研究者業績
基本情報
- 所属
- 藤田医科大学 医学部病理診断学 教授
- 学位
- 医学博士(三重大学)
- ORCID ID
https://orcid.org/0000-0002-7502-8724- J-GLOBAL ID
- 200901034217428831
- researchmap会員ID
- 5000002816
Tetsuya TSUKAMOTO is a full time Professor in the Department of Diagnostic Pathology, Fujita Health University School of Medicine, Toyoake, Japan. Medical Doctor (1987) in Mie University School of Medicine, Tsu, Japan and Doctor of Philosophy (1991) in Mie University Graduate School of Medicine, Tsu, Japan. Worked in cancer research in Aichi Cancer Center Research Institute, Nagoya, Japan, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA, and University of California at Berkeley, Berkeley, CA, USA. Involved in Pathological field in Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya and Department of Diagnostic Pathology, Fujita Health University School of Medicine, Toyoake, Japan, steering the clinical, teaching, training and research works. Member of Digital Pathology Association, Japan, Japanese Society of Pathology, Japanese Society of Clinical Cytology, Japanese Society of Toxicologic Pathology, and Japanese Cancer Association. He has over 200 peer reviewed research publications in oncological and experimental pathology and more than 20 book chapters to his credit. Currently he is involved in image analysis using deep learning and computer-aided detection/diagnosis in pathological cytological fields.
経歴
10-
2018年4月 - 現在
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2011年4月 - 2018年3月
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2010年4月 - 2011年3月
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2009年4月 - 2010年3月
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2004年4月 - 2009年3月
学歴
2-
1987年4月 - 1991年6月
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1981年4月 - 1987年3月
委員歴
1-
2009年9月 - 現在
受賞
4-
2016年11月
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2013年9月
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2010年8月
論文
196-
Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 27(5) 1016-1030 2024年9月BACKGROUND: The contribution of the tumor microenvironment and extracellular matrix to the aggressive biology of Gastric Cancer (GC) has been recently characterized; however, the role of EMILIN-1 in this context is unknown. EMILIN-1 is an essential structural element for the maintenance of lymphatic vessel (LV) integrity and displays anti-proliferative properties as demonstrated in skin and colon cancer. Given the key role of LVs in GC progression, the aim of this study was to investigate the role of EMILIN-1 in GC mouse models. METHODS: We used the syngeneic YTN16 cells which were injected subcutaneously and intraperitoneally in genetically modified EMILIN-1 mice. In alternative, carcinogenesis was induced using N-Methyl-N-nitrosourea (MNU). Mouse-derived samples and human biopsies were analyzed by IHC and IF to the possible correlation between EMILIN-1 expression and LV pattern. RESULTS: Transgenic mice developed tumors earlier compared to WT animals. 20 days post-injection tumors developed in EMILIN-1 mutant mice were larger and displayed a significant increase of lymphangiogenesis. Treatment of transgenic mice with MNU associated with an increased number of tumors, exacerbated aggressive lesions and higher levels of LV abnormalities. A significant correlation between the levels of EMILIN-1 and podoplanin was detected also in human samples, confirming the results obtained with the pre-clinical models. CONCLUSIONS: This study demonstrates for the first time that loss of EMILIN-1 in GC leads to lymphatic dysfunction and proliferative advantages that sustain tumorigenesis, and assess the use of our animal model as a valuable tool to verify the fate of GC upon loss of EMILIN-1.
