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  • 1
    Online Resource
    Online Resource
    A phase II study of novel three peptides combination with gemcitabine as a first-line therapy for advanced pancreatic cancer (VENUS-PC study).
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 15_suppl ( 2015-05-20), p. 3045-3045
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. 3045-3045
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2015.33.15_suppl.3045
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
    detail.hit.zdb_id: 2005181-5
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  • 2
    Online Resource
    Online Resource
    Abstract 1768: Real time in vivo imaging of brain metastasis visualized dynamic reaction of microglia against cancer cells
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1768-1768
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1768-1768
    Abstract: The brain metastasis of lung cancer is a crucial problem that causes poor clinical outcome and alters patient's quality of life. Previous evidences showed that cancer cells may escape from host immunity to form distant metastasis. However, the detailed interaction between lung cancer cells and immune cells in the brain niche is still unclear. Microglia and perivascular macrophages are the only resident immune cells in the brain parenchyma in physiological state. Here, we develop an in-vivo imaging method that can allow us to follow the immune cells and cancer progression in single cell resolution to evaluate immune reaction against cancer. Using this method, we evaluated microglial role in the development of brain-metastasis.Lung cancer cell line (CMT167mC) expressing mCherry was established from CMT167, a mice lung cancer cell line derived from C57BL/6. To generate brain-metastasis model mice, the cancer cells were injected via the internal carotid artery of the CX3XR1-GFP mice (Day 0), in which EGFP is specifically expressed in microglia and macrophage. The skull of the mice was replaced with a glass coverslip for chronic imaging (Day 1), and the fluorescently labeled cancer cells and microglia was simultaneously visualized using two-photon microscopy (Day 2-). The median survival of the brain-metastasis model mice after cancer cell injection was 15.0 days, and the fate of each embolized cell was followed for 14 days. Monitoring of 277 embolized cancer cells in the brain revealed 49.8% of cancer cells displaced from their original site, 40.4% developed micro-metastasis (MMs), and 6.9% were phagocytosed by microglia. We focused on the microglial role around the cancer cells that can form MMs, then the morphology and behavior of microglia around MMs was evaluated. The size of microglia around MMs ( & lt;100 µm from cancer cells) was significantly increased on day 6 and subsequently the density was increased on day 10, compared with microglia far from ( & gt;100 µm) cancer cells, suggesting that cancer cells can escape from activated microglia without being phagocytosed. Microglia depletion using pexidartinib can reduce the number and size of MMs that implicates activated microglia can inversely help tumor progression. Then we evaluated the functional role of a “Don't eat me” signal against microglia, which is a surface protein CD47 that inhibit the phagocytic action of macrophages. A knockout of the CD47 gene from CMT167mC significantly reduced the formation of MMs, increased phagocytosis by microglia, and prolonged the survival time of the model mice. The result suggests that this model provide a method to visualize immune reaction against cancer and validation of crucial target that reduce MMs. We are further exploring another critical factor that regulate development of brain metastasis using multi-omics analysis both on the activated microglia and on the cancer cells that formed MMs. Citation Format: Takahiro Tsuji, Hiroaki Wake, Mariko Shindo, Daisuke Kato, Hiroaki Ozasa, Toyohiro Hirai. Real time in vivo imaging of brain metastasis visualized dynamic reaction of microglia against cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1768.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1768
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
    Online Resource
    Online Resource
    Abstract PO039: Novel in vivo imaging method to evaluate "Don't eat me" signal of tumor against microglia
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 5_Supplement ( 2021-03-01), p. PO039-PO039
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 5_Supplement ( 2021-03-01), p. PO039-PO039
    Abstract: Tumor formation is promoted by increased expression of “Don’t eat me” signals such as CD47 in cancer cells that inhibit phagocytic action of macrophages. However, the signals can regulate generation of brain metastasis is still unclear. In the brain, microglia and perivascular macrophages are the only resident immune cells of the brain parenchyma. Here, we have developed an in-vivo imaging method that can allow us to evaluate microglial phagocytosis of tumor and to detemine the fates of cancer cells in the brain. The skull of the CX3CR1-EGFP mice, in which microglia is specifically labeled with EGFP, was replaced with a glass coverslip, and the fluorescently labeled lung cancer cells (CMT167-mCherry) were injected via the internal carotid artery of the mice. The fate of arrested cancer cells in the brain vascular was monitored for 12-16 days. Of the 324 cancer cells (4 mice), 49.8% (N=138) of cells displaced from their original site, 40.4% (N=112) of cells developed micro-metastasis, and 6.9% (N=27) of cells were processed by microglia resulting in cell death. To evaluate the “Don’t eat me” signal against microglia, a CD47 gene knockout cell line was monitored as well, and these cells developed significantly less micro-metastasizes compared with CD47 positive cells. This in vivo imaging of the brain metastasis potentially provide a method for monitoring of tumor fate and validation of crucial target. Citation Format: Takahiro Tsuji, Hiroaki Wake, Mariko Shindo, Daisuke Kato, Hiroaki Ozasa, Toyohiro Hirai. Novel in vivo imaging method to evaluate "Don't eat me" signal of tumor against microglia [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO039.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.TME21-PO039
