas antigen was also shown in activated T and B lymphocytes from peripheral blood. These lymphoblasts fell into apoptosis dose-dependently in the presence of anti-Fas monoclonal antibody, but resting lymphocytes that expressed both bcl-2 protein and Fas antigen did not undergo apoptosis. These findings suggest that bcl-2 expression prevents the apoptosis of lymphoid cells induced by the Fas antigen-dependent mechanism and that apoptosis of lymphocytes is exquisitely controlled, at least in part, by regulation of the bcl-2 and Fas genes.

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  • Aberrant expression of the monocyte/macrophage phenotype in a human T cell line immortalized by HTLV‐I and an adult T cell leukemia/lymphoma cell line 査読

    Ho Jong Jeon, Tadaatsu Akagi, Tadashi Yoshino, Kiyoshi Takahashi, Kazuhiko Hayashi, Eisaku Kondo, Ashit Baran Sarker, Norihiro Teramoto, Kotaro Fujiwara, Nobuya Ohara, Kanji Miyamoto

    Pathology International   44 ( 1 )   39 - 48   1994年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    An HTLV‐I‐immortalized human T cell line (JP‐2), a N‐methyl‐N′‐nitro‐N‐nitrosoguanidine‐treated JP‐2 line (JP‐2T), and an adult T cell leukemia cell line (ATL‐1T) were examined morphologically and phenotypically. All of these cell lines expressed some T cell markers, including CD4, and showed rearrangement of T cell receptor (TCR) genes, but they lacked CD3 and TCR antigens and expressed some myelomonocytic markers (CD68, HL‐21, CD15, CD16). JP‐2 cells grew in suspension, but JP‐2T and ATL‐1T cells, which mostly adhered to the surface of culture vessels, showed macrophage‐like morphological features and expressed more monocyte/macrophage markers (lysozyme, α1‐antitrypsin) and fibronectin. ATL‐1T cells transplanted into SCID mice lost the macrophage features. These results suggest that HTLV‐I infected T cells can express some macrophage features and that these cells may provide a model that will be useful in elucidating the phenotypic variability of T cell lymphomas. Copyright © 1994, Wiley Blackwell. All rights reserved

    DOI: 10.1111/j.1440-1827.1994.tb02584.x

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  • Expression of bcl-2 protein and bcl-2 mRNA in normal and neoplastic lymphoid tissues 査読

    Tadaatsu Akagi, Eisaku Kondo, Tadashi Yoshino

    Leukemia and Lymphoma   13 ( 1-2 )   81 - 87   1994年

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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:Informa Healthcare  

    The bcl-2 gene is a unique proto-oncogene that blocks apoptosis
    its product is localized on the inner mitochondrial membrane. In non neoplastic human lymphoid tissues, bcl-2 protein is strongly expressed in the small recirculating lymphocytes of the follicular mantle zone
    it is expressed less intensely in T-cell areas, and is almost absent from germinal center cells. Bcl-2 mRNA, in contrast to bcl-2 protein, is strongly expressed on most of the latter cells, a similar phenomenon also being observed in peripheral blood lymphocytes (PBL). Resting PBL express both bcl-2 mRNA and protein, while most lymphoblasts in mitogen-stimulated PBL cultures lose bcl-2 protein and become apoptotic, despite expressing higher levels of mRNA. Posttranscriptional regulation of the bcl-2 gene may cause this paradoxical down-regulation of bcl-2 protein and may play an important role in the clonal selection of lymphocytes. Bcl-2 protein is frequently expressed in follicular lymphomas bearing the t(14
    18) chromosomal translocation, but it is also widely expressed in many other B- and T-cell lymphomas without bcl-2 rearrangement, showing that mechanisms other than t(14
    18) translocation may deregulate bcl-2 expression. Many lymphoid and myeloid cell lines also express bcl-2 protein with no correlation being shown with differentiation stage. Thus, it is conceivable that bcl-2 protein may play a role in the oncogenesis of many hematolymphoid malignancies by interfering with programmed cell death, in concert with other oncogenes or tumor suppressor genes. © 1994 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

    DOI: 10.3109/10428199409051655

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  • A human T cell line with an abnormal trisomy 2 karyotype established by coculture of peripheral lymphocytes with an HTLV‐II‐infected simian leukocyte cell line 査読

    Nobuya Ohara, Kazuhiko Hayashi, Kanji Miyamoto, Norlko Tomita, Kotaro Fujiwara, Eisaku Kondo, Kiyoshi Takahashi, Yuji Ohtsuki, Tadaatsau Akagl

    Pathology International   43 ( 5 )   237 - 243   1993年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A new human T cell in with a chromosomal abnormality (47, XY, +2), designated AS‐IIA, was established by coculturing peripheral blood leukocytes of a healthy adult male with a lethally irradiated human T lymphotropic virus type II (HTLV‐II)‐infected simian leukocyted cell line (Si‐IIA). A polymerase chain reaction method showed that this interleukin‐2 (IL‐2)‐dependent cell line possessed the HTLV‐II provirus genome
    the cells also reacted with HTLV‐II‐positive human sera, anti‐HTLV‐I/II p24, and anti‐HTLV‐II gp46 antibodies. AS‐IIA cells expressed the suppressor/cytotoxic T cell markers CD3+, CD4‐, CD25+, and HLA‐DR+, with later conversion ot CD8‐. These cells showed better proliferation than other human HTLV‐II‐infected cell lines with normal karyotypes, but were not transplantable into severe combined immunodeficiency mice. Virus production from AS‐IIA was confirmed not only by electron microscopic examination, which revealed mature and immature type C virus particels, but also by the capacity of the line to immortalize human T cells. These results suggest that HTLV‐II shows broad tropism for T cells including CD4+ or CD8+, and that not only SI‐IIA, but also AS‐IIA, are goode sources of HTLV‐II. The authors of the present study believe that AS‐IIA may be a useful human T cell line for the investigation of HTLV‐II in comarison with HTLV‐I. Copyright © 1993, Wiley Blackwell. All rights reserved

    DOI: 10.1111/j.1440-1827.1993.tb01138.x

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▶ 全件表示

MISC

  • Intractable cellular population in follicular lymphomas

    Eisaku Kondo, Katsuyoshi Takata, Ken Saito

    CANCER SCIENCE   109   1057 - 1057   2018年1月

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    記述言語:日本語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:WILEY  

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  • Identification of TRA-1-60-Positive Cells As a Potent Refractory Population in Follicular Lymphomas

    Katsuyoshi Takata, Hidekazu Iioka, Tomoko Miyata-Takata, Yukari Miki, Tadashi Yoshino, Yoshinobu Maeda, Ken Saito, Christian Steidl, Eisaku Kondo

    BLOOD   128 ( 22 )   2016年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    0

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  • New technology to detect DNA methylation in plasma sample from lung cancer patients

    Keiko Shinjo, Eisaku Kondo, Yutaka Kondo

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2014-416

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  • Development of novel non-invasive anti-cancer drug delivery system using tumor-homing peptides

    Eisaku Kondo

    JOURNAL OF PHARMACOLOGICAL SCIENCES   124   30P - 30P   2014年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:JAPANESE PHARMACOLOGICAL SOC  

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  • TGF-beta synergistically stimulates malignant mesothelioma growth with defects in the Hippo pathway by inducing CTGF expression

    Makiko Fujii, Takeshi Toyoda, Hayao Nakanishi, Yasushi Yatabe, Ayuko Sato, Yasue Matsudaira, Hidemi Ito, Hideki Murakami, Yutaka Kondo, Eisaku Kondo, Tohru Tsujimura, Toyoaki Hida, Hirotaka Osada, Yoshitaka Sekido

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

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  • Nanomedicine and Drug Delivery

    Chiming Wei, Wenchi Wei, Michael Morris, Eisaku Kondo, Mikhail Gorbounov, Donald A. Tomalia

    Medical Clinics of North America   91 ( 5 )   863 - 870   2007年9月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

    This article discusses the use of nanotechnology in drug delivery approaches. Magnetic nanotechnology is finding wide applications in medicine, most notably in MRI and magnetic separation. The impedance biosensor is expected to find applications in monitoring cytokines in cancer, bone turnover markers in osteoporosis, and understanding neural-degenerative diseases. © 2007 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.mcna.2007.05.005

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  • The Fas antigen and Fas-mediated apoptosis in B-cell differentiation

    Tadaatsu Akagi, Tadashi Yoshino, Eisaku Kondo

    Leukemia and Lymphoma   28 ( 5-6 )   483 - 489   1998年

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:Informa Healthcare  

    In the B-cell lineage, Fas, a type 1 membrane protein belonging to the tumor necrosis factor receptor (TNF) family, is expressed on B-cells at a restricted developmental stage and on activated B-cells, but not on naive mature B-cells. Apoptosis mediated by Fas-Fas ligand interactions may be involved in the peripheral elimination of autoreactive B-cells and in the regulation of the immune response through deletion of B-cells activated by foreign antigens, as for the T-cell lineage. Fas-mediated apoptosis associated with B-cell activation is affected by costimulation through other accessory signaling molecules like CD40, whose ligands are on T-cells.

    DOI: 10.3109/10428199809058355

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講演・口頭発表等

  • Tumor-Homing Peptides for Tumor-Targeting Medicine 招待 国際会議

    Eisaku Kondo

    10th International Peptide Minisymposium(10th IPS)  2018年12月 

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    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • Peptide-based tumor tecnology using tumorhoming CPPs 招待 国際会議

    Eisaku Kondo

    The 4th RIKEN/Karolinska Insitutet/SciLifeLab Joint Symposium  2017年11月 

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    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

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産業財産権

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受賞

  • 新潟大学学長賞

    2020年  

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  • 内藤記念科学振興財団 奨励研究助成

    2015年  

    近藤英作

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  • 日本学術振興会(JSPS)特別研究員等審査会専門委員表彰

    2015年  

    近藤英作

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  • 公益財団法人 高松宮妃癌研究助成

    2010年  

    近藤英作

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  • 日本病理学会学術研究賞(The Japanese Society of Pathology, Pathology Research Award)

    2005年  

    近藤英作

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共同研究・競争的資金等の研究

  • ホーミングペプチドを基盤にした新規膵癌バイオマーカー及び膵癌標的化抗体医薬の開発

    2020年4月 - 2022年3月

    日本学術振興会  科学研究費助成事業 基盤研究B  腫瘍治療学

    近藤英作

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    担当区分:研究代表者 

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  • 新規グリオブラストーマ・ホーミングペプチドによる低侵襲性先進医療技術の開発研究

    研究課題/領域番号:17H03590  2017年4月 - 2020年3月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    近藤 英作, 小根山 千歳

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    配分額:17810000円 ( 直接経費:13700000円 、 間接経費:4110000円 )

    本年度の課題点は以下であった。
    1.候補として絞り込んだGL-4の疎水性の改良
    2.ペプチドの生体内安定性の改善(血漿に対する分解抵抗性の向上)
    <BR>
    L体のみで構成されるGL-4配列:RCXXXXLYPにおいて血漿分解試験の実施で、N端のArgが易分解性であることが判明した(血漿混和後20分以内に分解を起こす。)この問題に対して、反復型(タンデム型)GL-4:RCXXXLYP-G-RCXXXXLYP、およびレトロインバーソ型:pylxxxcr (小文字はD体アミノ酸)を作成し、細胞透過試験を実施し、タンデム型で選択的吸収性を保持した状態での生体内安定性の向上と吸収性の増強に成功し、2の課題点を克服するための改良策を得た。1の課題点の克服に関しては、単分散PEG(PEG2~PEG8)によるペプチドC端の修飾を考案し、現在修飾型タンデムGL-4の性能をヒトグリオブラストーマ細胞株数種類に対する細胞透過アッセイを行い検討中である。現在の経過では、オリジナルの9アミノ酸配列のGL-4に対し、タンデム型GL-4は約3倍~8倍の吸収性の向上を示しており、かつ正常グリアや正常神経細胞への吸収性は約1.7倍以下の増加レベルまでに抑制で来ている。(血漿分解耐性を増強しつつ、標的細胞と正常細胞との間の吸収性のウィンドウの拡大効果が期待できる。)レトロインバーソ型は原型のGL-4の選択的吸収性を損なわず、分解耐性であるが疎水性がやや増した点が好ましくない。この研究経過から、親水性の向上と吸収性の増強を同時に達成し、かつ従来の腫瘍選択性を保持する最適のPEG修飾フォームが間もなく決定できるため、次いで当初の計画であるin vivo studyを実施して本年度内に基本設計を完成する。

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  • 標的細胞ホーミングペプチド創成技術による実効的なスキルス癌標的化PDCの開発

    2016年4月 - 2022年3月

    日本医療研究開発機構 (AMED)  次世代がん医療創生事業 P-CREATE 

    近藤英作

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    担当区分:研究代表者 

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  • iPS細胞マーカーTRA-1-60はがん難治性の指標か?