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Cancer Science 2024年8月22日Abstract Approximately 660,000 women are diagnosed with cervical cancer annually. Current screening options such as cytology or human papillomavirus testing have limitations, creating a need to identify more effective ancillary biomarkers for triage. Here, we evaluated whether metabolomic analysis of cervical mucus metabolism could be used to identify biomarkers of cervical intraepithelial neoplasia (CIN) and cervical cancer. The case–control group consisted of 181 CIN, 69 squamous cell carcinoma (SCC) patients, and 48 healthy controls in the primary cohort. We undertook metabolomic analyses using ultra‐HPLC–tandem mass spectrometry. Univariate and multivariate analyses were carried out to profile metabolite characteristics, and receiver operating characteristic (ROC) analysis identified biomarker candidates. Five metabolites conferred the highest discriminatory power for SCC: oxidized glutathione (GSSG) (area under the ROC curve, 0.924; 95% confidence interval, 0.877–0.971), malic acid (0.914, 0.859–0.968), kynurenine (0.884, 0.823–0.945), GSSG/glutathione (GSH) (0.936, 0.892–0.979), and kynurenine/tryptophan (0.909, 0.856–0.961). Malic acid was the best marker for detection of CIN2 or worse (0.858, 0.793–0.922) and was a clinically useful metabolite. We confirmed the reproducibility of the results by validation cohort. Additionally, metabolomic analyses revealed eight pathways strongly associated with cervical neoplasia. Of these, only the tricarboxylic acid cycle was strongly associated with all CINs and cancer, indicating active energy production. Aberrant arginine metabolism by decreasing arginine and increasing citrulline might reduce tumor immunity. Changes in cysteine‐methionine and GSH pathways might drive the initiation and progression of cervical cancer. These results suggest that metabolic analysis can identify ancillary biomarkers and could improve our understanding of the pathophysiological mechanisms underlying cervical neoplasia.
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Cell Metabolism 36(8) 1806-1822.e11 2024年8月
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British journal of cancer 2024年6月7日 査読有りBACKGROUND: The proliferation of cancer-associated fibroblasts (CAFs) hampers drug delivery and anti-tumor immunity, inducing tumor resistance to immune checkpoint blockade (ICB) therapy. However, it has remained a challenge to develop therapeutics that specifically target or modulate CAFs. METHODS: We investigated the involvement of Meflin+ cancer-restraining CAFs (rCAFs) in ICB efficacy in patients with clear cell renal cell carcinoma (ccRCC) and urothelial carcinoma (UC). We examined the effects of Am80 (a synthetic retinoid) administration on CAF phenotype, the tumor immune microenvironment, and ICB efficacy in cancer mouse models. RESULTS: High infiltration of Meflin+ CAFs correlated with ICB efficacy in patients with ccRCC and UC. Meflin+ CAF induction by Am80 administration improved ICB efficacy in the mouse models of cancer. Am80 exerted this effect when administered prior to, but not concomitant with, ICB therapy in wild-type but not Meflin-deficient mice. Am80-mediated induction of Meflin+ CAFs was associated with increases in antibody delivery and M1-like tumor-associated macrophage (TAM) infiltration. Finally, we showed the role of Chemerin produced from CAFs after Am80 administration in the induction of M1-like TAMs. CONCLUSION: Our data suggested that Am80 administration prior to ICB therapy increases the number of Meflin+ rCAFs and ICB efficacy by inducing changes in TAM phenotype.
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Cancer Science 2024年5月15日Abstract Currently, human papillomavirus tests and cytology are used to screen for cervical cancer. However, more accurate ancillary screening tests are needed. MicroRNAs (miRNAs) and cytokines are promising biomarkers that are aberrantly expressed in cervical cancer. Therefore, the potential of developing new screening markers based on the levels of miRNAs and cytokines in serum and local mucus samples from the same patients with cervical neoplasia was investigated. miRNA screening was performed by microarray and measurement using real‐time reverse‐transcriptase PCR. Cytokine were measured using multiplex bead assay, and changes in expressions were analyzed based on disease severity. As lesions progressed, miR‐20b‐5p, −155‐5p, −144‐3p, −451a, and −126‐3p expression levels were increased in mucus, and miR‐16‐5p, −223‐3p, and ‐451a expression levels were decreased in serum. Regarding cytokines, IL‐6, IL‐8, monocyte chemoattractant protein‐1, Eotaxin, interferon‐γ, and RANTES were increased, whereas granulocyte–colony‐stimulating factor (G‐CSF) was significantly decreased in mucus. miRNAs and cytokines in serum did not have high diagnostic accuracy. However, a combination of miR‐20b‐5p, ‐451a, ‐126‐3p, Eotaxin, as well as G‐CSF in mucus samples, had high diagnostic accuracy with an area under the receiver operating characteristic curve of 0.989 (0.979–0.999). Our results suggest that using mucus for this ancillary test is more beneficial than serum.