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    Online Resource
    Online Resource
    Abstract 1151: Real-time visualization of brain metastasis in vivo
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1151-1151
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 1151-1151
    Abstract: Research into physiological phenomena has taken a leap forward by recent advanced optical bio imaging techniques. Traditionally, physiological phenomena including cell division, cell function, molecular transport and expression, and signal transduction were detected by biochemical methods. However, this information lacked high resolution spatial or temporal information. Using recent bio imaging techniques, both spatial and temporal information can be integrated across the molecular, cellular and systems levels that allow us to further investigate the hierarchical interaction of organ systems. Here, we have developed an in vivo imaging method to visualize brain metastasis of lung cancer which provides real-time information of their proliferation, metastasis and the immune reaction for cancer cells. CMT167 and LLC1 cell lines which expressed mCherry or Venus were established. The fluorescently labeled cell lines were administered into the brain via the carotid artery or direct injection to the CX3CR1-GFP mice, transgenic mice in which microglia was specifically labeled with GFP. The metastasis cancer and the immune reaction were visualized using 2-photon microscopy for 14 days. Interaction between cancer cells and microglia was observed. We identified heterogeneity of the interaction between microglia and cancer cells. Some microglia cells showed phagocytosis-like response to cancer. Other microglia touched, surrounded, and released cancer cells without phagocytotic response. These interactions between microglia and cancer cells could be observed by 3-6 hours continuous real-time in vivo imaging. Further study to address detailed mechanism for microglia reaction is in progress. This research has potential to provide the information of brain metastasis in vivo and to be a new solution to elucidate the process of immunity and niche. Citation Format: Takahiro Tsuji, Hiroaki Wake, Hiroaki Ozasa, Koichiro Haruwaka, Hitomi Ajimizu, Yuto Yasuda, Yuichi Sakamori, Takashi Nomizo, Young Hak Kim, Toyohiro Hirai. Real-time visualization of brain metastasis in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1151.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-1151
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
    Online Resource
    Online Resource
    A Case of Goblet Cell Carcinoid Tumor of Vermiform Appendix Diagnosed Following Appendectomy for Acute Appendicitis
    Yamaguchi University Medical Association ; 2004
    In:  Yamaguchi Medical Journal Vol. 53, No. 3 ( 2004), p. 173-178
    Details
    In: Yamaguchi Medical Journal, Yamaguchi University Medical Association, Vol. 53, No. 3 ( 2004), p. 173-178
    Type of Medium: Online Resource
    ISSN: 0513-1731 , 1880-4462
    Uniform Title: 虫垂炎にて発症した虫垂杯細胞カルチノイドの1例
    URL: Article
    DOI: 10.2342/ymj.53.173
    Language: English , Japanese
    Publisher: Yamaguchi University Medical Association
    Publication Date: 2004
    detail.hit.zdb_id: 2222958-9
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  • 6
    Online Resource
    Online Resource
    YAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation
    Springer Science and Business Media LLC ; 2020
    In:  Nature Communications Vol. 11, No. 1 ( 2020-01-03)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2020-01-03)
    Abstract: Despite the promising clinical efficacy of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in patients with ALK-rearranged lung cancer, some tumor cells survive and eventually relapse, which may be an obstacle to achieving a cure. Limited information is currently available on the mechanisms underlying the initial survival of tumor cells against alectinib. Using patient-derived cell line models, we herein demonstrate that cancer cells survive a treatment with alectinib by activating Yes-associated protein 1 (YAP1), which mediates the expression of the anti-apoptosis factors Mcl-1 and Bcl-xL, and combinatorial inhibition against both YAP1 and ALK provides a longer tumor remission in ALK-rearranged xenografts when compared with alectinib monotherapy. These results suggest that the inhibition of YAP1 is a candidate for combinatorial therapy with ALK inhibitors to achieve complete remission in patients with ALK-rearranged lung cancer.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-019-13771-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2553671-0
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  • 7
    Online Resource