    研究課題/領域番号:16K15245  2016年4月 - 2018年3月

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    近藤 英作, 奥田 修二郎, 阪口 政清

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    配分額:3640000円 ( 直接経費:2800000円 、 間接経費:840000円 )

    TRA-1-60は糖鎖修飾型PODXL1であることから、ヒト膵がん細胞株においてPODXL1ノックアウトクローンを作成し機能解析した。結果、MiaPaCa-2, AsPC1, Panc-1 PODXL1-KO(PODXL1 -/-)クローンは膵がん肝転移を劇的に抑制した。即ち、PODXL1は膵がんの転移能獲得に直接に機能していることが判明した。PODXL1は複数のサイトカイン受容体と結合能を持ち、がん組織内でこれら受容体の機能活性化に働いていることが判明した膵がん患者病理組織では、上記の遺伝子機能を反映し、腫瘍の浸潤先進部や肝転移巣で高発現していることが判明した。

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  • ミトコンドリア機能型p14ペプチドによる新たな基盤情報の獲得と制がん技術の開発

    研究課題/領域番号:15K08415  2015年4月 - 2018年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    齋藤 憲, 近藤 英作

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    配分額:4810000円 ( 直接経費:3700000円 、 間接経費:1110000円 )

    本研究ではp14ペプチドをベースとし増殖抑制を最大限に引き出すペプチドの改良を行い、これまでのがん増殖抑制効果を上回る配列を見出した。この改良型p14ペプチド(p14MIS)は効率的にミトコンドリア移行・局在を示し、効率的にミトコンドリア膜電位の低下を誘導する。また、系統の異なる各種がん細胞株に対する改良型p14ペプチドの増殖抑制効果は細胞の種類によって異なることが判明し、各種がん細胞におけるミトコンドリアp14ARF発現、ATPAF1発現とミトコンドリア膜電位に依存することが示唆された。以上の結果は、抗腫瘍性機能分子としての改良型p14ペプチドを用いた新たな治療学的基盤戦略の可能性を与える。

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  • 樹状細胞選択的がんワクチンデリバリーシステムの開発

    研究課題/領域番号:26430179  2014年4月 - 2017年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    葛島 清隆, 近藤 英作

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    配分額:5200000円 ( 直接経費:4000000円 、 間接経費:1200000円 )

    ペプチド-cDNAライブラリーを用いて、樹状細胞に特異的に侵入する10個程度のアミノ酸からなる細胞透過性ペプチド(CPP)を同定した。蛍光物質としてFITCおよびGFPをこれらのペプチドに融合したものを種々の細胞にパルスする実験結果から、同定したペプチドは樹状細胞、B細胞、単球等のミエロイド系の細胞に透過し易い性質を有していることが判明した。非選択的CPP(R10;アルギニン10個)、2種類の同定したDC選択性CPP(H03LとF04L)にCTLエピトープを付加した長鎖ペプチドを用いた実験結果から、H03LとF04LはR10に比べて、DCおよびB細胞上での抗原提示が線維芽細胞上より優れていた。

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  • オールイン型デンドリマーを用いた癌の「見張り」リンパ節のイメージング・薬物送達

    研究課題/領域番号:26410227  2014年4月 - 2017年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    児島 千恵, 近藤 英作, 小川 美香子

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    配分額:5200000円 ( 直接経費:4000000円 、 間接経費:1200000円 )

    日本の死因の第一位である癌の克服のため、本研究では、転移性癌細胞の最初の通り道であるリンパ節の正確なイメージングと薬物送達を行うことを目的とした。まず、サイズや構造を制御でき、かつデリバリー機能をもつデンドリマーとよばれる合成高分子の構造最適化を行い、リンパ節へ多く移行するデンドリマーを得た。そして、このデンドリマーにイメージング剤を付与し、リンパ節の検出に成功した。さらに、癌細胞集積性と抗腫瘍活性を併せ持つデンドリマーを作製し、癌細胞に選択的な殺傷効果を示すデンドリマーを作製することにも成功した。

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  • 細胞選択的侵入ペプチドを用いた神経疾患治療戦略

    研究課題/領域番号:25293048  2013年4月 - 2016年3月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    松下 正之, 片桐 千秋, 近藤 英作

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    配分額:17160000円 ( 直接経費:13200000円 、 間接経費:3960000円 )

    グリオブラストーマの細胞株(U87)を標的としたペプチドスクリーニングを行い、グリオブラストーマ細胞に選択的に侵入するペプチドを発見した。このペプチドは10アミン酸からなるが、両端からアミノ酸を欠損させ、腫瘍選択性を維持する7アミノ酸からなる最小機能ペプチド配列を決定した。この短鎖ペプチドはグリオブラストーマ細胞株だけでなく、脳腫瘍モデルマウスへのペプチドの静脈投与により腫瘍特異的にシグナルを検出し生体での利用も可能である。我々の開発した脳腫瘍選択的ペプチドを用いたPETプローブや抗がん剤とペプチドの結合による標的治療への展開を計画している。