MISC
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J Biophys Chem 3 156-173 2012年 査読有り
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INTERNATIONAL JOURNAL OF CANCER 130(2) 259-266 2012年1月 査読有りHelicobacter pylori (H. pylori) infection and high intake of various traditional salt-preserved foods are regarded as risk factors for human gastric cancer. We previously reported that Chinese cabbage contains indole compounds, such as indole-3-acetonitrile, a mutagen precursor. 1-Nitrosoindole-3-acetonitrile (NIAN), formed by the treatment of indole-3-acetonitrile with nitrite under acidic conditions, shows direct-acting mutagenicity. In the present study, NIAN administration by gavage to Mongolian gerbils (MGs) at the dose of 100 mg/kg two times a week resulted in three adduct spots (1.6 adducts/108 nucleotides in total), detected in DNA samples from the glandular stomach by 32P-postlabeling methods. Treatment with six consecutive doses of 100 mg/kg of NIAN, two times a week for 3 weeks, induced welland moderatelydifferentiated glandular stomach adenocarcinomas in the MGs at the incidence of 31% under H. pylori infection at 54104 weeks. Such lesions were not induced in MGs given broth alone, broth + NIAN or infection with H. pylori alone. Thus, endogenous carcinogens formed from nitrosation of indole compounds could be critical risk factors for human gastric cancer development under the influence of H. pylori infection.
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PLOS ONE 6(11) e26640 2011年11月 査読有りAn animal model for the early detection of common fatal diseases such as ischemic diseases and cancer is desirable for the development of new drugs and treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in a number of diseases, including cancer. Here, we established transgenic (Tg) mice that carry HRE/ODD-luciferase (HOL) gene, which generates bioluminescence in an HIF-1-dependent manner and was successfully used in this study to monitor HIF-1 activity in ischemic tissues. To monitor carcinogenesis in vivo, we mated HOL mice with rasH2 Tg mice, which are highly sensitive to carcinogens and are used for short-term carcinogenicity assessments. After rasH2-HOL Tg mice were treated with N-methyl-N-nitrosourea, bioluminescence was detected noninvasively as early as 9 weeks in tissues that contained papillomas and malignant lesions. These results suggest that the Tg mouse lines we established hold significant potential for monitoring the early onset of both ischemia and carcinogenesis and that these lines will be useful for screening chemicals for carcinogenic potential.
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Journal of toxicologic pathology 24(3) 173-7 2011年9月 査読有りA subcutaneous mass was found in the lower ventral neck region of a 55-week-old male Mongolian gerbil (Meriones unguiculatus). Histopathologically, the mass involved salivary glands and featured diffuse proliferation of pleomorphic neoplastic cells with large necrotic foci. The lesion was well demarcated from the surrounding tissue, although invasive growth to fibrous septa was occasionally observed. The neoplastic cells were mainly arranged in irregular sheets with severe cellular atypia, round to oval nuclei and varying amounts of eosinophilic cytoplasm. Mitotic figures and multinucleated giant cells were frequent. Immunohistochemical analysis revealed that the neoplastic cells were strongly positive for vimentin and S-100 and negative for NSE, cytokeratin, α-SMA, c-kit, factor VIII, CD34, α-1-antitrypsin, lysozyme and MSR-A. Based on the results, the mass was diagnosed as an undifferentiated sarcoma of the salivary gland. To the best of our knowledge, this is the first report of such a tumor in Mongolian gerbils.
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ENVIRONMENTAL AND MOLECULAR MUTAGENESIS 52(3) 244-252 2011年4月 査読有りTumor development in the skin may be a multistep process where multiple genetic alterations occur successively. The p53 gene is involved in genome stability and thus is referred to as "the guardian of the genome." To better understand the antigenotoxic effects of p53 in ultraviolet light B (UVB)induced mutagenesis, mutations were measured in the epidermis of UVB-irradiated p53(+/+) and p53(-/-) gpt delta mice. In the mouse model, point mutations and deletions are separately identified by the gpt and Spi(-) assays, respectively. The mice were exposed to UVB at single doses of 0.5, 1.0, or 2.0 kJ/m(2). The mutant frequencies (MFs) were determined 4 weeks after the irradiation. All doses of UVB irradiation enhanced gpt MFs by about 10 times than that of unirradiated mice. There were no significant differences in gpt MFs and the mutation spectra between p53(+/+) and p53(-/-) mice. The predominant mutations induced by UVB irradiation were G: C to A: T transitions at dipyrimidines. In contrast, in unirradiated p53(-/-) mice, the frequencies of Spi(-) large deletions of more than 1 kb and complex-type deletions with rearrangements were significantly higher than those of the Spi(-) large deletions in p53(+/+) counterparts. The specific Spi(-) mutation frequency of more than 1 kb deletions and complex types increased in a dose-dependent manner in the p53(-/-) mice. However, no increase of such large deletions was observed in irradiated p53(+/+) mice. These results suggest that the antigenotoxic effects of p53 may be specific to deletions and complex-type mutations induced by double-strand breaks in DNA. Environ. Mol. Mutagen. 52:244-252, 2011. (C) 2010 Wiley-Liss, Inc.