    Online Resource
    Intrahepatic Biliary Stricture Caused by a Retrograde Transhepatic Biliary Drainage Tube: A Case Report
    The Japanese Journal of Gastroenterological Surgery ; 2006
    In:  The Japanese Journal of Gastroenterological Surgery Vol. 39, No. 6 ( 2006), p. 672-676
    Details
    In: The Japanese Journal of Gastroenterological Surgery, The Japanese Journal of Gastroenterological Surgery, Vol. 39, No. 6 ( 2006), p. 672-676
    Type of Medium: Online Resource
    ISSN: 0386-9768 , 1348-9372
    Uniform Title: 逆行性経肝胆道ドレナージチューブによって引き起こされた良性肝内胆管狭窄の１例
    URL: Article
    DOI: 10.5833/jjgs.39.672
    Language: Japanese , Japanese
    Publisher: The Japanese Journal of Gastroenterological Surgery
    Publication Date: 2006
    detail.hit.zdb_id: 2303686-2
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  • 8
    Online Resource
    Online Resource
    Abstract 3451: Microglial phagocytosis suppressed the development of metastatic tumors in the imaging model of brain metastasis
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3451-3451
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3451-3451
    Abstract: Brain metastasis of lung cancer is a crucial problem that causes poor clinical outcomes and alters patient quality of life. Previous evidence showed that lung cancer cells (LUCs) may escape from host immunity to form distant metastases. We previously used an original imaging model of brain metastasis (IBrM) to show a heterogeneous interaction between microglia, the tissue macrophages in the brain, and LUCs in the brain niche. The findings confirmed that microglia can phagocytose metastatic cancer cells. Here, we show that genetic deletion of the “don’t eat me” signals of cancer cells can promote phagocytic activity of microglia against LUCs. We injected an adenocarcinoma lung cancer cell line expressing mCherry (CMT167mC) via the internal carotid artery of the CX3CR1-EGFP mice, whose microglia had been specifically labeled with EGFP. The microglia and LUCs were visualized in vivo simultaneously by two-photon microscopy for 14 days. The tumor fate and microglial response against cancer cells were evaluated at single cell resolution in the IBrM. CD24, CD47, and/or PDL1 were deleted in CMT167mC cells using CRISPR/Cas9 to examine the effect of the “don’t eat me” signals. The dynamic behavior of LUCs and the microglial phagocytosis activity against LUCs were visualized in living mice. Microglial phagocytosis was significantly increased by single deletion of CD47 or CD24 compared with WT cells. Combined deletion of CD47 and CD24 also synergically increased microglial phagocytosis, resulting in reduced IBrM and prolonged mouse survival. By contrast, deletion of PD-L1 did not enhance microglial phagocytosis or prolong survival. The pharmacological or genetic conditional depletion of microglia canceled both the increased phagocytosis and the extended survival time, suggesting that the effect of “don't eat me” signals was microglia-dependent. These results indicate that suppression of both CD24 and CD47 in LUCs enhances microglial phagocytic activity and suppresses the metastatic formation of LUCs. Furthermore, the combined use of CRISPR/Cas9 in LUCs and in vivo imaging allows us to evaluate potential therapeutic targets associated with microglial phagocytosis. We are currently using single cell RNA-seq and cell-to-cell communication analysis of the brain tumor and surrounding niche to explore other signal pathways that regulate tumor phagocytosis by microglia and to identify potential therapeutic targets. Citation Format: Takahiro Tsuji, Hiroaki Wake, Mariko Shindo, Daisuke Kato, Hiroaki Ozasa, Toyohiro Hirai. Microglial phagocytosis suppressed the development of metastatic tumors in the imaging model of brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2 022;82(12_Suppl):Abstract nr 3451.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-3451
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
    Online Resource
    Online Resource
    A Case of Hepatocellular Adenoma with Difficulty in Preoperative Diagnosis
    Yamaguchi University Medical Association ; 2004
    In:  Yamaguchi Medical Journal Vol. 53, No. 3 ( 2004), p. 165-171
    Details
    In: Yamaguchi Medical Journal, Yamaguchi University Medical Association, Vol. 53, No. 3 ( 2004), p. 165-171
    Type of Medium: Online Resource
    ISSN: 0513-1731 , 1880-4462
    Uniform Title: 術前診断が困難であった肝細胞腺腫の１例
    URL: Article
    DOI: 10.2342/ymj.53.165
    Language: Japanese , Japanese
    Publisher: Yamaguchi University Medical Association
    Publication Date: 2004
    detail.hit.zdb_id: 2222958-9
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  • 10
    Online Resource
    Online Resource
    A Case of over 11 Years of Survival with Several Chemotherapies and 3 Times Bowel Reconstructions after Non-curative Resected Gastric Cancer due to Peritoneal Dissemination
    Yamaguchi University Medical Association ; 2006
    In:  Yamaguchi Medical Journal Vol. 55, No. 2/3 ( 2006), p. 81-85
    Details
    In: Yamaguchi Medical Journal, Yamaguchi University Medical Association, Vol. 55, No. 2/3 ( 2006), p. 81-85
    Type of Medium: Online Resource
    ISSN: 0513-1731 , 1880-4462
    Uniform Title: 腹膜播種を伴う進行胃癌術後に化学療法および３回の消化管再建術を経て１１年以上生存中の一例
    URL: Article
    DOI: 10.2342/ymj.55.81
    Language: Japanese , Japanese
    Publisher: Yamaguchi University Medical Association
    Publication Date: 2006
    detail.hit.zdb_id: 2222958-9
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