The role of inflammatory biomarker OLMF4 to the malignancy of inflammatory bowel disease related tumors

• Project/Area Number: 18K07026
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Kitasato University
• Principal Investigator: Yoshida Tsutomu 北里大学, 医学部, 教授 (90316943)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 炎症性腸疾患 / 潰瘍性大腸炎 / 悪性腫瘍 / Olfactomedin-4 / OLFM4 / クローン病 / 発癌 / olfactomedin-4 / 悪性度 / olfactomedin 4 / 上皮間葉連関

Outline of Final Research Achievements

To elucidate the poorer differentiation and prognosis of inflammatory bowel disease related tumor, we analyzed the association of biomarker OLMF4. OLFM4 binds frizzled-7, which would lead the suppression of WNT/beta-catenin pathway. OLMF4 was secreted in exosome, and exosomal OLMF4 inhibited the expression of activated form of beta-catenin and EMT markers. Expression of OLMF4 in inflammatory foci of UC-related tumors was reduce along with the tumorigenesis, which suggests the relationship with the malignancy of tumors. It is possible that suppression of EMT by OLMF4 secreted in exosome would be the cause of the malignant potential of IBD related tumor.

Academic Significance and Societal Importance of the Research Achievements

潰瘍性大腸炎及びクローン病は若年発症の難病炎症性腸疾患(IBD)で、患者数は増加している。長期罹患により悪性腫瘍を多発発症すると共に、通常型大腸癌に比して低分化で悪性度が高いことが知られているが、その機序は明らかになっていない。今回の研究成果は、申請者がこれまでに明らかにしてきたIBD特異的バイオマーカーであるOLFM4(olfactomedin-4)が、IBD関連腫瘍の高悪性度特性に関わっていることを明らかにするもので、特にexosome型分泌が関与することを明らかにしたことは学術的にも新機軸である。