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国立がん研究センターがん研究開発費総括研究報告書(Web) 2010(1) 00001 (WEB ONLY) 2011年
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CARCINOGENESIS 32(1) 35-41 2011年1月 査読有りChronic inflammation is deeply involved in induction of aberrant DNA methylation, but it is unclear whether any type of persistent inflammation can induce methylation and how induction of cell proliferation is involved. In this study, Mongolian gerbils were treated with five kinds of inflammation inducers [Helicobacter pylori with cytotoxin-associated gene A (CagA), H.pylori without CagA, Helicobacter fells, 50% ethanol (EtOH) and saturated sodium chloride (NaCl) solution]. Two control groups were treated with a mutagenic carcinogen that induces little inflammation (20 p.p.m. of N-methyl-N-nitrosourea) and without any treatment. After 20 weeks, chronic inflammation with lymphocyte and macrophage infiltration was prominent in the three Helicobacter groups, whereas neutrophil infiltration was mainly observed in the EtOH and NaCl groups. Methylation levels of eight CpG islands significantly increased only in the three Helicobacter groups. By Ki-67 staining, cell proliferation was most strongly induced in the NaCl group, demonstrating that induction of cell proliferation is not sufficient for methylation induction. Among the inflammation-related genes, IIIb, Nos2 and Tnf showed increased expression specifically in the three Helicobacter groups. In human gastric mucosae infected by H.pylori, NOS2 and TNF were also increased. These data showed that inflammation due to infection of the three Helicobacter strains has a strong potential to induce methylation, regardless of their CagA statuses, and increased cell proliferation was not sufficient for methylation induction. It was suggested that specific types of inflammation characterized by expression of specific inflammation-related genes, along with increased cell proliferation, are necessary for methylation induction.
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ASIAN PACIFIC JOURNAL OF CANCER PREVENTION 12(10) 2759-2762 2011年 査読有りCollagenous colitis (CC) is an illness characterized by chronic diarrhea with possible effects on neoplastic development, but there have been no reports in animals. We therefore tried to establish CC development in a Mongolian gerbil (MG) model by long-term continuous lansoprazole (LPZ) administration and aimed to clarify the relationship between LPZ administration and CC occurrence. We divided 69 gerbils into 6 groups: Helicobacter pylori (Hp)-infected+high-dose LPZ, Hp-infected+low-dose-LPZ, Hp-infected, high-dose-LPZ, low-dose-LPZ, and control. The gerbils were sacrificed and entire colons were excised at experimental weeks 27, 54, and 108. We examined colonic lesions by staining of Swiss-roll intestines pathologically. A total of 3 gerbils had CC-like lesions in the proximal colon. All MGs with CC-like lesions were from LPZ treated groups (3 of 35; 8.6%). The thickened subepithelial collagen band detected in these lesions strongly resembled that of human CC lesions. Immunohistochemical analysis indicated a tendency for more chromogranin A-positive cells in the upper layer of colonic crypt following continuous LPZ administration. In conclusion, we successfully established development of CC-like lesions in an MG model by continuous LPZ administration and determined that the ectopic endocrine cells that were induced by LPZ administration may influence the occurrence of these lesions in the colon.
