マイクロサテライト不安定性を呈する発癌機構の統合的理解と新たな治療体系の確立

2015 Fiscal Year Annual Research Report

• Project/Area Number: 25253080
• Research Institution: The University of Tokyo
• Principal Investigator: 渡邉 聡明 東京大学, 医学部附属病院, 教授 (80210920)
• Co-Investigator(Kenkyū-buntansha): 佐藤 俊朗 慶應義塾大学, 医学部, 准教授 (70365245)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 大腸癌 / マイクロサテライト不安定性 / DNAメチル化 / 鋸歯状腺腫 / オルガノイド

Outline of Annual Research Achievements

①大腸鋸歯状病変およびMSI大腸癌からのオルガノイド株の樹立、分子生物学的解析
本年度は大腸serrated pathwayに帰属する大腸腫瘍オルガノイド株の拡充を行い、最終的には鋸歯状病変5株、MSI大腸癌8株を樹立した。レファレンスとなる非MSI大腸癌オルガノイド等を含め、55のオルガノイド株から成る大腸腫瘍オルガノイドライブラリが整備された。全てのオルガノイド株に対して詳細な分子生物学的解析を行った結果、大腸鋸歯状病変およびMSI大腸癌オルガノイドそれぞれに特徴的なプロファイルを同定した。さらに、ドライバー遺伝子変異と相関し、MSI大腸癌オルガノイドは通常培養に必要な幹細胞ニッチ因子への要求性が極めて低いことを見出した。
②異種移植を用いたMSI大腸癌担癌マウスモデルの作製
患者由来オルガノイドを用いた本年度までのin silico, in vitro研究の臨床への応用を視野に入れ、免疫不全マウスへの異種移植モデルを作成した。いずれのMSI大腸癌オルガノイドも臨床検体の病理像と類似した腫瘍を形成し、腫瘍形成能はニッチ因子要求性の程度を反映していた。さらに、脾臓に移植したMSI大腸癌オルガノイドはいずれもロバストに肝転移を形成し、個別化治療を見据えた機能的な橋渡しモデルを作製することに成功した
③分子生物学的プロファイルに基づいた治療の導出
①にて得られた臨床情報および分子生物学的情報がタグ付された大腸癌オルガノイド、および②にて得られた異種移植モデルに立脚し、腫瘍抑制効果を有する薬剤の検討を行った。大腸癌治療として保険収載されている薬剤をvalidationとして使用し、臨床での効果とin vitro, vivoでの腫瘍抑制効果が相関していることが確認された。現在幅広い薬剤を用いたスクリーニング系を整備しており、MSI大腸癌に有意に治療効果を発揮する治療薬の創出を目指している。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] A Colorectal Tumor Library Demonstrates Progressive Loss of Niche Factor Requirements during Tumorigenesis (2016)
  • Author(s): Fujii M, Shimokawa M, Date S, Takano A, Matano M, Nanki K, Ohta Y, Toshimitsu K, Nakazato Y, Kawasaki K, Uraoka T, Watanabe T, Kanai T, Sato T
  • Journal Title: Cell Stem Cell Volume: 未定 Pages: 未定
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Outcome of salvage surgery for colorectal cancer initially treated by upfront endoscopic therapy. (2016)
  • Author(s): Nozawa H, Ishihara S, Fujishiro M, Kodashima S, Ohtani K, Yasuda K, Nishikawa T, Tanaka T, Tanaka J, Kiyomatsu T, Kawai K, Hata K, Kazama S, Sunami E, Kitayama J, Watanabe T.
  • Journal Title: Surgery Volume: 159 Pages: 713-20
  • DOI: 10.1016/j.surg.2015.09.008
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Efficient genetic engineering of human intestinal organoids using electroporation. (2015)
  • Author(s): Fujii M, Matano M, Nanki K, Sato T.
  • Journal Title: Nature Protocols Volume: 10 Pages: 1474-85
  • DOI: 10.1038/nprot.2015.088.
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids. (2015)
  • Author(s): Matano M, Date S, Shimokawa M, Takano A, Fujii M, Ohta Y, Watanabe T, Kanai T, Sato T.
  • Journal Title: Nature Medicine Volume: 21 Pages: 256-62
  • DOI: 10.1038/nm.3802
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines 2014 for treatment of colorectal cancer. (2015)
  • Author(s): Watanabe T, Itabashi M, et al,; Japanese Society for Cancer of the Colon and Rectum.
  • Journal Title: Int J Clin Oncol Volume: 20 Pages: 207-39
  • DOI: 10.1007/s10147-015-0801-z.
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Benefit of primary tumor resection in stage IV colorectal cancer with unresectable metastasis: a multicenter retrospective study using a propensity score analysis. (2015)
  • Author(s): Ishihara S, Nishikawa T, Tanaka T, Tanaka J, Kiyomatsu T, Kawai K, Hata K, Nozawa H, Kazama S, Yamaguchi H, Sunami E, Kitayama J, Sugihara K, Watanabe T.
  • Journal Title: Int J Colorectal Dis. Volume: 30 Pages: 807-12
  • DOI: 10.1007/s00384-015-2228-4.
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Phospholipase A2 Group III and Group X Have Opposing Associations with Prognosis in Colorectal Cancer. (2015)
  • Author(s): Kazama S, Kitayama J, Hiyoshi M, Taketomi Y, Murakami M, Nishikawa T, Tanaka T, Tanaka J, Kiyomatsu T, Kawai K, Hata K, Yamaguchi H, Nozawa H, Ishihara S, Sunami E, Watanabe T.
  • Journal Title: Anticancer Res. Volume: 35 Pages: 2983-90
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Initial safety report on the tolerability of modified FOLFOX6 as adjuvant therapy in patients with curatively resected stage II or III colon cancer (JFMC41-1001-C2: JOIN trial). (2015)
  • Author(s): Kotaka M, Yoshino T, Oba K, Shinozaki K, Touyama T, Manaka D, Matsui T, Ishigure K, Hasegawa J, Inoue K, Goto K, Sakamoto J, Saji S, Ohtsu A, Watanabe T.
