Blocking fibrinolytic system in mice reduces colorectal carcinogenesis associated with chronic colitis.

• Project/Area Number: 24591983
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Juntendo University
• Principal Investigator: SAKAMOTO kazuhiro 順天堂大学, 医学部, 教授 (60205763)
• Co-Investigator(Kenkyū-buntansha): KOMIYAMA Hiromitsu 順天堂大学, 医学部, 講師 (30348982) ; HATTORI Koichi 順天堂大学, 医学部, 先任准教授 (10360116)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 新規がん増殖機構 / 線維素溶解系 / マトリックスメタロプロテイナーゼ / 大腸癌 / プラスミン阻害剤 / 大腸発がんモデル / 大腸がん / 血液線維素溶解系 / 線溶系阻害剤 / Azoxymethane (AOM) / 大腸がんモデルマウス / 担がんモデル / 新規分子療法 / 線溶系 / 大腸癌モデルマウス / MMP-9 / azoxymethane

Outline of Final Research Achievements

Ulcerative colitis patients have a high risk of developing colitis cancer. The fibrinolytic system with plasmin is activated in patients with inflammatory bowel disease(IBD) as well as Matrix Metalloproteinases. We showed MMP family control the ectodomain shedding of TNF. Genetic and Pharmacological inhibition of plasmin can be regarded as a novel therapeutic target for the treatment of IBD. Plasmin inhibition could control colon inflammation and prevent colon carcinoma development in both model of Dxtran Sulfate Sodium-induced(DSS) colitis and Azoxymethane/DSS colitic cancer. Moreover,blockade of plasmin prevented the infiltration of inflammatory myeloid cell and releasing the inflammatory cytokine such as TNF and CXCL5. Regarding of colitic cancer, plasmin regulated the migration of macrophages in tumor microenvironment . Our data provided evidence the inhibition of plasmin prevents the inflammatory response during acute colitis and during IBD-associated colon cancer development.