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Journal of Oncology 528353 2011年 査読有りOur understanding of the pathogenesis of bladder cancer has improved considerably over the past decade. Translating these novel pathobiological discoveries into therapies, prevention, or strategies to manage patients who are suspected to have or who have been diagnosed with bladder cancer is the ultimate goal. In particular, the chemoprevention of bladder cancer development is important, since urothelial cancer frequently recurs, even if the primary cancer is completely removed. The numerous alterations of both oncogenes and tumor suppressor genes that have been implicated in bladder carcinogenesis represent novel targets for therapy and prevention. In addition, knowledge about these genetic alterations will help provide a better understanding of the biological significance of preneoplastic lesions of bladder cancer. Animal models for investigating bladder cancer development and prevention can also be developed based on these alterations. This paper summarizes the results of recent preclinical and clinical chemoprevention studies and discusses screening for bladder cancer. Copyright © 2011 Takuji Tanaka et al.
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ASIAN PACIFIC JOURNAL OF CANCER PREVENTION 12(4) 1049-1054 2011年 査読有りProton pump inhibitors (PPIs) are routinely used for control of upper gastrointestinal disorders, often with long-term application. However, there has been some concern about the long-term safety and the possibility of cancer induction and development of neuroendocrine tumors (NET) in the stomach. We therefore analyzed the influence of PPI use on tumor development histologically, immunohistochemically, and serologically in the glandular stomachs of Helicobacter pylori (Hp)-infected and uninfected Mongolian gerbils (MGs). 53 MGs were divided into 6 groups: Hp+25PPI, Hp+5PPI, Hp, 25PPI, 5PPI, and controls. The high-dose Hp+25PPI and 25PPI groups received the PPI (lansoprazole) at 25mg/kg/day, and the low-dose Hp+5PPI and 5PPI groups were given 5mg/kg/day. After 50 or 100 weeks, animals were sacrificed humanely, and the glandular stomach samples were evaluated histologically and phenotypically, using antibodies against chromogranin A (CgA), gastrin and gastric inhibitory polypeptide (GIP). Serum gastrin levels were also examined. NETs occurred in the Hp+25PPI, Hp+5PPI, Hp, and 25PPI groups, but there was no synergistic effect between Hp-infection and high-dose PPI administration. Serum gastrin was increased statistically by Hp infection and high-dose PPI administration, but not influenced by the low-dose. The NETs featured expression of CgA, but not gastrin or GIP. In conclusions, PPI at low dose had no influence on development of carcinomas and NETs in the Hp-infected and uninfected glandular MG stomach, suggesting clinical safety. However, PPI at high dose increased NET development and serum gastrin in the MG model.
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INTERNATIONAL JOURNAL OF CANCER 126(6) 1467-1473 2010年3月 査読有りThe present study investigated the preventive effects of etodolac, a selective cyclo-oxygenase (COX)-2 inhibitor, on metachronous cancer development after endoscopic resection of early gastric cancer. Among 267 early gastric cancer patients who underwent endoscopic resection, 47 patients with extensive metaplastic gastritis were selected based on endoscopic findings and our previously described criteria of serum pepsinogen (PG) test-positive and Helicobacter pylori antibody-negative conditions. Nonrandomized etodolac treatment (300 mg/day) was administered to 26 patients (Group A), while the remaining 21 patients were untreated (Group B). No significant differences in age, sex distribution, lifestyle factors or extent of metaplastic gastritis at baseline were identified between groups. Patients were followed for metachronous cancer development with endoscopy every 6-12 months for up to 5 years. Mean (standard deviation) follow-up period was 4.2 (0.9) years. In Group B, 5 cancers developed (incidence rate = 6,266/100,000 person-years), significantly more than the 1 cancer in Group A (incidence rate = 898/100,000 person-years; p < 0.05). Long-term etodolac treatment did not influence the extent of metaplastic gastritis as revealed by endoscopic findings or by serum PG levels, but effectively reduced metachronous cancer development in patients with extensive metaplastic gastritis. These results strongly suggest that chemoprevention of cancer in the metaplastic stomach is possible by controlling COX-2 expression.
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日本毒性病理学会講演要旨集 26th 90-90 2010年2月
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CANCER RESEARCH 70(4) 1430-1440 2010年2月 査読有りAltered patterns of DNA methylation associated with Helicobacter pylori (HP) infection of gastric epithelial cells are thought to contribute to gastric cancer risk. However, it is unclear whether this increased risk reflects an infection-associated inflammatory response or the infection itself. In this study, we sought to clarify mechanisms in a gerbil model of gastric cancer where we showed that HP infection is causally involved in induction of aberrant DNA methylation. By genome-wide screening, CpG islands that were aberrantly methylated in gerbil gastric cancer cell lines were isolated, and 10 islands were shown to be specifically methylated only in gastric mucosae infected with HP. By temporal analysis, methylation levels in gastric epithelial cells started to increase at 5 to 10 weeks after infection and reached high levels by 50 weeks. When HP was eradicated, methylation levels markedly decreased 10 and 20 weeks later, but they remained higher than those in gerbils that were not infected by HP. Expression levels of several inflammation-related genes (CXCL2, IL-1 beta, NOS2, and TNF-beta) paralleled the temporal changes of methylation levels. Significantly suppressing inflammation with the immunosuppressive drug cyclosporin A did not affect colonization by HP but blocked the induction of altered DNA methylation. Our findings argue that DNA methylation alterations that occur in gastric mucosae after HP infection are composed of transient components and permanent components, and that it is the infection-associated inflammatory response, rather than HP itself, which is responsible for inducing the altered DNA methylation. Cancer Res; 70(4); 1430-40. (C) 2010 AACR.
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Helicobacter Research 14(16) 447-453 2010年
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INTERNATIONAL JOURNAL OF CANCER 125(8) 1786-1795 2009年10月 査読有りNuclear factor-kappa B (NF-kappa B) plays a major role in host inflammatory responses and carcinogenesis and as such is an important drug target for adjuvant therapy. In this study, we examined the effect of caffeic acid phenethyl ester (CAPE), an NF-kappa B inhibitor, on Helicobacter pylori (H. pylori)-induced NF-kappa B activation in cell culture and chronic gastritis in Mongolian gerbils. In AGS gastric cancer cells, CAPE significantly inhibited H. pylori-stimulated NF-kappa B activation and mRNA expression of several inflammatory factors in a dose-dependent manner, and prevented degradation of I kappa B-alpha and phosphorylation of p65 subunit. To evaluate the effects of CAPE on H. pylori-induced gastritis, specific pathogen-free male, 6-week-old Mongolian gerbils were intragastrically inoculated with H. pylori, fed diets containing CAPE (04.1%) and sacrificed after 12 weeks. Infiltration of neutrophils and mononuclear cells and expression of NF-kappa B p50 subunit and phospho-I kappa B-alpha were significantly suppressed by 0.1% CAPE treatment in the antrum of H. pylori-infected gerbils. Labeling indices for 5'-bromo-2'-deoxyuridine both in the antrum and corpus and lengths of isolated pyloric glands were also markedly reduced at the highest dose, suggesting a preventive effect of CAPE on epithelial proliferation. Furthermore, in the pyloric mucosa, mRNA expression of inflammatory mediators including tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-2, IL-6, KC (IL-8 homologue), and inducible nitric oxide synthase was significantly reduced. These results suggest that CAPE has inhibitory effects on H. pylori-induced gastritis in Mongolian gerbils through the suppression of NF-kappa B activation, and may thus have potential for prevention and therapy of H. pylori-associated gastric disorders. (C) 2009 UICC
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CANCER PREVENTION RESEARCH 2(8) 751-758 2009年8月 査読有りStatins are commonly used lipid-lowering drugs that reduce the risk of cardiovascular morbidity and mortality. Although recent studies have pointed to chemopreventive effects of statins against various cancers, their efficacy for gastric cancer is unclear. Here, we examined the effects of pitavastatin, a lipophilic statin, on Helicobacter pylori (H. pylori) associated stomach carcinogenesis and gastritis using Mongolian gerbil and mouse models. The animals were allocated to H. pylori + N-methyl-N-nitrosourea administration (gerbils, 52 weeks) or H. pylori infection alone groups (gerbils and mice, 12 weeks). After H. pylori infection, they were fed basal diets containing 0 to 10 ppm of pitavastatin. The incidences of H. pylori-associated gastric adenocarcinomas and degrees of chronic gastritis were not decreased by pitavastatin compared with those of control values. Expression of interleukin-1 beta and tumor necrosis factor-alpha mRNAs in the pyloric mucosa was markedly up-regulated in pitavastatin-treated animals. Furthermore, in the H. pylori infected groups, serum total cholesterol, triglyceride, and low-density lipoprotein levels were significantly increased by pitavastatin treatment, contrary to expectation. In the short-term study, H. pylori-infected gerbils and mice also showed significant up-regulation of serum triglyceride levels by pitavastatin, whereas total cholesterol was markedly reduced and low-density lipoprotein exhibited a tendency for decrease in noninfected animals. These findings indicate pitavastatin to be ineffective for suppressing gastritis and chemoprevention of gastric carcinogenesis in H. pylori-infected gerbils. Our serologic results also suggest that the H. pylori infection and consequent severe chronic gastritis interfere with the cholesterol-lowering effects of pitavastatin.