  • Journal Title: Cancer Chemother Pharmacol. Volume: 76 Pages: 75-84
  • DOI: 10.1007/s00280-015-2757-0.
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] High RAD54B expression: an independent predictor of postoperative distant recurrence in colorectal cancer patients. (2015)
  • Author(s): Nagai Y, Yamamoto Y, Yasuhara T, Hata K, Nishikawa T, Tanaka T, Tanaka J, Kiyomatsu T, Kawai K, Nozawa H, Kazama S, Yamaguchi H, Ishihara S, Sunami E, Yamanaka T, Miyagawa K, Watanabe T.
  • Journal Title: Oncotarget Volume: 6 Pages: 21064-73
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Prognostic Impact of Histologic Type in Curatively Resected Stage IV Colorectal Cancer: A Japanese Multicenter Retrospective Study. (2015)
  • Author(s): Shibata J, Kawai K, Nishikawa T, Tanaka T, Tanaka J, Kiyomatsu T, Hata K, Nozawa H, Kazama S, Yamaguchi H, Ishihara S, Sunami E, Kitayama J, Sugihara K, Watanabe T.
  • Journal Title: Ann Surg Oncol Volume: 15 Pages: S621-9
  • DOI: 10.1245/s10434-015-4846-z.
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] CD133 Expression in Lymph Node Metastases Is Associated with Tumor Aggressiveness During Lymph Node Metastasis in Colorectal Cancer. (2015)
  • Author(s): Kazama S, Kishikawa J, Yasuda K, Otani K, Nishikawa T, Tanaka T, Tanaka J, Kiyomatsu T, Kawai K, Hata K, Nozawa H, Yamaguchi H, Ishihara S, Sunami E, Watanabe T.
  • Journal Title: Anticancer Res Volume: 35 Pages: 6599-605
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Predictors and outcome of complete removal of colorectal cancer with synchronous lung metastases. (2015)
  • Author(s): Nozawa H, Tanaka J, Nishikawa T, Tanaka T, Kiyomatsu T, Kawai K, Hata K, Kazama S, Yamaguchi H, Ishihara S, Sunami E, Kitayama J, Nakajima J, Kokudo N, Watanabe T.
  • Journal Title: Mol Clin Oncol Volume: 3 Pages: 1041-1047
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A multicenter phase II study of preoperative chemoradiotherapy with S-1 plus oxaliplatin for locally advanced rectal cancer (SHOGUN trial). (2015)
  • Author(s): Matsusaka S, Ishihara S, Kondo K, Horie H, Uehara K, Oguchi M, Murofushi K, Ueno M, Mizunuma N, Shimbo T, Kato D, Okuda J, Hashiguchi Y, Nakazawa M, Sunami E, Kawai K, Yamashita H, Okada T, Ishikawa Y, Nakajima T, Watanabe T.
  • Journal Title: Radiother Oncol Volume: 116 Pages: 209-13
  • DOI: 10.1016/j.radonc.2015.08.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Surveillance colonoscopy for colitis-associated dysplasia and cancer in ulcerative colitis patients. (2015)
  • Author(s): Hata K, Kishikawa J, Anzai H, Shinagawa T, Kazama S, Ishii H, Nozawa H, Kawai K, Kiyomatsu T, Tanaka J, Tanaka T, Nishikawa T, Otani K, Yasuda K, Yamaguchi H, Ishihara S, Sunami E, Kitayama J, Watanabe T.
  • Journal Title: Dig Endosc Volume: 28 Pages: 260-5
  • DOI: 10.1111/den.12505
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Recent advances in robotic surgery for rectal cancer. (2015)
  • Author(s): Ishihara S, Otani K, Yasuda K, Nishikawa T, Tanaka J, Tanaka T, Kiyomatsu T, Hata K, Kawai K, Nozawa H, Kazama S, Yamaguchi H, Sunami E, Kitayama J, Watanabe T.
  • Journal Title: Int J Clin Oncol Volume: 20 Pages: 633-40
  • DOI: 10.1007/s10147-015-0854-z
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The preoperative platelet to lymphocyte ratio is a prognostic marker in patients with stage II colorectal cancer. (2015)
  • Author(s): Ozawa T, Ishihara S, Nishikawa T, Tanaka T, Tanaka J, Kiyomatsu T, Hata K, Kawai K, Nozawa H, Kazama S, Yamaguchi H, Sunami E, Kitayama J, Watanabe T.
  • Journal Title: Int J Colorectal Dis Volume: 30 Pages: 1165-71
  • DOI: 10.1007/s00384-015-2276-9
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Analysis of anastomotic leakage after rectal surgery: A case-control study. (2015)
  • Author(s): Tanaka J, Nishikawa T, Tanaka T, Kiyomatsu T, Hata K, Kawai K, Kazama S, Nozawa H, Yamaguchi H, Ishihara S, Sunami E, Kitayama J, Watanabe T.
  • Journal Title: Ann Med Surg Volume: 11 Pages: 183-6
  • DOI: 10.1016/j.amsu.2015.05.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant