Ojima, Hidenori

写真a

Affiliation

School of Medicine, Department of Pathology (Shinanomachi)

Position

Associate Professor (Non-tenured)

 

Papers 【 Display / hide

  • Steatotic and nonsteatotic scirrhous hepatocellular carcinomas reveal distinct clinicopathological features

    Hatano M., Ojima H., Masugi Y., Tsujikawa H., Hiraoka N., Kanai Y., Shimada K., Shinoda M., Sakamoto M.

    Human Pathology (Human Pathology)  86   222 - 232 2019.04

    ISSN  00468177

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    © 2018 Elsevier Inc. We investigated the clinicopathological and molecular characteristics of scirrhous hepatocellular carcinoma (HCC) to elucidate its uniqueness. Samples from 120 resected HCC cases underwent immunohistochemical analysis. Tumor area containing fibrous stroma and the percentage of steatotic cells within the tumor were evaluated. In our previous report, tumors were immunohistochemically subclassified as biliary/stem cell markers–positive (B/S) (cytokeratin 19 and/or sal-like protein 4 and/or epithelial cell adhesion molecule positive), Wnt/β-catenin signaling–related markers–positive (W/B) (β-catenin and/or glutamine synthetase positive), or all markers–negative (−/−) groups. Thirty-seven cases (31%) with fibrous stroma making up ≥50% of the largest tumor area were defined as scirrhous HCC (sHCC); the other 83 cases (69%) were categorized as common HCC (cHCC). Clinicopathologically, sHCC had fewer poorly differentiated tumors (P =.037) and a higher percentage of cases with steatosis (P =.025) than cHCC. sHCC cases were further divided into two subgroups: those with ≥5% steatotic cells (steatotic sHCC) and those with <5% steatotic cells (nonsteatotic sHCC). Hepatitis B virus infection was more frequent in nonsteatotic sHCC (P =.029), and non-B, non-C cases were more frequent in steatotic sHCC (P =.006). Steatotic sHCC tended to have a longer time to recurrence than nonsteatotic sHCC and cHCC. Most nonsteatotic sHCC cases belonged to B/S group, whereas most steatotic sHCC belonged to −/− group. The same tendency in sHCC was shown in another cohort. Distinct features were seen in steatotic and nonsteatotic sHCC, and both sHCC subgroups exhibited different clinicopathological and molecular features from cHCC. These findings support the hypothesis that sHCC is an independent entity.

  • Establishment of Patient-Derived Organoids and Drug Screening for Biliary Tract Carcinoma

    Saito Y., Muramatsu T., Kanai Y., Ojima H., Sukeda A., Hiraoka N., Arai E., Sugiyama Y., Matsuzaki J., Uchida R., Yoshikawa N., Furukawa R., Saito H.

    Cell Reports (Cell Reports)   2019

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    © 2019 The Author(s) Biliary tract carcinomas (BTCs) are among the most aggressive malignancies and have a poor prognosis. Here, we successfully established organoid lines derived from intrahepatic cholangiocarcinoma, gallbladder cancer, and neuroendocrine carcinoma of the ampulla of Vater. These organoids derived from BTCs were cultured stably for >1 year and closely recapitulated the histopathology, gene expression, and genetic alterations evident in the primary tumors. Gene expression profiling of the organoids revealed that SOX2 could be a potential prognostic biomarker for patients with BTC. We screened a compound library consisting of drugs used clinically for their ability to suppress organoids derived from BTCs and found that the antifungal drugs amorolfine and fenticonazole significantly suppressed the growth of organoids derived from BTCs with minimal toxicity to normal biliary epithelial cells. Patient-derived organoids may be a powerful research tool for the clarification of molecular pathogenesis and the discovery of biomarkers and therapeutic drugs for refractory cancers.

  • Induction of differentiation of intrahepatic cholangiocarcinoma cells to functional hepatocytes using an organoid culture system

    Saito Y., Nakaoka T., Muramatsu T., Ojima H., Sukeda A., Sugiyama Y., Uchida R., Furukawa R., Kitahara A., Sato T., Kanai Y., Saito H.

    Scientific Reports (Scientific Reports)  8 ( 1 )  2018.12

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    © 2018 The Author(s). Intrahepatic cholangiocarcinoma (IHCC) is a highly aggressive malignancy with a poor prognosis. It is thought to originate from cholangiocytes, which are the component cells of intrahepatic bile ducts. However, as patients with viral hepatitis often develop IHCC, it has been suggested that transformed hepatocytes may play a role in IHCC development. To investigate whether IHCC cells can be converted to functional hepatocytes, we established organoids derived from human IHCC and cultured them under conditions suitable for hepatocyte differentiation. IHCC organoids after hepatocyte differentiation acquired functions of mature hepatocytes such as albumin secretion, bile acid production and increased CYP3A4 activity. Studies using a mouse model of IHCC indicate that Wnt3a derived from macrophages recruited upon inflammation in the liver may promote the malignant transformation of hepatocytes to IHCC cells. The results of the present study support the recently proposed hypothesis that IHCC cells are derived from hepatocytes.

  • Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification

    Kurebayashi Y., Ojima H., Tsujikawa H., Kubota N., Maehara J., Abe Y., Kitago M., Shinoda M., Kitagawa Y., Sakamoto M.

    Hepatology (Hepatology)  68 ( 3 ) 1025 - 1041 2018.09

    ISSN  02709139

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    © 2018 by the American Association for the Study of Liver Diseases. Immune cells constitute an important element of tumor tissue. Accumulating evidence indicates their clinicopathological significance in predicting prognosis and therapeutic efficacy. Nonetheless, the combinations of immune cells forming the immune microenvironment and their association with histological findings remain largely unknown. Moreover, it is unclear which immune cells or immune microenvironments are the most prognostically significant. Here, we comprehensively analyzed the immune microenvironment and its intratumor heterogeneity in 919 regions of 158 hepatocellular carcinomas (HCCs), and the results were compared with the corresponding histological and prognostic data. Consequently, we classified the immune microenvironment of HCC into three distinct immunosubtypes: Immune-high, Immune-mid, and Immune-low. The Immune-high subtype was characterized by increased B-/plasma-cell and T cell infiltration, and the Immune-high subtype and B-cell infiltration were identified as independent positive prognostic factors. Varying degrees of intratumor heterogeneity of the immune microenvironment were observed, some of which reflected the multistep nature of HCC carcinogenesis. However, the predominant pattern of immunosubtype and immune cell infiltration of each tumor was prognostically important. Of note, the Immune-high subtype was associated with poorly differentiated HCC, cytokeratin 19 (CK19) + , and/or Sal-like protein 4 (SALL4) + high-grade HCC, and Hoshida's S1/Boyault's G2 subclasses. Furthermore, patients with high-grade HCC of the predominant Immune-high subtype had significantly better prognosis. These results provide a rationale for evaluating the immune microenvironment in addition to the usual histological/molecular classification of HCC. Conclusion: The immune microenvironment of HCC can be classified into three immunosubtypes (Immune-high, Immune-mid, and Immune-low) with additional prognostic impact on histological and molecular classification of HCC. (Hepatology 2018).

  • Epigenome mapping of human normal purified hepatocytes: Personal epigenome variation and genome-epigenome correlation

    Arai E., Miura F., Totoki Y., Yamashita S., Tian Y., Gotoh M., Ojima H., Nakagawa H., Takahashi Y., Nakamura H., Hama N., Kato M., Kimura H., Suzuki Y., Ito T., Shibata T., Kanai Y.

    Epigenomics (Epigenomics)  10 ( 7 ) 955 - 979 2018.07

    ISSN  17501911

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    © 2018 Yae Kanai. Aim: The aim of this study was to reveal the epigenome landscape of human normal hepatocytes. Materials & methods: Cells purified from partial hepatectomy specimens of Japanese patients were subjected to whole-genome bisulfite sequencing using postbisulfite adaptor tagging, chromatin immunoprecipitation sequencing, RNA sequencing and whole-genome sequencing. Results: CHG and CHH methylations were inversely associated with gene expression. Histone modification profiles of personal differentially methylated regions (pDMRs) differed considerably among samples. pDMRs were observed around the transcription start sites of genes whose expression is reportedly regulated by CpG methylation. pDMRs were frequently observed in the vicinity of single-nucleotide variations and insertions/deletions. Conclusion: Genetic variations may induce epigenetic variations, generating individual differences in the phenotypes of normal hepatocytes through variations in expression.

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

  • 胆道がんの臨床病理学的特徴を規定する遺伝子発現・異常の同定と診断・治療への応用

    2017.04
    -
    2020.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 尾島 英知, Grant-in-Aid for Scientific Research (C), Principal Investigator

  • Investigation of molecular mechanisms involved in carcinogenesis, proliferation and progression of billiary tract carcinoma and its application to clinical treatment

    2014.04
    -
    2017.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 尾島 英知, Grant-in-Aid for Scientific Research (C), Principal Investigator

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    We have elucidated the molecular mechanisms of carcinogenesis, proliferation and progression of billiary tract carcinoma (BTC) using numerous BTC-related bio-resources. As a result, four candidate genes associated with different sites of tumor locations were found and immunohistochemical study using surgical specimens confirmed the consistency of their expression with the tumor existing sites. Analysis of 50 candidate genes associated with IDCC (Intraductal Carcinoma Component) as one of the histopathological BTC spreading and malignancy factors revealed that many highly expressed genes in the tumor group without IDCC (high-grade group) were involved in tumor malignancy related with metastasis or invasion. This data supported the clinicopathological features of IDCC. Furthermore, we have established in vitro assay system of BTC that enables preclinical study and appropriates parameters for novel anticancer drugs which targeting the above genes.

 

Courses Taught 【 Display / hide

  • GENERAL PATHOLOGY

    2020

  • DISEASES OF ORGAN SYSTEMS

    2020

  • GENERAL PATHOLOGY

    2019

  • DISEASES OF ORGAN SYSTEMS

    2019