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ONCOLOGY REPORTS 21(3) 609-613 2009年3月 査読有りWe have investigated the expression of osteopontin (OPN) and CDX2 in advanced gastric cancers, and analyzed correlations with clinicopathological features to assess their prognostic potential. One-hundred and nine patients suffering from gastric cancer were recruited. Expression of OPN and CDX2 and other molecular markers was determined by immunohistochernistry. The total positive rate for OPN expression was 46.8%, with a relation to depth of cancer invasion and down regulation of intestinal markers (P<0.001). but not age, gender, or histological type. OPN was more frequently expressed in CDX2-negative (39/109=35.7%) as compared with positive lesions (12/109=11.0%) and a significant reverse correlation was noted between the two factors (P<0.001). Patients with positive OPN tumors had worse 5-year survival than those with OPN-negative cancer (P<0.001). Further analysis revealed the OPN-/CDX2(+) group to have better 5-year survival than all the other three groups: OPN+/CDX2(-), OPN-/CDX2(-) and OPN+/CDX2(+). With multivariate analysis for 5-year survival, OPN was the most significant predictor of a poor prognosis of advanced gastric cancer (P=0.0043), with tumor depth of invasion as another independent indicator (P=0.0315). Osteopontin is a useful prognostic marker in gastric cancer, and combined with CDX2, may have particular advantage for predicting survival of advanced gastric cancer patients. Furthermore the present results provide a clue that in gastric cancer, CDX2 may be a transcription factor modulating the expression of osteopontin.
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HEPATO-GASTROENTEROLOGY 56(90) 542-546 2009年3月 査読有りBackground/Aims: Endoscopic Resection (ER) has been performed for early gastric cancers, and metachronous gastric cancers (MGCs) were occasionally observed. Most MGCs were classified histologically as the differentiated type. However, there have been no data on the gastric and intestinal phenotypic classification of MGCs. In our previous study, Hp-infection in MG may trigger intestinalization of gastric cancers. We therefore speculate the phenotype shift in MGC lesions under Hp-chronic-infection. Methodology: We examined the 17 MGC lesions phenotypically and histologically by using several gastric and intestinal epithelial cell markers, MUC5AC, MUC6, MUC2 and villin. Results: Most lesions (16/17) exhibited the differentiated type. In 8 first cancers, the lesions were divided phenotypically into 2 G, 4 GI, 1 I, and 1 N types. In 9 second/third cancers, the lesions were divided phenotypically into 3 G, 1 GI, 4 I, and 1 N types. The first lesions (6/8) had more gastric phenotypic expression compared with the second/third ones (4/9) in the MGCs, although there was no significant difference between two groups (P=0.28). Conclusion: Our present data suggest the possibility that the cancer retaining G type is detected endoscopically earlier than that obtaining the intestinal phenotypic expression by the phenotypic shift, which may partially explain the MGC occurrence.
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日本毒性病理学会講演要旨集 25th 72 2009年
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Helicobacter Research 13(1) 43-47 2009年
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Curr Res in Cancer 3 89-97 2009年 査読有り
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HISTOLOGY AND HISTOPATHOLOGY 24(1) 31-40 2009年1月 査読有りRUNX3 is a novel tumor suppressor in gastric carcinogenesis and an important factor for differentiation of chief cells in the normal gastric fundic mucosa. In this study, we confirmed RUNX3 immunolocalization in the fundic gland (bottom part) but minimum in surface mucous cell epithelium (top part) in the isolated gland from fundic mucosa. We also analyzed RUNX3 expression by immunohistochemistry in 102 gastric cancers and made a histological assessment of the expression of differentiation markers to evaluate interrelations. Among them, 45 and 57 cases were judged to be RUNX3 positive and negative, respectively, and 33 and 69 cases were pepsinogen I positive and negative, with no link to histological types. RUNX3 expression was significantly associated with that of pepsinogen I (P < 0.001), but not mucins, including MUC5AC and MUC6, or the parietal or intestinal phenotypes. In conclusion, the present study showed, for the first time to our knowledge, a relation between RUNX3 and pepsinogen I expression in human gastric cancers. RUNX3 is strongly associated with chief cell phenotypic expression in human gastric cancers, as well as in normal gastric mucosa, and could be considered to play an important role in maintaining the chief cell phenotype.