Research Products

• [Journal Article] Clinicopathological features of PD-L1 protein expression, EBV positivity, and MSI status in patients with advanced gastric and esophagogastric junction adenocarcinoma in Japan (2022)
  • Author(s): Yoshida Tsutomu、Ogura Go、Tanabe Mikiko、Hayashi Takuo、Ohbayashi Chiho、Azuma Mizutomo、Kunisaki Chikara、Akazawa Yoichi、Ozawa Soji、Matsumoto Sohei、Suzuki Takayoshi、Mitoro Akira、Fukunaga Tetsu、Shimizu Akiko、Fujimoto Go、Yao Takashi
  • Journal Title: Cancer Biology & Therapy Volume: 23 Issue: 1 Pages: 191-200
  • DOI: 10.1080/15384047.2022.2038002
  • Peer Reviewed
• [Journal Article] Cytology Reporting System for Lung Cancer from the Japan Lung Cancer Society and the Japanese Society of Clinical Cytology: An Extensive Study Containing More Benign Lesions (2021)
  • Author(s): Yoshizawa Akihiko、Hiroshima Kenzo、Takenaka Akemi、Haba Reiji、Kawahara Kunimitsu、Minami Yuko、Kakinuma Hirokuni、Shibuki Yasuo、Miyake Shinji、Kajio Kenta、Kiyonaga Kana、Nagatomo Moe、Nishimura Sanako、Mano Masayuki、Matsubayashi Jun、Motoi Noriko、Nagao T.、Nakatsuka S.、Yoshida Tsutomu、Satoh Y.
  • Journal Title: Acta Cytologica Volume: 66 Issue: 2 Pages: 124-133
  • DOI: 10.1159/000520426
  • Peer Reviewed
• [Journal Article] Expression of CA2 and CA9 carbonic anhydrases in ulcerative colitis and ulcerative colitis‐associated colorectal cancer (2020)
  • Author(s): Nakada Norihiro、Mikami Tetuo、Horie Kayo、Nagashio Ryo、Sakurai Yasutaka、Sanoyama Itaru、Yoshida Tsutomu、Sada Miwa、Kobayashi Kiyonori、Sato Yuichi、Okayasu Isao、Murakumo Yoshiki
  • Journal Title: Pathology International Volume: 70 Issue: 8 Pages: 523-532
  • DOI: 10.1111/pin.12949
  • Peer Reviewed
• [Journal Article] Cytology Reporting System for Lung Cancer from the Japan Lung Cancer Society and Japanese Society of Clinical Cytology: An Interobserver Reproducibility Study and Risk of Malignancy Evaluation on Cytology Specimens (2020)
  • Author(s): Hiroshima K、Yoshizawa A、Takenaka A、Haba R、Kawahara K、Minami Y、Kakinuma H、Shibuki Y、Miyake Si、Kajio K、Miyamoto K、Nagatomo M、Nishimura S、Mano Mi、Matsubayashi J、Motoi N、Nagao T、Nakatsuka S、Yoshida T、Satoh Y
  • Journal Title: Acta Cytologica Volume: - Issue: 5 Pages: 1-11
  • DOI: 10.1159/000506431
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] EGFR mutation genotyping and ALK status determination in liquid-based cytology samples of non-small cell lung cancer (2019)
  • Author(s): Yukitoshi Satoh, Yukiko Matsuo, Tatsuru Kuba, Kazuya Yamashita, Mariko Sawano, Shusaku Tozaka, Hirotsugu Yamazaki, Dai Sonoda, Masashi Mikubo, Nasahiro Naito, Yoshio Matsui, Kazu Shiomi, Tsutomu Yoshida, Yoshiki Murakumo
  • Journal Title: Virshows Archiv Volume: - Issue: 5 Pages: 753-762
  • DOI: 10.1007/s00428-019-02692-9
  • Peer Reviewed
• [Journal Article] A retrospective study of definitive chemoradiotherapy in patients with resectable small cell neuroendocrine carcinoma of the esophagus. (2019)
  • Author(s): Chikatoshi Katada, Shouko Komori, Tsutomu Yoshida, Shogo Kawakami, Akinori Watanabe, Kenji Ishido, Mizutomo Azuma, Takuya Wada, Kei Hosoda, Keishi Yamashita, Naoki Hiki, Satoshi Tanabe, Hiromichi Ishiyama, Wasaburo Koizumi.
  • Journal Title: Esophagus Volume: 47 Issue: 2 Pages: 716-719
  • DOI: 10.1007/s10388-019-00686-9
  • NAID: 40022193296
  • Peer Reviewed
• [Journal Article] Ciliated muconodular papillary tumors of the lung: Cytologic features and diagnostic pitfalls in intraoperative examinations (2019)
  • Author(s): Mikubo Masashi、Maruyama Raito、Kakinuma Hirokuni、Yoshida Tsutomu、Satoh Yukitoshi
