Targeting tumor microenvironment as a novel therapeutic strategy for pancreatic cancer using a genetically-engineered mouse model

2012 Fiscal Year Final Research Report

• Project/Area Number: 22501004
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: The University of Tokyo
• Principal Investigator: ISAYAMA Hiroyuki 東京大学, 医学部附属病院, 講師 (70376458)
• Co-Investigator(Kenkyū-buntansha): IJICHI Hideaki 東京大学, 医学部附属病院, 助教 (70463841)
• Project Period (FY): 2010 – 2012
• Keywords: 膵癌 / 微小環境 / 腫瘍間質相互作用 / マクロファージ / 線維芽細胞 / CXCR2 / CTGF / 遺伝子改変マウス

Research Abstract

A genetically-engineered mouse model, containing mutant Kras expression and Tgfbr2 knockout, recapitulates histological features of human pancreatic cancer, demonstrating adenocarcinoma with abundant fibrosis. The murine pancreatic cancer cells secret CXCR2 ligands, which induce CTGF expression in the stromal fibroblasts, resulting in tumor promotion through angiogenesis. Inhibiting the tumor-stromal interactions in the tumor microenvironment demonstrated anti-tumor effect and can be a therapeutic option for pancreatic cancer. The pancreatic cancer tissues contain abundant macrophage infiltration, however, targeting the macrophages as a therapy of pancreatic cancer should be further investigated.

Research Products

• [Journal Article] Therapeutic effect of c-Jun N-terminal kinase inhibition on pancreatic cancer. (2013)
  • Author(s): Ryota Takahashi, Yashuhiro Hirata,Kousuke Sakitani, Wachiko Nakata, Hiroto Kinoshita, Yoku Hayakawa, Hayato Nakagawa, Kei Sakamoto, Yoko Hikiba, Hideaki Ijichi , Harold L Moses, Shin Maeda, Kazuhiko Koike.
  • Journal Title: Cancer Science Volume: Vol.104 Pages: 337-344
  • Peer Reviewed
• [Journal Article] Inhibition of CXCLs/CXCR2 axis in the tumor microenvironment might be a potent therapeutics for pancreatic cancer. (2012)
  • Author(s): Hideaki Ijichi.
  • Journal Title: OncoImmunology Volume: Vol.1 Pages: 569-571
  • Peer Reviewed
• [Journal Article] Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma. (2011)
  • Author(s): Hideaki Ijichi, Anna Chytil, Agnieska E Gorska, Mary E Aakre, Brian Bierie, Motohisa Tada, Dai Mohri, Koji Miyabayashi, Yoshinari Asaoka, Shin Maeda, Tsuneo Ikenoue, Keisuke Tateishi, Christopher VE Wright, Kazuhiko Koike, Masao Omata, Harold L Moses.
  • Journal Title: Journal of Clinical Investigation Volume: Vol.121 Pages: 4106-4117
  • Peer Reviewed
• [Presentation] 膵臓癌に対するJNK標的療法についての検討 (2013)
  • Author(s): 高橋良太
  • Organizer: 第50回日本臨床分子医学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2013-04-12
• [Presentation] 遺伝子改変膵発癌マウスモデルを用いた膵癌研究の臨床への橋渡し的展開 (2012)
  • Author(s): 伊地知秀明
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 東京
  • Year and Date: 2012-04-20
• [Presentation] 膵癌微小環境におけるCXCケモカイン/CXCR2Axis阻害の重要性 (2011)
  • Author(s): 伊地知秀明
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2011-10-03
• [Presentation] 膵発癌マウスモデルを用いた膵癌化学療法の臨床への橋渡し的展開 (2011)
  • Author(s): 伊地知秀明
  • Organizer: 第97回日本消化器病学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-05-15
• [Presentation] Blockade of CXC chemokines/CXCR2 axis inhibits pancreatic ductal adenocarcinoma progression (2010)
  • Author(s): 伊地知秀明
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪市
  • Year and Date: 2010-09-23
• [Presentation] Blockade of CXC chemokines/CXCR2 axis inhibits pancreatic ductal adenocarcinoma progression (2010)
  • Author(s): Hideaki Ijichi
  • Organizer: Joint Meeting of 14th International Association of Pancreatology and 41th Japanese Pancreas Society
  • Place of Presentation: 福岡市
  • Year and Date: 2010-07-11
• [Presentation] Blockade of CXC chemokines/CXCR2 axis inhibits pancreatic ductal adenocarcinoma progression through anti-angiogenesis (2010)
  • Author(s): Hideaki Ijichi
  • Organizer: The 101st Annual Meeting of American Association for Cancer Research
  • Place of Presentation: Washington D.C.
  • Year and Date: 2010-04-18