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ASIAN PACIFIC JOURNAL OF CANCER PREVENTION 10(5) 883-886 2009年 査読有りEndoscopy can be used for sequential observation of gastric carcinogenesis in animal models. In the present study, we applied endoscopic examination and biopsy technique on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced stomach cancer in rats using a newly-developed flexible 2.5 mm endoscope. A total of 36 rats were divided into MNNG-treated and non-treated groups, observed on gastric endoscopy every 5 weeks, and sacrificed at week 10, 25, 35, and 50. The sequential growth process of MNNG-induced gastric tumor was clearly found by the endoscopic examination. Endoscopic appearances including incidence and size of tumor were well consistent with histological findings. In addition, biopsy specimens could be extracted from gastric mucosa in living rats using a biopsy forceps. These results indicate that the endoscopic technique can be a useful tool for investigating gastric carcinogenesis by sequential observation and collection of biopsy specimens.
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ONCOLOGY REPORTS 21(1) 107-112 2009年1月 査読有りWe have previously demonstrated that gastric and intestinal endocrine cell (End-cell) marker expression is important for assessment of the histogenesis of endocrine cell tumors. However, the End-cell phenotypes of carcinoid tumors in the rectum remain largely unclear. We therefore examined marker expression of rectal carcinoid tumors. We evaluated 20 rectal carcinoid tumors (as well as 8 from the stomach for comparison) phenotypically, using gastrin, gastric inhibitory polypeptide (GIP) and glucagons-like peptide-1 (GLP-1) as End-cell markers. Rectal carcinoid tumors were divided into 3 endocrine-gastric (e-G), 16 endocrine-gastric-and-intestinal mixed (e-GI), 1 endocrine intestinal (e-I), and 0 endocrine-null (e-N) types, thus 19 (e-G+ e-GI types, 95%) had gastric phenotypic expression, while 17 (e-GI+ e-I types, 85%) harbored intestinal elements. Stomach carcinoid tumors were classified as 6 e-G and 2 e-N types, respectively. In conclusion, most rectal carcinoid tumors exhibited the e-GI type, suggesting the importance of gastric End-cell marker expression for histogenesis of the rectal carcinoid tumors. Further studies of pathological and biological analyses are needed to clarify the histogenesis of the carcinoid tumors.
書籍等出版物
7講演・口頭発表等
76-
5th Digital Pathology & AI Congress Asia 2019 2019年4月2日 招待有り
共同研究・競争的資金等の研究課題
20-
日本学術振興会 科学研究費助成事業 2022年4月 - 2025年3月
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日本学術振興会 科学研究費助成事業 2020年4月 - 2023年3月
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日本学術振興会 科学研究費助成事業 2020年4月 - 2023年3月
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日本学術振興会 科学研究費助成事業 2019年4月 - 2023年3月
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日本学術振興会 科学研究費助成事業 2017年4月 - 2020年3月
教育内容・方法の工夫（授業評価等を含む）
1-
件名組織診断評価方法の説明開始年月日2011/04終了年月日2013/03概要臨床実習に陽性対照を示して、適確な組織診断をする方法を説明した。
作成した教科書、教材、参考書
1-
件名毒性病理組織学改訂版概要「腺胃glandular stomach」を分担執筆
その他教育活動上特記すべき事項
3-
件名第27回藤田保健衛生大学医学部医学教育ワークショップ開始年月日2009/04/11終了年月日2009/04/12概要「小グループ学習の充実」
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件名三重大学全学FD終了年月日2010/09/14概要「多様なPBLを導入した授業デザイン」
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件名第１回藤田保健衛生大学大学院ファカルティデベロップメント（FD）講習会終了年月日2012/07/25概要「 バーチャルスライドシステムの教育・研修への利用：サーバ運用における個人情報保護の留意点」を受講