Identification of specific markers for cancer stem cells and anti-cancer therapy targeting cancer stem cells

2013 Fiscal Year Final Research Report

• Project/Area Number: 24659363
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: CHIBA Tsutomu 京都大学, 医学(系)研究科(研究院), 教授 (30188487)
• Co-Investigator(Kenkyū-buntansha): SENO Hiroshi 京都大学, 医学研究科, 講師 (90335266)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: 癌幹細胞 / 組織幹細胞 / Hes1 / Dckl1 / 大腸ポリープ / 癌幹細胞治療

Research Abstract

We examined effects of targeting Hes1 and Dcamkl1, possible cancer stem cell markers, on colonic cancer cells. Hes1-specific siRNAs significantly reduced growth of human colonic cancer cells. In addition, we also examined the effect of Hes1-siRNA to ApcMin mice. Finally, we obtained Dckl1-positive cells from both normal intestine and polyps of ApcMin mice by FACS sorting, and found several transcripts specifically expressed in Dcamkl1-positive tumor cells. The siRNAs or inhibitors specific for the molecules exclusively expressed in Dcamkl1-positive tumor cells inhibited tumor cell growth without affecting normal epithelial cells. These data suggested possible anti-cancer strategy targeting cancer stem cells without affecting normal tissue stem cells.