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  • 腫瘍吸収性ペプチドとナノテクノロジーを融合した革新的難治性腫瘍標的医療技術の開発

    研究課題/領域番号:25290062  2013年4月 - 2016年3月

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    近藤 英作, 古賀 浩徳, 瀧川 奈義夫, 瀧川 奈義夫

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    配分額:16900000円 ( 直接経費:13000000円 、 間接経費:3900000円 )

    デンドリマーおよびリポソームとのペプチドコンジュゲートは、これらの粒子単独の場合の肝臓への高度集積性は抑制されたが、in vivo動態の計測では完全な肝吸収性の回避には至らず、むしろペプチド単独フォームの方が実効的な標的腫瘍への集積の選択性を保持することが判明した。そこで、がんに卓越した選択的吸収性を発揮できる腫瘍高度選択的集積性ペプチド(腫瘍ホーミングペプチド)のランダムペプチドライブラリーからの分離・開発を実施し、ヒト膵がん、胆管がん(胆道がん)、脳腫瘍(グリオブラストーマ)各々の系統に対応するホーミングペプチドとして獲得した。これらについては国内特許申請を完了した。

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  • ペプチド性分子治療を目指したがん抑制遺伝子機能回復型抗腫瘍ペプチド創成への挑戦

    研究課題/領域番号:25670263  2013年4月 - 2015年3月

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    近藤 英作

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    配分額:3770000円 ( 直接経費:2900000円 、 間接経費:870000円 )

    準備研究で得られていたプロトタイプP14ARF機能回復型ペプチド全長27アミノ酸残基配列から12アミノ酸コア配列を同定し、さらにがん細胞内で効果的に機能性配列を単独型に開裂させることのできるcleavage motifの挿入に成功し、最終機能型ペプチドr9-CB-p14MISを創成した。これを静脈投与した担癌マウスモデルにて、同ペプチドの生体低侵襲性と有意な抗腫瘍効果を確認できた。従って、r9-CB-p14MISは正常系の細胞への傷害性が低く、かつ多種類の系統のp14不活化の起こっている生物学的高度悪性腫瘍に幅広く応用できる可能性が確証された。

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  • 細胞選択的透過型ペプチドを応用した膵がん・がん間質の新規標的化DDS技術の開発

    研究課題/領域番号:25112716  2013年4月 - 2015年3月

    日本学術振興会  科学研究費助成事業 新学術領域研究(研究領域提案型)  新学術領域研究(研究領域提案型)

    近藤 英作

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    配分額:7540000円 ( 直接経費:5800000円 、 間接経費:1740000円 )

    硬癌(スキルスがん)を形成する頻度の高い悪性腫瘍は、治療学上一般に難治がんとして認識されており、腫瘍細胞の生物学的性質とともに豊富な間質構成分の存在がその要因として問題視されている。このがん間質の治療抵抗性に関与する理由としては、間質が組織内がん細胞への薬物浸透のバリアとなることの他に、がん-間質相互反応による腫瘍細胞側への増殖・浸潤・転移の促進効果などの影響が報告されている。本研究の最終目的は、新規制がん医療技術として、難治がん組織を構成する間質成分に対する治療学的標的技術の基盤を作ることにあり、そのためのバイオツールとしてがん間質に取り込まれる特殊機能ペプチドを獲得することを具体的な目標とした。そこでまず、がん間質構成分の中から制がんに有効な標的目標細胞を検索し、間質内に存在する間葉系幹細胞(MSC)が膵がんの増殖進展、浸潤に促進的に働くことを分子細胞学的に解析し、結果を得た。本研究期間における成果として、1.MSCとヒト膵がん細胞との共存下では、MMP-3, MMP-9, Amphiregrinの分泌亢進が可溶性分画に認められる。2.MSCフェノタイプ(CD105+, CD73+, CD29+, CD44+, CD45-, CD34-, CD31-)を示す間葉系細胞が実際のヒト膵がん患者腫瘍組織内に存在している。3.ヒトMSCに高度にシフトした吸収性を発揮する特殊機能ペプチド候補を獲得した。

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  • 悪性腫瘍における新規増殖因子OGFOD1の制がん分子機序の解明

