Nishihara, Hiroshi

写真a

Affiliation

School of Medicine, Clinical and Translational Research Center Genomics Unit, Keio Cancer Center, Keio University Graduate School of Medicine (Shinanomachi)

Position

Professor

Related Websites

Contact Address

35 Shinanomachi, Shinjukuku, Tokyo, Japan

Telephone No.

0353154375

Fax No.

+81353154495

Profile 【 Display / hide

  • 学 歴
    1995年(平成7年)3月 北海道大学医学部卒業(医学士)
    1999年(平成11年)3月 北海道大学大学院医学研究科 病理系専攻医学博士課程修了、学位取得(博士(医学))
    2002年(平成14年)3月 ~ 2004年(平成16年)7月
    Molecular pharmacology at University of California, San Diego, Department of Pharmacology (Dr. Paul A. Insel; as a research fellow)

    職 歴
    1999年(平成11年)4月 北海道大学医学部附属病院 病理部 (医員)
    2000年(平成12年)4月 北海道大学大学院医学研究科 分子細胞病理学 (助手)
    2008年(平成20年)10月 北海道大学大学院医学研究科 探索病理学講座 (特任准教授)
    2012年(平成24年)11月 北海道大学病院臨床研究開発センター 生体試料管理室 (室長(兼任))
    2015年(平成27年)1月 北海道大学大学院医学研究科探索病理学講座 (特任教授)
    2016年(平成28年)4月 北海道大学病院がん遺伝子診断部 (統括マネージャー(兼任))
    2017年(平成29年)4月 国立病院機構 北海道がんセンター がんゲノム医療センター(センター長)
    北海道大学病院 がん遺伝子診断部 客員教授(兼任;2018年3月まで)
    札幌医科大学医学部 客員教授(兼任;2019年3月まで)
         長崎大学医学部 客員教授(兼任)
    2017年(平成29年)7月 慶應義塾大学医学部 客員教授(兼任) 腫瘍センターゲノム医療ユニット  
    2017年(平成29年)11月 慶應義塾大学医学部 特任教授 腫瘍センターゲノム医療ユニット長
    社会医療法人北斗 北斗病院 病理・遺伝子診断科長(兼任)
    2018年(平成30年)10月 鹿児島大学医学部 客員教授(兼任)
    2019年(平成31年)4月  慶應義塾大学医学部 教授 臨床研究推進センター・腫瘍センターゲノム医療ユニット
    筑波大学医学部 客員教授(兼任)

Academic Background 【 Display / hide

  • 1989.04
    -
    1995.03

    Hokkaido University, 医学部, 医学科

    日本, University, Graduated, Master's course

  • 1995.04
    -
    1999.03

    Hokkaido University, 大学院, 医学研究科

    日本, Graduate School, Completed, Doctoral course

Academic Degrees 【 Display / hide

  • 博士(医学), Hokkaido University, Coursework, 1999.03

Licenses and Qualifications 【 Display / hide

  • 医師, 医師, 1995.04

 

Papers 【 Display / hide

  • Impaired mitochondrial oxidative phosphorylation capacity in epicardial adipose tissue is associated with decreased concentration of adiponectin and severity of coronary atherosclerosis

    Nakajima T., Yokota T., Shingu Y., Yamada A., Iba Y., Ujihira K., Wakasa S., Ooka T., Takada S., Shirakawa R., Katayama T., Furihata T., Fukushima A., Matsuoka R., Nishihara H., Dela F., Nakanishi K., Matsui Y., Kinugawa S.

    Scientific Reports (Scientific Reports)  9 ( 1 )  2019.12

     View Summary

    © 2019, The Author(s). Epicardial adipose tissue (EAT), a source of adipokines, is metabolically active, but the role of EAT mitochondria in coronary artery disease (CAD) has not been established. We investigated the association between EAT mitochondrial respiratory capacity, adiponectin concentration in the EAT, and coronary atherosclerosis. EAT samples were obtained from 25 patients who underwent elective cardiac surgery. Based on the coronary angiographycal findings, the patients were divided into two groups; coronary artery disease (CAD; n = 14) and non-CAD (n = 11) groups. The mitochondrial respiratory capacities including oxidative phosphorylation (OXPHOS) capacity with non-fatty acid (complex I and complex I + II-linked) substrates and fatty acids in the EAT were significantly lowered in CAD patients. The EAT mitochondrial OXPHOS capacities had a close and inverse correlation with the severity of coronary artery stenosis evaluated by the Gensini score. Intriguingly, the protein level of adiponectin, an anti-atherogenic adipokine, in the EAT was significantly reduced in CAD patients, and it was positively correlated with the mitochondrial OXPHOS capacities in the EAT and inversely correlated with the Gensini score. Our study showed that impaired mitochondrial OXPHOS capacity in the EAT was closely linked to decreased concentration of adiponectin in the EAT and severity of coronary atherosclerosis.

  • Epithelial-to-mesenchymal transition is a mechanism of ALK inhibitor resistance in lung cancer independent of ALK mutation status

    Fukuda K., Takeuchi S., Arai S., Katayama R., Nanjo S., Tanimoto A., Nishiyama A., Nakagawa T., Taniguchi H., Suzuki T., Yamada T., Nishihara H., Ninomiya H., Ishikawa Y., Baba S., Takeuchi K., Horiike A., Yanagitani N., Nishio M., Yano S.

    Cancer Research (Cancer Research)  79 ( 7 ) 1658 - 1670 2019.04

    ISSN  00085472

     View Summary

    © 2019 American Association for Cancer Research. Mutations in the ALK gene are detectable in approximately 40% of ALK-rearranged lung cancers resistant to ALK inhibitors. Although epithelial-to-mesenchymal transition (EMT) is a mechanism of resistance to various targeted drugs, its involvement in ALK inhibitor resistance is largely unknown. In this study, we report that both ALK-mutant L1196M and EMT were concomitantly detected in a single crizotinib-resistant lesion in a patient with ALK-rearranged lung cancer. Digital PCR analyses combined with microdissection after IHC staining for EMT markers revealed that ALK L1196M was predominantly detected in epithelial-type tumor cells, indicating that mesenchymal phenotype and ALK mutation can coexist as independent mechanisms underlying ALK inhibitor-resistant cancers. Preclinical experiments with crizotinib-resistant lung cancer cells showed that EMT associated with decreased expression of miR-200c and increased expression of ZEB1 caused cross-resistance to new-generation ALK inhibitors alectinib, ceritinib, and lorlatinib. Pretreatment with the histone deacetylase (HDAC) inhibitor quisinostat overcame this resistance by reverting EMT in vitro and in vivo. These findings indicate that HDAC inhibitor pretreatment followed by a new ALK inhibitor may be useful to circumvent resistance constituted by coexistence of resistance mutations and EMT in the heterogeneous tumor. Significance: These findings show that dual inhibition of HDAC and ALK receptor tyrosine kinase activities provides a means to circumvent crizotinib resistance in lung cancer.

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

    Tanaka H., Kitahara K., Sasaki N., Nakao N., Sato K., Narita H., Shimoda H., Matsusaki M., Nishihara H., Masamune A., Kano M.

    Biomaterials (Biomaterials)  192   355 - 367 2019.02

    ISSN  01429612

     View Summary

    © 2018 Elsevier Ltd Desmoplasia is a hallmark of pancreatic cancer and consists of fibrotic cells and secreted extracellular matrix (ECM) components. Various in vitro three-dimensional (3D) models of desmoplasia have been reported, but little is known about the relevant thickness of the engineered fibrotic tissue. We thus measured the thickness of fibrotic tissue in human pancreatic cancer, as defined by the distance from the blood vessel wall to tumor cells. We then generated a 3D fibrosis model with a thickness reaching the clinically observed range using pancreatic stellate cells (PSCs), the main cellular constituent of pancreatic cancer desmoplasia. Using this model, we found that Collagen fiber deposition was increased and Fibronectin fibril orientation drastically remodeled by PSCs, but not normal fibroblasts, in a manner dependent on Transforming Growth Factor (TGF)-β/Rho-Associated Kinase (ROCK) signaling and Matrix Metalloproteinase (MMP) activity. Finally, by targeting Secreted Protein, Acidic and Rich in Cysteine (SPARC) by siRNA, we found that SPARC expression in PSCs was necessary for ECM remodeling. Taken together, we developed a 3D fibrosis model of pancreatic cancer with a clinically relevant thickness and observed aberrant SPARC-dependent ECM remodeling in cancer-derived PSCs.

  • Pathways of Progression From Intraductal Papillary Mucinous Neoplasm to Pancreatic Ductal Adenocarcinoma Based on Molecular Features

    Omori Y., Ono Y., Tanino M., Karasaki H., Yamaguchi H., Furukawa T., Enomoto K., Ueda J., Sumi A., Katayama J., Muraki M., Taniue K., Takahashi K., Ambo Y., Shinohara T., Nishihara H., Sasajima J., Maguchi H., Mizukami Y., Okumura T., Tanaka S.

