Cellular clearance leading to peritoneal dissemination of pancreatic cancer and a new role of peritoneal mesothelium -From defense to promotion-

• Project/Area Number: 17K10701
• 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: INOUE Shigetaka 九州大学, 医学研究院, 共同研究員 (00529802)
• Co-Investigator(Kenkyū-buntansha): 進藤 幸治 九州大学, 大学病院, 助教 (00788432) ; 佐田 政史 九州大学, 医学研究院, 共同研究員 (10783508) ; 宮坂 義浩 九州大学, 医学研究院, 共同研究員 (40507795) ; 三好 圭 九州大学, 大学病院, 助教 (70755272) ; 大内田 研宙 九州大学, 大学病院, 講師 (20452708)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 膵癌 / 播種 / 腹膜中皮細胞 / leading cell / spheroid / CAF / 脂肪由来間質細胞 / organoid / 腹膜播種 / clearance / PSC / オルガノイド

Outline of Final Research Achievements

First, we focused on adipocytes, because of the pancreas is a retroperitoneal organ surrounded by adipose tissue, and adipocytes are considered to have a significant relationship with infiltration and dissemination outside the pancreas.
Adipose tissue-derived stromal cells infiltrated pancreatic cancer and, when activated, acted as fibroblasts and secreted cytokines. Furthermore, by producing a high-density collagen matrix, it promoted extra-pancreatic invasion.
We also conducted experiments using KPC mice for the purpose of clarifying the leading cells. We have shown that acinar-to-ductal metaplasia (ADM) exists in association with tumor infiltrate. Moreover, gene expression analysis of ADM region of human tumors showed that cancer-related ADM and acinar atrophy contributed to local tumor cell invasion.

Academic Significance and Societal Importance of the Research Achievements

膵癌は豊富な細胞外基質を伴うdesmoplasiaを病理学的特徴とし、以前より癌細胞と間質細胞が相互に作用しその悪性度を増す癌間質相互作用の重要性が示唆されており、微小環境における新たな癌間質相互作用のあり方に関する解析が進められている。しかし、膵癌腹膜播種に関しては、播種巣における微小環境まで含めて検討した解析はない。
本研究においては脂肪細胞や膵星細胞の癌間質相互作用、特に膵癌浸潤促進因子についての新たな知見を示すことができた。今後、PMCsを直接用いた実験を再検討することで、他の間質細胞で確認されたleadingなどを示すことができれば、腹膜播種形成機序の解明に近づくと考えている。

Research Products

• [Journal Article] Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer?stromal interaction and metastasis (2019)
  • Author(s): Yan Zilong、Ohuchida Kenoki、Fei Shuang、Zheng Biao、Guan Weiyu、Feng Haimin、Kibe Shin、Ando Yohei、Koikawa Kazuhiro、Abe Toshiya、Iwamoto Chika、Shindo Koji、Moriyama Taiki、Nakata Kohei、Miyasaka Yoshihiro、Ohtsuka Takao、Mizumoto Kazuhiro、Hashizume Makoto、Nakamura Masafumi
  • Journal Title: Journal of Experimental & Clinical Cancer Research Volume: 38 Issue: 1 Pages: 221-221
  • DOI: 10.1186/s13046-019-1226-8
  • Peer Reviewed / Open Access
• [Journal Article] Cancer-associated acinar-to-ductal metaplasia within the invasive front of pancreatic cancer contributes to local invasion. (2019)
  • Author(s): Kibe S, Ohuchida K, Ando Y, Takesue S, Nakayama H, Abe T, Endo S, Koikawa K, Okumura T, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Shimamoto M, Ohtsuka T, Mizumoto K, Oda Y, Nakamura M.
  • Journal Title: Cancer Lett Volume: 444 Pages: 70-81
  • DOI: 10.1016/j.canlet.2018.12.005
  • Peer Reviewed / Open Access
• [Journal Article] Pancreatic stellate cells reorganize matrix components and lead pancreatic cancer invasion via the function of Endo180 (2018)
  • Author(s): Koikawa K, Ohuchida K, Takesue S, Ando Y, Kibe S, Nakayama H, Endo S, Abe T, Okumura T, Horioka K, Sada M, Iwamoto C, Moriyama T, Nakata K, Miyasaka Y, Ohuchida R, Manabe T, Ohtsuka T, Nagai E, Mizumoto K, Hashizume M, Nakamura M.
  • Journal Title: Cancer Letters Volume: 412 Pages: 143-154
  • DOI: 10.1016/j.canlet.2017.10.010
  • Peer Reviewed / Open Access
• [Presentation] 膵癌におけるERK1/2阻害剤による癌間質相互作用の抑制効果の検討 (2019)
  • Author(s): 新川智彦、厳子龍、大内田研宙、大坪慶志輝、松本奏吉、米永晃子、相良亜希子、関維雨、馮海旻、安藤陽平、岐部晋、武居晋、中山宏道、進藤幸治、森山大樹、仲田興平、宮坂義浩、永井俊太郎、大塚隆生、中村雅史
  • Organizer: 第119回日本外科学会定期学術集会
• [Presentation] 膵星細胞が誘導する新たな膵癌局所微小浸潤機序の解明 (2017)
  • Author(s): 肥川和寛、大内田研宙、森山大樹、仲田興平、宮坂義浩、真鍋達也、大塚隆生、永井英司、水元一博、中村雅史
  • Organizer: 第25回日本消化器関連学会週間 第15回日本消化器外科学会大会
• [Presentation] Pancreatic organoids elucidate the new mechanisms of pancreatic cancer local invasion (2017)
  • Author(s): K Koikawa, K Ohuchida, Y Ando, S Kibe, H Nakayama, S Takesue, Z Yan, T Abe, T Okumura, C Iwamoto, T Moriyama, K Nakata, Y Miyasaka, Y Okabe, T Ohtuka, K Mizumoto, M Nakamura
  • Organizer: The 48th Annual Meeting of The American Pancreatic Association
  • Int'l Joint Research