    研究課題/領域番号:24659170  2012年4月 - 2015年3月

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    齋藤 憲, 近藤 英作

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    配分額:3900000円 ( 直接経費:3000000円 、 間接経費:900000円 )

    近年、OGFOD1はリボソームタンパク質のプロリン残基を水酸化する機能をもつことが報告されたが、その機能本態および癌での役割はいまだ解明されていない。私たちは、多系統の腫瘍細胞株においてOGFOD1が核に局在すること、また患者病理標本での発現解析により食道扁平上皮癌を含む多種類のがん組織でOGFOD1が高発現していることを認めた。また食道扁平上皮癌細胞におけるOGFOD1 knockdownではp21cip1の低下と細胞周期の停止が認められ、CDK阻害剤によりOGFOD1の発現低下および細胞増殖の抑制が観察された。これらの結果はOGFOD1が食道癌の増殖に必須な分子であることを示唆する。

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  • バイオツールを用いた新規中皮腫治療法の開発

    研究課題/領域番号:24650650  2012年4月 - 2014年3月

    日本学術振興会  科学研究費助成事業 挑戦的萌芽研究  挑戦的萌芽研究

    関戸 好孝, 近藤 英作, 藤井 万紀子

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    配分額:3900000円 ( 直接経費:3000000円 、 間接経費:900000円 )

    悪性中皮腫は極めて難治性であり現在有効な抗がん剤、分子標的剤はない。中皮腫に対する新規治療法の開発を目指し本研究を推進した。中皮腫で高頻度に不活性化しているがん抑制遺伝子p16INK4aに着目し、その機能を回復させる細胞膜透過性機能ペプチドを用いて検討を行った。その結果、中皮腫細胞特異的に細胞傷害性が誘導され、バイオツールを用いた新規治療法の有効性が確認された。さらに、中皮腫細胞で恒常的に活性化しているYAPがん遺伝子産物について解析した。YAPと結合する転写因子TEADファミリー分子の詳細が明らかになり、YAPを標的とする特異的な分子標的治療法の具体的戦略についての知見が集積した。

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  • 分子標的薬耐性難治性肺がんをモデルにした新規ペプチド創薬基盤技術へのチャレンジ

    研究課題/領域番号:23590442  2011年 - 2012年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    近藤 英作

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    配分額:5200000円 ( 直接経費:4000000円 、 間接経費:1200000円 )

    先進医療の現場で難治性として危急の解決課題となっているチロシンキナーゼ阻害性分子標的薬耐性変異型肺がん細胞を研究対象として、その分子病理学的特徴をgefitinib感受性肺がん細胞と比較解析した。結果、耐性変異型細胞ではgefitinibが特異的に誘導する癌抑制遺伝子p14ARFの発現が起こらないことを見出した。さらに、gefitinib効果の作用点となるミトコンドリア局在型p14ARFのコード領域内のコア配列を決定し、感受性方とともに耐性変異型細胞の増殖抑制・アポトーシス誘導に機能する抗腫瘍ペプチドのプロトタイプの開発に成功した。

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  • 細胞選択的導入ペプチドを用いた疾患治療戦略

    研究課題/領域番号:22390038  2010年 - 2012年

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    松下 正之, 中村 真理子, 砂川 昌範, 近藤 英作

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    配分額:18330000円 ( 直接経費:14100000円 、 間接経費:4230000円 )

    ランダムペプチドライブラリーをソースとしてヒト各種がん細胞を対象とした広汎なスクリーニングを行うことにより、このライブラリー中から標的とする細胞の系統別に対応して高浸透能を発揮する新規細胞侵入ペプチドを分離する技術を確立した。

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  • DDS応用の基盤となる多種類の新規ヒトがん細胞選択的透過性ペプチドの開発と応用

    研究課題/領域番号:21200078  2009年 - 2011年

    日本学術振興会  科学研究費助成事業 新学術領域研究(研究課題提案型)  新学術領域研究(研究課題提案型)

    近藤 英作, 斎藤 憲, 松下 正之

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    配分額:30940000円 ( 直接経費:23800000円 、 間接経費:7140000円 )

    約一兆種類ほどの組み合わせの人工アミノ酸配列を含むペプチドライブラリーの中からヒトがん細胞膜を透過して細胞内に高い効率で取り込まれる性質を持つ約10種類(大腸がん、乳がん、肺がん、肝がん、骨肉腫、リンパ腫、白血病など)の発生系統(発生母地)の異なる悪性腫瘍それぞれに対応して目的とする腫瘍細胞に選択的に高い浸透性を発揮する腫瘍ホーミングペプチドを分離・同定し、これら腫瘍ホーミングペプチドによる多様な応用性を包括した新規生体低侵襲性ドラッグデリバリーシステムの基盤の構築に成功した。