Research Products

• [Journal Article] Inhibition of Plasmin Protects Against Colitis in Mice by Suppressing Matrix Metalloproteinase 9-mediated Cytokine Release From Myeloid Cells. (2015)
  • Author(s): Munakata S, Tashiro Y, Nishida C, Sato A, Komiyama H, Shimazu H, Dhahri D, Salama Y, Eiamboonsert S, Takeda K, Yagita H, Tsuda Y, Okada Y, Nakauchi H, Sakamoto K, Heissig B, Hattori K.
  • Journal Title: Gastroenterology, Volume: 148 Pages: 565-578
  • Peer Reviewed / Open Access
• [Journal Article] Proposal of new classification for Stage III colon cancer based on the lymph node ratio: Analysis of 4172 patients from multi-institutional database in Japan (2015)
  • Author(s): Sugimoto K, Sakamoto K, Tomiki Y, Goto M, Kotake K, Sugihara K
  • Journal Title: Ann Surg Oncol Volume: 22 Issue: 2 Pages: 528-534
  • DOI: 10.1245/s10434-014-4015-9
  • Peer Reviewed / Open Access
• [Journal Article] An effective 5-fluorouracil, levofolinate, and oxaliplatin therapy for recurrent breast cancer: a case report (2014)
  • Author(s): Takahashi M, Niwa K, Ishiyama S, Sugimoto K, Komiyama H, Yaginuma Y, Kojima Y, Goto M, Okuzawa A, Tomiki Y, Sakamoto
  • Journal Title: J Med Case Rep Volume: 8 Pages: 1-6
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of Predictive Factors for Lymph Node Metastasis in Submucosal Invasive Colorectal Carcinoma (2014)
  • Author(s): Sugimoto K, Sato K, Maekawa H, Sakurada M, Orita H, Ito T and Wada R
  • Journal Title: Surgical Science Volume: 5 Pages: 75-83
  • Open Access
• [Journal Article] Efficacy of Postoperative Adjuvant Chemotherapy According to Prognostic Factor in Patients with Stage III Colon Cancer (2014)
  • Author(s): Sugimoto K, Sakamoto K, Tomiki Y, Goto M, Kojima Y, Komiyama H, Takahashi M, Ishiyama S, Niwa K and Okubo H
  • Journal Title: Journal of Cancer Therapy Volume: 5 Pages: 806-816
  • Peer Reviewed / Open Access
• [Journal Article] Investigation of free cancer cells in peripheral blood using CEA mRNA expression in perioperative colorectal cancer patients. (2013)
  • Author(s): Nagayasu K, Komiyama H, Ishiyama S, Ogura D, Takahashi R, Tashiro Y, Niwa K, Sugimoto K, Kojima Y, Goto M, Tomiki Y, Niwa S, Sakamoto K.
  • Journal Title: Molecular and clinical oncology Volume: 1 Issue: 4 Pages: 668-674
  • DOI: 10.3892/mco.2013.109
  • Peer Reviewed
• [Journal Article] The validity of predicting prognosis by lymph node ratio in node-positive colon cancer (2013)
  • Author(s): Sugimoto K, Sakamoto K, Tomiki Y, Goto M, Kojima Y, Komiyama H
  • Journal Title: Dig Surg Volume: 30 Pages: 368-374
• [Journal Article] Investigation of peripheral blood free cancer cells using CEA mRNA in perioperative colorectal cancer patients (2013)
  • Author(s): Nagayasu K. , Ogura D. , Niwa S. , Takahashi R. , Kawai M. , Komiyama H. , Takahashi M. , Kojima Y. , Goto M. , Tomiki Y. , and Sakamoto K.
  • Journal Title: Molecular and Clinical Oncology Volume: 1 Pages: 2013-2013
  • Peer Reviewed
• [Journal Article] Inhibition of PAI-1 induces neutrophil-driven neoangiogenesis and promotes tissue regeneration via production of angiocrine factors in mice (2012)
  • Author(s): Yoshihiko Tashiro, Chiemi Nishida, Kaori Sato-Kusubata, Makiko Ohki-Koizumi, Makoto Ishihara, Aki Sato, Ismael Gritli, Hiromitsu Komiyama, Yayoi Sato, Takashi Dan, Toshio Miyata, Ko Okumura, Yuichi Tomiki, Kazuhiro Sakamoto, Hiromitsu Nakauchi, Beate Heissig, and Koichi Hattori.
  • Journal Title: Blood Volume: 119 Issue: 26 Pages: 6382-6393
  • DOI: 10.1182/blood-2011-12-399659
  • Peer Reviewed
• [Journal Article] Analysis of the effects of alleviating adverse events and improving completion in colorectal cancer patients with postoperative adjuvant chemotherapy with PSK. (2012)
  • Author(s): Sugimoto K, Takahashi R, Ishiyama S, Hata M, Kamiyama H, Komiyama H, Takahashi M, Kojima Y, Goto M, Sengoku H, Tomiki Y, Sakamoto K.
  • Journal Title: 順天堂医学 Volume: 58 Pages: 422-30
  • NAID: 130005058698
• [Presentation] 腹腔内癒着における線溶系阻害因子PAI-1の機能解明 (2015)
  • Author(s): 本庄薫平,宗像慎也,小見山博光，Heissig Beate,服部浩一,坂本一博
  • Organizer: 第115回日本外科学会定期学術集会
  • Place of Presentation: 名古屋,名古屋国際会議場
  • Year and Date: 2015-04-16 – 2015-04-18
• [Presentation] セリンプロテアーゼ阻害薬によるDextran sulfate sodium誘発腸炎の抑制 (2015)
  • Author(s): 盧尚志,宗像慎也,小見山博光，Heissig Beate,服部浩一,坂本一博
  • Organizer: 第115回日本外科学会定期学術集会
  • Place of Presentation: 名古屋,名古屋国際会議場
  • Year and Date: 2015-04-16 – 2015-04-18
• [Presentation] Inflammatory bowel disease モデルにおける線溶系を介した抑制機序 (2015)
  • Author(s): 宗像慎也,小見山博光，坂本一博,Heissig Beate,服部浩一
  • Organizer: お茶の水がん学アカデミア 第111回集会
  • Place of Presentation: 東京,順天堂大学
  • Year and Date: 2015-02-25
• [Presentation] 大腸癌における血清p53抗体の検討 (2014)
  • Author(s): 高橋里奈，呉 一眞，本庄薫平，盧 尚志，青木 順，岡澤 裕，，水越幸輔，河合雅也，嵩原一裕，宗像慎也，石山 隼，杉本起一，小見山博光，高橋 玄，柳沼行宏，小島 豊，五藤倫敏，奥澤淳司，，冨木裕一，坂本一博
  • Organizer: 2014 JDDW 第12回日本消化器外科学会大会
  • Place of Presentation: 神戸，神戸国際展示場・ポートピアホテル
  • Year and Date: 2014-10-23 – 2014-10-26
• [Presentation] Comparative Genomic Hybridization (CGH) を用いた 大腸がんの肝転移と予後因子の検討 (2014)
  • Author(s): 河合雅也，小見山博光，呉 一眞，本庄薫平，盧 尚志,
  • Organizer: 2014 JDDW 第56回日本消化器病学会大会
  • Place of Presentation: 神戸，神戸国際展示場・ポートピアホテル
  • Year and Date: 2014-10-23 – 2014-10-26
• [Presentation] The subsequent epithelial-mesenchymal and mesenchymal-epithelial transition model barely depicts colon cancer metastasis (2014)
  • Author(s): Yu Okazawa, Kosuke Mizukoshi, Hiromitsu Komiyama, Tomoaki Hujii, Michitoshi Goto, Sonoko Habu, Kazuhiro Sakamoto, Akira Orimo
  • Organizer: 第73回日本癌学会学術集会
  • Place of Presentation: 横浜，パシフィコ横浜
  • Year and Date: 2014-09-24 – 2014-09-26
• [Presentation] PAI-1阻害剤による血管新生及び組織再生促進療法 (2013)
  • Author(s): 1. 田代良彦，宗像慎也，西田知恵美，石原誠人，Gritli Ismael，島津 浩，佐藤亜紀，楠畑かおり，小泉摩季子，小見山博光，坂本一博，宮田敏夫，中内啓光，Heissig Beate，服部浩一
  • Organizer: 第12回日本再生医療学会総会
  • Place of Presentation: 横浜
• [Presentation] The development of gross hepatic and pulmonary metastases in a patient-derived colorectal tumor xenograft model. (2013)
  • Author(s): 2. Kosuke Mizukoshi，Yu Okazawa，Hiromitsu Komiyama，Tomoaki Fujii，Yasuhiko Ito， Michitoshi Goto，Sonoko Habu，Okio Hino，Kazuhiro Sakamoto and Akira Orimo
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] PAI 1阻害剤による血管新生及び組織再生促進療法 (2013)
  • Author(s): 宗像慎也
  • Organizer: 第113回日本外科学会定期学術集会
  • Place of Presentation: 福岡
• [Book] Treatment Strategy for Acute Appendicitis (2014)
  • Author(s): Takehara K，Sakamoto K
  • Publisher: Appendicitis: Risk Factors, Management Strategies and Clinical Implications, Angela S. Marmo, 2014. Nova Science Publishers
• [Remarks] 順天堂大学 下部消化管外科
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/kabusyoukakan/
• [Remarks] 順天堂大学 下部消化管外科学
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/kabusyoukakan/
• [Patent(Industrial Property Rights)] 術後癒着モデル及びその作成方法 (2014)
  • Inventor(s): 本庄薫平,宗像慎也，小見山博光，坂本一博
  • Industrial Property Rights Holder: 本庄薫平,宗像慎也，小見山博光，坂本一博
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-11-06
• [Patent(Industrial Property Rights)] 大腸がんの転移又は再発リスクの評価方法 (2014)
  • Inventor(s): 小見山博光，坂本一博，奥澤淳司，大津敬，林崎良英，伊藤昌,川路英
  • Industrial Property Rights Holder: 小見山博光，坂本一博，奥澤淳司，大津敬，林崎良英，伊藤昌,川路英
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-01-31
• [Patent(Industrial Property Rights)] 患者原発性大腸癌の個別化転移モデルマウスの作製方法 (2013)
  • Inventor(s): 折茂彰，水越幸，岡澤裕，五藤倫敏，小見山博光，樋野興夫，坂本一博
  • Industrial Property Rights Holder: 折茂彰，水越幸，岡澤裕，五藤倫敏，小見山博光，樋野興夫，坂本一博
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-09-18