  • Journal Title: Diagnostic Cytopathology Volume: 47 Issue: 7 Pages: 716-719
  • DOI: 10.1002/dc.24169
  • Peer Reviewed
• [Journal Article] Analysis of BRCAness with multiplex ligation-dependent probe amplification using formalin-fixed and paraffin-embedded pancreatic ductal adenocarcinoma tissue obtained via endoscopic ultrasound-guided fine-needle aspiration biopsy (2019)
  • Author(s): Okuwaki Kosuke、Masutani Hironori、Imaizumi Hiroshi、Yoshida Tsutomu、Kida Mitsuhiro、Iwai Tomohisa、Yamauchi Hiroshi、Tadehara Masayoshi、Adachi Kai、Watanabe Masafumi、Kurosu Takahiro、Koizumi Wasaburo
  • Journal Title: Pancreatology Volume: 19 Issue: 3 Pages: 419-423
  • DOI: 10.1016/j.pan.2019.02.010
  • Peer Reviewed
• [Journal Article] Proposal for an Organ-Specific Chronic Inflammation - Remodeling - Carcinoma Sequence (2019)
  • Author(s): Okayasu Isao、Ichinoe Masaaki、Yoshida Tsutomu
  • Journal Title: Gastrointestinal Disorders Volume: 1 Issue: 3 Pages: 341-357
  • DOI: 10.3390/gidisord1030028
  • Peer Reviewed / Open Access
• [Journal Article] Vascular endothelial growth factor receptor 1 tyrosine kinase signaling facilitates healing of DSS-induced colitis by accumulation of Tregs in ulcer area (2019)
  • Author(s): Betto Tomohiro、Amano Hideki、Ito Yoshiya、Eshima Koji、Yoshida Tsutomu、Matsui Yoshio、Yamane Sakiko、Inoue Tomoyoshi、Otaka Fumisato、Kobayashi Kiyonori、Koizumi Wasaburo、Shibuya Masabumi、Majima Masataka
  • Journal Title: Biomedicine & Pharmacotherapy Volume: 111 Pages: 131-141
  • DOI: 10.1016/j.biopha.2018.12.021
  • Peer Reviewed / Open Access
• [Journal Article] Peroxiredoxin 1 expression in active ulcerative colitis mucosa identified by proteome analysis and involvement of thioredoxin based on immunohistochemistry (2019)
  • Author(s): Horie Kayo、Mikami Tetuo、Yoshida Tsutomu、Sato Yuichi、Okayasu Isao
  • Journal Title: Oncology Letters Volume: 15 Pages: 2364-2372
  • DOI: 10.3892/ol.2017.7549
  • Peer Reviewed / Open Access
• [Journal Article] Reducing DNA damage by formaldehyde in liquid‐based cytology preservation solutions to enable the molecular testing of lung cancer specimens (2018)
  • Author(s): Matsuo Yukiko、Yoshida Tsutomu、Yamashita Kazuya、Satoh Yukitoshi
  • Journal Title: Cancer Cytopathology Volume: 126 Issue: 12 Pages: 1011-1021
  • DOI: 10.1002/cncy.22069
  • Peer Reviewed / Open Access
• [Journal Article] Molecular alterations in a new cell line (KU-Lu-MPPt3) established from a human lung adenocarcinoma with a micropapillary pattern (2018)
  • Author(s): Matsuo Yukiko、Shiomi Kazu、Sonoda Dai、Mikubo Masashi、Naito Masahito、Matsui Yoshio、Yoshida Tsutomu、Satoh Yukitoshi
  • Journal Title: Journal of Cancer Research and Clinical Oncology Volume: 144 Issue: 1 Pages: 75-87
  • DOI: 10.1007/s00432-017-2541-0
  • Peer Reviewed / Open Access
• [Presentation] 日本人胃癌におけるPD-L1発現、MSI status及びEBV陽性評価：多施設共同後方視的観察研究 (2019)
  • Author(s): 吉田 功、小倉豪、田辺美樹子、林大久生、大林千穂、東瑞智、國崎主税、赤澤陽一、小澤壯治、松本壮平、鈴木孝良、美登路昭、福永哲、清水晶子、藤本豪、八尾隆史
  • Organizer: 第57回日本癌治療学会学術集会
• [Presentation] JSCC-JLCSによる新たな判定基準の提案. (2019)
  • Author(s): 廣島健三、佐藤之俊、吉田 功、柿沼廣邦、長尾俊孝、松林純、三宅真司、中塚伸一、眞能正幸、竹中明美、元井紀子、澁木康雄、南優子、吉澤明彦、羽場礼次、河原邦光
  • Organizer: 第60回日本臨床細胞学会春期大会
• [Presentation] 炎症性バイオマーカーOLFM4からみた炎症性腸疾患関連腫瘍の特異性の解明. (2019)
  • Author(s): 横山 慧、吉田 功、橋村美紀、三枝 信
  • Organizer: 第108回日本病理学会総会
• [Presentation] Olfactomedin-4の炎症性腸疾患関連腫瘍発生における役割. (2018)
  • Author(s): 横山 慧、吉田 功、橋村美紀、三枝 信.
  • Organizer: 第107回日本病理学会総会
• [Remarks] 北里大学医学部病理学（三枝単位）
  • URL: https://www.kitasato-u.ac.jp/med/research/departments/medicine/byouri-s.html