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  • 反応性濾胞と濾胞性リンパ腫の転写後翻訳機構の違いに注目した発現分子の比較研究

    研究課題/領域番号:20590366  2008年 - 2010年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    近藤 英作

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    配分額:4810000円 ( 直接経費:3700000円 、 間接経費:1110000円 )

    非腫瘍性胚中心B細胞とそこを発生母地とする難治性リンパ腫である濾胞性リンパ腫について、特異的に発現変動のあるmicro RNAを探索することにより、濾胞性リンパ腫発生の転写後遺伝子制御機構の特徴の一端を明らかにすることを目指した。ヒト病理組織からのマイクロダイセクションサンプルのmiRNAプロファイリングおよびセルソーティング法による抽出細胞のreal-time PCR両手法を総合した解析では、濾胞性リンパ腫で胚中心に比較して、miR-146aおよびmiR-193bの発現亢進が認められ、一方miR-26aは発現が抑制されていた。B 細胞特異的にmiR-146aの過剰発現をもたらすトランスジェニックマウスを作製した検索では、胚中心形成刺激に対して野生型よりも胚中心の増生傾向が認められるようである。この現象については現在検証中である。

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  • 高分化ヒト膵β細胞株を用いたバイオ人工膵臓開発の基礎的研究

    研究課題/領域番号:18390347  2006年 - 2007年

    日本学術振興会  科学研究費助成事業 基盤研究(B)  基盤研究(B)

    小林 直哉, 山辻 知樹, 田畑 泰彦, 桑木 賢也, 加藤 順, 近藤 英作, 岩垣 博巳

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    配分額:17970000円 ( 直接経費:15300000円 、 間接経費:2670000円 )

    高分化ヒト膵β細胞株を独自に作成した。当該細胞をソースとした埋め込み式バッグ型バイオ人工膵臓を開発して新規糖尿病治療法を開発するための基礎的研究を施行した。
    1.ヒト膵β細胞株NAKT-15細胞の機能的培養法の検討
    自己組織化ゲルであるピュラマトリックスの上でヒト膵β細胞株を培養することで、膵島様形態の形成が促進され細胞機能が向上した。
    2.BAPデバイスの作成
    内面が細胞接着性ポリペプチドで加工されたハイデンシティ・ポリエチレン膜で外面がエチレンビニールアルコール膜で構成される埋め込み式バッグ型BAPを作成した。電子顕微鏡検査にて、材質が均一であることを確認した。さらに、ラット膵島が良好にハイデンシティ・ポリエチレン膜上に付着することを形態学的に確認した。
    3.BAPデバイスの至適埋め込み場所とその生体適合性の検討
    ラットの腹部にBAPデバイスを埋め込み、大網でラップすることで良好な新生血管がBAPデバイス周囲に誘導された。当該デバイスの周囲にジェラチンゲル化した塩基性線維芽細胞成長因子で塗布することで、誘導される血管が1.2倍に増加した。
    4.in vitroでのBAPデバイスの機能評価
    ラット膵島を2,000個BAPデバイスに封入して、in vitroで培養したところ、膵島機能が28日間保持されることが確認された。

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  • 超高効率蚕白分子輪送系を応用した難治性リンパ腫に対する新規抗体療法の開発

    研究課題/領域番号:16590279  2004年 - 2005年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    近藤 英作

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    配分額:3600000円 ( 直接経費:3600000円 )