    Gastroenterology (Gastroenterology)  156 ( 3 ) 647 - 661.e2 2019.02

    ISSN  00165085

     View Summary

    © 2019 AGA Institute Background & Aims: Intraductal papillary mucinous neoplasms (IPMNs) are regarded as precursors of pancreatic ductal adenocarcinomas (PDAs), but little is known about the mechanism of progression. This makes it challenging to assess cancer risk in patients with IPMNs. We investigated associations of IPMNs with concurrent PDAs by genetic and histologic analyses. Methods: We obtained 30 pancreatic tissues with concurrent PDAs and IPMNs, and 168 lesions, including incipient foci, were mapped, microdissected, and analyzed for mutations in 18 pancreatic cancer-associated genes and expression of tumor suppressors. Results: We determined the clonal relatedness of lesions, based on driver mutations shared by PDAs and concurrent IPMNs, and classified the lesions into 3 subtypes. Twelve PDAs contained driver mutations shared by all concurrent IPMNs, which we called the sequential subtype. This subset was characterized by less diversity in incipient foci with frequent GNAS mutations. Eleven PDAs contained some driver mutations that were shared with concurrent IPMNs, which we called the branch-off subtype. In this subtype, PDAs and IPMNs had identical KRAS mutations but different GNAS mutations, although the lesions were adjacent. Whole-exome sequencing and methylation analysis of these lesions indicated clonal origin with later divergence. Ten PDAs had driver mutations not found in concurrent IPMNs, called the de novo subtype. Expression profiles of TP53 and SMAD4 increased our ability to differentiate these subtypes compared with sequencing data alone. The branch-off and de novo subtypes had substantial heterogeneity among early clones, such as differences in KRAS mutations. Patients with PDAs of the branch-off subtype had a longer times of disease-free survival than patients with PDAs of the de novo or the sequential subtypes. Conclusions: Detailed histologic and genetic analysis of PDAs and concurrent IPMNs identified 3 different pathways by which IPMNs progress to PDAs—we call these the sequential, branch-off, and de novo subtypes. Subtypes might be associated with clinical and pathologic features and be used to select surveillance programs for patients with IPMNs.

  • Practical procedures for the integrated diagnosis of astrocytic and oligodendroglial tumors

    Sonoda Y., Yokoo H., Tanaka S., Kinoshita M., Nakada M., Nishihara H., Ichimura K., Oka H., Shibahara J., Hashimoto N., Kenemura Y., Natsume A., Nobusawa S., Ueki K., Komori T., Shibuya M., Matsumura A.

    Brain Tumor Pathology (Brain Tumor Pathology)  36 ( 2 ) 56 - 62 2019

    ISSN  14337398

     View Summary

    © 2019, The Japan Society of Brain Tumor Pathology. The publication of the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 WHO CNS) represented a major change in the classification of brain tumors. However, many pathologists in Japan cannot diagnose astrocytic or oligodendroglial tumors according to the 2016 WHO CNS due to financial or technical problems. Therefore, the Japan Society of Brain Tumor Pathology established a committee for molecular diagnosis to facilitate the integrated diagnosis of astrocytic and oligodendroglial tumors in Japan. We created three levels of diagnoses: Level 1 was defined as simple histopathological diagnosis using hematoxylin and eosin staining and routine cell lineage-based immunostaining. Level 2 was defined as immunohistochemical diagnosis using immunohistochemical examinations using R132H mutation-specific IDH1, ATRX, and/or p53 antibodies. Level 3 was defined as molecular diagnosis, such as diagnosis based on 1p/19q status or the mutation status of the IDH1 and IDH2 genes. In principle, astrocytic and oligodendroglial tumors should be diagnosed based on the 2016 WHO CNS and/or cIMPACT-NOW criteria; however, the findings obtained through our diagnostic flowchart can be added to the histological diagnosis in parentheses. This classification system would be helpful for pathologists with limited resources.

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Reviews, Commentaries, etc. 【 Display / hide

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • Gene profiling for pressure ulcer

    2017.07
    -
    2020.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 西原 広史, Grant-in-Aid for Scientific Research (B), Principal Investigator

  • Clinical Sequence Platform for Brain Tumor

    2017.04
    -
    2020.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 西原 広史, Grant-in-Aid for Scientific Research (C), Principal Investigator