Research Products

• [Journal Article] Deletion of nardilysin prevents tieh development of steatohepatitis and liver fibrotic changes (2014)
  • Author(s): Ishizu-Higashi S, Seno H, Nishi E, Matsumoto Y, Ikuta K, Tsuda M, Kimura Y, Takada Y, Kimura Y, Nakanishi Y, Kanda K, Komekado H, Chiba T.
  • Journal Title: PLos One Volume: (in press)
  • DOI: 10.1371/journal.pone.0098017
  • Peer Reviewed
• [Journal Article] A model of liver carcinogenesis originating from hepatic progenitor cells with accumulation of genetic alterations (2014)
  • Author(s): Kim SK, Nasu A, Komori J, Shimizu T, Matsumoto Y, Minaki Y, Kohno K, Shimizu K, Uemoto S, Chiba T, Marusawa H.
  • Journal Title: Int J Cancer Volume: 134 Pages: 1067-1076
  • DOI: 10.1002/ijc.28445
  • Peer Reviewed
• [Journal Article] Sox9-dependent acinar-to-ductal reprogramming is critical for neoplasia formation (2013)
  • Author(s): Fukuda A, Chiba T.
  • Journal Title: Gastroenterology (Selected Summary) Volume: 145 Pages: 904-907
  • DOI: 10.1053/j.gastro.2013.08.028
• [Journal Article] Heparan sulfate on intestinal epithelial cells plays a critical role in intestinal crypt homeostasis via Wnt/β-catenin signaling (2013)
  • Author(s): Yamamoto S, Nakase H, Matsuura M, Honzawa Y, Matsumura K, Uza N, Yamaguchi Y, Mizoguchi E, Chiba T.
  • Journal Title: Am J Physiol Gastrointest Liver Phisiol Volume: 305 Pages: G241-G249
  • DOI: 10.1152/ajpgi.00480.2012
  • Peer Reviewed
• [Journal Article] Inhibitory role of Gas6 in intestinal tumorigenesis (2013)
  • Author(s): Akitake-Kawano R, Seno H, Nakatsuji M, Kimura Y, Nakanishi Y, Yoshioka T, Kanda K, Kawada M, Kawada K, Sakai Y, Chiba T.
  • Journal Title: Carcinogenesis Volume: 34 Pages: 1567-1574
  • DOI: 10.1093/carcin/bgt069
  • Peer Reviewed
• [Journal Article] Dclk1 distinguishes between tumor and normal stem cells in the intestine (2013)
  • Author(s): Nakanishi Y, Seno H, Fukuoka A, Ueo T, Yamaga Y, Maruno T, Nakanishi N, Kanda K, Komekado H, Kawada M, Isomura A, Kawada K, Sakai Y, Yanagita M, Kageyama R, Kawaguchi Y, Taketo MM, Yonehara S, Chiba T.
  • Journal Title: Nature Genet Volume: 45 Pages: 98-103
  • DOI: 10.1038/ng.2481
  • Peer Reviewed
• [Journal Article] Morris JP 4th, Hebrok M. Bmi1 is required for regeneration of the exocrine pancreas in mice (2012)
  • Author(s): Fukuda A.
  • Journal Title: Gastroenterology Volume: 143 Pages: 821-831
  • DOI: 10.1053/j.gastro.2012.05.009
  • Peer Reviewed
• [Journal Article] The role of Hes genes in intestinal development, homeostasis and tumor formation (2012)
  • Author(s): Ueo T, Imayoshi T, Kobayashi T, Ohtsuka T, Seno H, Nakae H, Chiba T, Kageyama R.
  • Journal Title: Development Volume: 139 Pages: 1071-1082
  • DOI: 10.1242/dev.069070
  • Peer Reviewed
• [Journal Article] Nardilysin and ADAM proteases promote gastric cancer cell growth by activating intrinsic cytokine signaling via enhanced ectodomain shedding of TNFα (2012)
  • Author(s): Kanda K, Komekado H, Sawabu T, Ishizu S, Nakanishi U, Nakatsuji M, Akitake-Kawano R, Ohono M, Hiraoka Y, Kawada M, Kawada K, Sakai Y, Matsumoto K, Kunichika M, Kimura T, Seno H, Nishi E, Chiba T.
  • Journal Title: EMBO Mol Med Volume: 4 Pages: 396-411
  • DOI: 10.1002/emmm.201200216
  • Peer Reviewed
• [Journal Article] Gastroesophageal reflux disease symptoms and dietary behaviors are significant correlates of short sleep duration in the general population : The Nagahama Study
  • Author(s): Murase K, Tabara Y, Takahashi Y, Muro S, Yamada R, Setoh K, Kawaguchi M, Kadotani H, Kosugi S, Sekine A, Nakayama T, Mishima M, Chiba T, Chin K, Matsuda F.
  • Journal Title: Sleep Volume: (in press)
  • URL: http://www.journalsleep.org/AcceptedPapers/SP-854-13.pdf
  • Peer Reviewed
• [Presentation] Dclk1 discriminates between tumor and normal stem cells in the intestine (2013)
  • Author(s): 妹尾浩、中西祐貴、千葉勉
  • Organizer: シンポジウムがん幹細胞研究に基づく新たながん治療戦略第36回日本分子生物学会年会
  • Place of Presentation: 神戸神戸国際会議場
  • Year and Date: 2013-12-04
• [Presentation] 腸腫瘍幹細胞特異的マーカーDclk1の同定 (2013)
  • Author(s): 中西祐貴、上尾太郎、妹尾浩
  • Organizer: International Sessionsがん幹細胞第72回日本癌学会総会
  • Place of Presentation: 横浜パシフィコ横浜
  • Year and Date: 2013-10-04
• [Presentation] Intestinal tumors are continuously renewed by Dclk1-positive tumor stem cells (2013)
  • Author(s): Nakanishi Y, Seno H, Chiba T.
  • Organizer: American Association of Cancer Research, Annual Meeting 2013
  • Place of Presentation: Washington DC, USA, Walter E. Washington Convention Center
  • Year and Date: 2013-04-10
• [Presentation] 正常腸管および腸腫瘍におけるDclk1/Lgr5陽性細胞の役割 (2013)
  • Author(s): 中西祐貴、妹尾浩、上尾太郎
  • Organizer: 第99回日本消化器病学会総会
  • Place of Presentation: 鹿児島かごしま県民交流センター
  • Year and Date: 2013-03-23
• [Presentation] The role of Dclk1-positive cells in the intestinal homeostasis. 2012 James W. Freston Single Topic Conference (2012)
  • Author(s): Nakanishi Y, Seno H, Ueo T, Chiba T.
  • Organizer: Gastrointestinal Stem Cell Biology and Pathobiology
  • Place of Presentation: Chicago, USA, Intercontinental Hotel Chicago
  • Year and Date: 20120827-28
• [Presentation] Dclk1 discriminates between tumor and normal stem cells in the intestine (2012)
  • Author(s): Seno H.
  • Organizer: GI Research Academy 2012
  • Place of Presentation: Tokyo, Japan, Keidanren Hall
  • Year and Date: 2012-06-15
• [Presentation] 腸腫瘍幹細胞特異的マーカーDcamkl1の同定 (2012)
  • Author(s): 中西祐貴、上尾太郎、妹尾浩
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 東京京王プラザホテル
  • Year and Date: 2012-04-20
• [Presentation] Hes1は大腸上皮細胞の位置を規定し、ニッチ由来のWntやBMPシグナルによる分化制御に関与する (2012)
  • Author(s): 上尾太郎、妹尾浩、仲瀬裕志
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 東京京王プラザホテル
  • Year and Date: 2012-04-19
• [Remarks] 1. JSPSホームページ科研費NEWS2013年度VOL1
  • URL: http://www.jsps.go.jp/j-grantsinaid/22_letter/data/news_2013_vol1/p17.pdf
• [Remarks] 2.京都大学ホームページ癌幹細胞を特定するマーカー同定に成功～新世代の癌治療法開発に期待～
  • URL: http://www.kyoto-u.ac.jp/ja/news_data/h/h1/news6/2012/121203_1.htm