    まず、平成14〜15年度基盤研究C(2)での計画の機能性p16 peptideの当超高効率蛋白分子輸送系による細胞内デリバリーによる高悪性度リンパ腫群増殖抑制システムの確立を継続研究し、成果としてまとめ"Molecular Cancer Therapeutics, 3(12) Dec 2004"に報告した。平成16年度計画の第一段階実験として当トランスポーターが輸送・導入できる蛋白分子の範囲を検定し、2-3kDaの低分子から抗体を含め約500kDaレベルの高分子量蛋白まで導入可能であることが判明した。次に特異抗体が細胞内に取り込まれ且つ抗原特異的局在を示すか否かについて抗actin mAbを用いて検定し、肝癌細胞(上皮系)・骨肉腫細胞(間葉系)・メラノーマ細胞(神経系)など多系統の細胞で効率よく取り込みが見られ、抗体はアクチンの分布に一致する局在を示したが、p53抗体などによる核内抗原の捕捉はうまくいかなかった。また抗体フォームの最適化をwhole antibody, F(ab')2で検討したが両者に明かな違いはなかった。抗体の当システムを応用した細胞内デリバリーは、以上の問題点の克服のため現在継続的に研究中である。ここで、もうひとつの大きな可能性として重要な当システムによる同時多重分子標的系構築が可能であるかを研究した。対象に難治性悪性腫瘍ヒトグリオブラストーマを選び、これらが喪失した癌抑制遺伝子p16^<INK4a>、p14^<ARF>の同時機能回復による腫瘍増殖抑制を試みた。結果、p16^<INK4a>、p14^<ARF>機能を代償する機能性ペプチドを導入した腫瘍細胞株U87ΔEGFRでは、最大95%以上の劇的な増殖抑制を認めた。さらに、脳腫瘍モデルマウスを作成し、経静脈的に当輸送系による同時二重標的を施行したin vivo studyでも、二重標的群は統計学的に明かな有意差を持って生存期間の延長を認めた。

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  • サイクリンDのマントル細胞リンパ腫発生・進展における分子制御機構の解析

    研究課題/領域番号:14570143  2002年 - 2003年

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    近藤 英作

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    配分額:3500000円 ( 直接経費:3500000円 )

    予後不良の難治性リンパ腫であるマントルリンパ腫ではt(11;14)という特異的核型異常によるCyclin D1の過剰発現が確認されているが、腫瘍化における機能は未知である。Cyclin D1の機能を抑制して起こる変化を解析するために、当初抗cyclin D1モノクロナル抗体産生ハイブリドーマより得られるScFvをPTD(HIV-1 tat遺伝子由来のタンパク細胞内導入ドメイン)と融合させ導入することを目論んだが、TATはマントル腫細胞への導入効率が悪く実用面で問題があり、新しい導入システムの開発が必要となった。また、ScFvの使用は煩雑なためシステムの簡便化と考えCyclin D1の機能を阻害するp16癌抑制遺伝子の機能を回復する機能性p16ペプチドを導入するシステムの構築をまず目指した(マントル細胞腫では高頻度でp16の発現が消失)。結果、導入ペプチドの結合に有効な疎水性ポケットを有しかつ細胞内高浸透能を発揮する改良型ペプチド・トランスポータの開発とこれを利用したp16機能性ペプチドの導入による超効率的増殖抑制システムの確立に成功した。改良型ペプチド・トランスポータは既存のPTD-peptide(TAT, poly-Arg-fusion peptideなど)に比較すると約20-30倍増の驚異的な導入効率を発揮し、機能発揮に必要なペプチドの要求濃度を従来の1/100-1/50に軽減することができ、また99%以上の導入効率を実現、さらにprimary lymphoma cell新鮮材料を含めて、p16の発現を欠損した多種類の高悪性度白血病・リンパ腫細胞の増殖を著明に抑制した。関連研究成果は一部重要な関与を共有するものとしてEur.J.Immunol.Vol.33,p1-11,2003及びJ.Clin.Exp.Hematopathol.Vol.43,p21-27,2003に報告している。当Transporterは現在、特許申請を検討中である。また、以上の研究成果は必要とするデータを採り終えたので、論文を作成し分子標的治療関連分野を有する医科学誌に平成16年4月現在投稿中である。

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その他研究活動

  • 分子病理専門医(日本病理学会認定:第1回分子病理専門医試験合格)

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  • Pathology International Editorial board

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  • Japanese Journal of Clinical Oncology Reviewer board

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  • 愛知医科大学客員教授

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  • 日本専門医機構・日本病理学会認定 病理専門医 病理指導医

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担当経験のある授業科目(researchmap)

  • 先端医科学研究概説

    2014年
    -
    現在
    機関名:新潟大学

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  • 病理学総論

    2014年
    -
    現在
    機関名:新潟大学

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  • 生体防御と感染(総合講義)

    2014年
    -
    現在
    機関名:新潟大学

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  • 病気と遺伝学

    2014年
    -
    現在
    機関名:新潟大学

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担当経験のある授業科目

  • 医学論文を読む(ジャーナルクラブ)A

    2021年
    -
    現在
    機関名:新潟大学

  • 病理総論

    2015年
    -
    現在
    機関名:新潟大学

  • 生体防御と感染(総合)

    2015年
    -
    現在
    機関名:新潟大学