The development of pancreatic cancer therapy based on regulating extracellular matrix remodeling by pancreatic stellate cells

• Project/Area Number: 25462117
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kyushu University
• Principal Investigator: MIYASAKA Yoshihiro 九州大学, 医学(系)研究科(研究院), 助教 (40507795)
• Co-Investigator(Kenkyū-buntansha): TANAKA Masao 九州大学, 医学研究院, 教授 (30163570) ; NAKATA Kohei 九州大学, 大学病院, 特別教員 (30419569)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 膵癌 / 膵星細胞 / 細胞外マトリックス / 低酸素 / PLOD2 / 線維構築

Outline of Final Research Achievements

We generate cell-free 3D matrices from PSCs. The cell-free 3D matrices containing abundant fibronectin and collagen fibers closely resembled in vivo stromal matrices. To assess the impact of hypoxia on ECM organization, we measured fibronectin fiber orientation in 3D matrices derived from PSCs. We found that 3D matrices from PSCs under hypoxia displayed an organized parallel fibronectin orientation compared with random fiber arrangement in the 3D matrices derived from PSCs under normoxia. Cancer cells movement within 3D matrices derived from PSCs under hypoxia was directionally persistent. PLOD2 in PSCs was the gene that potentially regulates ECM fiber architecture under hypoxia. Knockdown of PLOD2 in PSCs blocked parallel fiber architecture of 3D matrices, leading to decreased directional migration of cancer cells within the matrices.

Research Products

• [Journal Article] Hypoxic stellate cells of pancreatic cancer stroma regulate extracellular matrix fiber organization and cancer cell motility (2016)
  • Author(s): Sada M, Ohuchida K, Horioka K, Okumura T, Moriyama T, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Nakamura M
  • Journal Title: Cancer Lett. Volume: 372 Issue: 2 Pages: 210-218
  • DOI: 10.1016/j.canlet.2016.01.016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Overexpression of microRNA-5100 decreases the aggressive phenotype of pancreatic cancer cells by targeting PODXL. (2016)
  • Author(s): Chijiiwa Y, Moriyama T, Ohuchida K, Nabae T, Ohtsuka T, Miyasaka Y, Fujita H, Maeyama R, Manabe T, Abe A, Mizuuchi Y, Oda Y, Mizumoto K, Nakamura M
  • Journal Title: Int J Oncol Volume: 48 Issue: 4 Pages: 1688-1700
  • DOI: 10.3892/ijo.2016.3389
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] TM4SF1 as a prognostic marker of pancreatic ductal adenocarcinoma is involved in migration and invasion of cancer cells (2015)
  • Author(s): Zheng B, Ohuchida K, Cui L, Zhao M, Shindo K, Fujiwara K, Manabe T, Torata N, Moriyama T, Miyasaka Y, Ohtsuka T, Takahata S, Mizumoto K, Oda Y, Tanaka M
  • Journal Title: Int J Oncol. Volume: 47 Issue: 2 Pages: 490-498
  • DOI: 10.3892/ijo.2015.3022
  • Peer Reviewed
• [Journal Article] Pirfenidone inhibits desmoplasia of pancreatic cancer by regulating stellate cells. (2013)
  • Author(s): Shingo Kozono, Kenoki Ohuchida, Daiki Eguchi, Naoki Ikenaga, Kenji Fujiwara, Ming Zhao, Lin Cui, Koji Shindo, Kazuhiro Mizumoto, and Masao Tanaka
  • Journal Title: Cancer Research Volume: 73 Issue: 7 Pages: 2345-2356
  • DOI: 10.1158/0008-5472.can-12-3180
  • Peer Reviewed
• [Presentation] Pancreatic Stellate Cells Lead and Promote the Local Invasion of Cancer Cells, by Physically Remodeling the Extracellular Matrix with Collagen Fiber Alignment in Pancreatic Cancer (2015)
  • Author(s): Koikawa K, Ohuchida K, Sada M, Abe T, Endo S, Horioka K, Moriyama T, Miyasaka Y, Ohtsuka T, Ohuchida R, Ueki T, Nagai E, Mizumoto K, Nakamura M
  • Organizer: American Pancreatic Association 46th Annual Meeting
  • Place of Presentation: San Diego(USA)
  • Year and Date: 2015-11-04
  • Int'l Joint Research
• [Presentation] 低酸素環境下膵星細胞はPLOD2誘導性間質リモデリングによって膵癌の浸潤を促進する (2015)
  • Author(s): 佐田政史、大内田研宙、奥村隆志、千々岩芳朗、吉田真樹、田中友晴、堀岡宏平、鄭彪、水内祐介、藤原謙次、森山大樹、宮坂義浩、大塚隆生、高畑俊一、小田義直、水元一博、田中雅夫
  • Organizer: 第115回日本外科学会定期学術集会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-04-16
• [Presentation] 膵癌細胞は腹膜中皮細胞と相互作用により腹膜播種を促進する (2015)
  • Author(s): 阿部俊也、大内田研宙、遠藤翔、肥川和寛、吉田真樹、千々岩芳朗、奥村隆志、田中友晴、佐田政史、堀岡宏平、藤原謙次、森山大樹、宮坂義浩、大塚隆生、高畑俊一、水元一博、田中雅夫
  • Organizer: 第115回日本外科学会定期学術集会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-04-16
• [Presentation] 膵癌間質におけるCD90とα-SMA発現の意義
  • Author(s): 佐田政史
  • Organizer: 第113回日本外科学会定期学術集会
  • Place of Presentation: 福岡市
• [Presentation] Clinical Significance of Stromal CD90 and alpha-SMA Expression in Pancreatic Cancer
  • Author(s): Masafumi Sada
  • Organizer: American Pancreatic Association, 44th Annual Meeting
  • Place of Presentation: Miami, USA