Identification of the organ-specific cancer leading cells and regulation of the tumor micro-environment remodeling which leads to cancer cell metastasis.

• Project/Area Number: 16H05418
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kyushu University
• Principal Investigator: NAKAMURA Masafumi 九州大学, 医学研究院, 教授 (30372741)
• Co-Investigator(Kenkyū-buntansha): 大塚 隆生 九州大学, 医学研究院, 准教授 (20372766) ; 大内田 研宙 九州大学, 大学病院, 講師 (20452708) ; 三好 圭 九州大学, 大学病院, 助教 (70755272) ; 江口 大樹 九州大学, 医学研究院, 共同研究員 (90726390) ; 宮坂 義浩 九州大学, 大学病院, 助教 (40507795) ; 森山 大樹 九州大学, 大学病院, 助教 (70586859)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2018: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2017: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2016: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
• Keywords: 膵癌 / 腹膜中皮細胞 / リーディングセル / 癌間質相互作用 / 間質リモデリング / 膵星細胞 / 癌微小環境 / 腹膜播種 / 中皮細胞

Outline of Final Research Achievements

In the present study, we investigated the interaction between the pancreatic cancer cells (PCCs) and the cancer-associated stroma cells, such as the peritoneal mesothelial cells (PMCs) and pancreatic stellate cells (PSCs), in vitro assays. PMCs pre-invaded into the collagen gels, and remodeled collagen fibers as increasing the parallel fiber orientation along to the direction of cell invasion. In the 3D co-culture system and mouse orthotopic models, PSCs promoted PCCs invasion into stroma, following the basement membrane destruction through the activation of MMP2 and MT1MMP in PSCs, These data suggest that stromal cells which promote cancer cell invasion via destruction of basement membrane, or remodeling of collagen fibers can be a new target to regulate the pancreatic cancer metastasis.

Academic Significance and Societal Importance of the Research Achievements

本研究は膵癌の予後を規定する転移メカニズムを解明するために、膵癌と間質細胞の相互作用に着目して研究を行い、腹膜中皮細胞や膵星細胞といった間質細胞の膵癌細胞の浸潤における新たな機序の解明を行った。間質細胞が寄与する新たな浸潤メカニズムが解明できたことにより、これらを制御する新規の膵癌転移制御方法の開発が可能となった。その制御法を臨床応用することによって今後の膵癌患者の予後改善に寄与し得ると考えられる。

Research Products

• [Journal Article] Adipose tissue-derived stromal cells are sources of cancer-associated fibroblasts and enhance tumor progression by dense collagen matrix (2018)
  • Author(s): Okumura T, Ohuchida K, Kibe S, Iwamoto C, Ando Y, Takesue S, Nakayama H, Abe T, Endo S, Koikawa K, Sada M, Horioka K, Mochidome N, Arita M, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Hashizume M, Nakamura M
  • Journal Title: Int J Cancer Volume: 144 Issue: 6 Pages: 1401-1413
  • DOI: 10.1002/ijc.31775
  • Peer Reviewed / Open Access
• [Journal Article] Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma (2018)
  • Author(s): Koikawa K、Ohuchida K、Ando Y、Kibe S、Nakayama H、Takesue S、Endo S、Abe T、Okumura T、Iwamoto C、Moriyama T、Nakata K、Miyasaka Y、Ohtsuka T、Nagai E、Mizumoto K、Hashizume M、Nakamura M
  • Journal Title: Cancer Letters Volume: 425 Pages: 65-77
  • DOI: 10.1016/j.canlet.2018.03.031
  • Peer Reviewed / Open Access
• [Journal Article] Cancer-associated peritoneal mesothelial cells lead the formation of pancreatic cancer peritoneal dissemination. (2017)
  • Author(s): Abe T, Ohuchida K, Koikawa K, Endo S, Okumura T, Sada M, Horioka K, Zheng B, Moriyama T, Nakata K, Miyasaka Y, Manabe T, Ohtsuka T, Nagai E, Mizumoto K, Hashizume M, Nakamura M.
  • Journal Title: Int J Oncol Volume: 50 Issue: 2 Pages: 457-467
  • DOI: 10.3892/ijo.2016.3829
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 膵オルガノイドを用いた浸潤性膵管癌の新たな局所微小浸潤機序の解明 (2018)
  • Author(s): 米永晃子、肥川和寛、大内田研宙、進藤幸治、仲田興平、森山大樹、宮坂義浩、大塚隆生、水元一博、中村雅史
  • Organizer: 第49回日本膵臓学会大会
• [Presentation] Endo180 Expression and Histologic Categorization in Cancer Stroma is an Independent Prognostic Index in Pancreatic Cancer. (2018)
  • Author(s): Koikawa K, Ohuchida K, Yonenaga A, Sagara A, Ando Y, Kibe S, Takesue S,Nakayama H, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Mizumoto K, Nakamura M
  • Organizer: 49th Annual Meeting of the APA
  • Int'l Joint Research
• [Presentation] Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma (2018)
  • Author(s): Koikawa K, Ohuchida K, Ando Y, Kibe S, Nakayama H, Takesue S, Endo S, Abe T, Okumura T, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Nagai E, Mizumoto K, Hashizume M, Nakamura M
  • Organizer: Pancreas 2018
  • Int'l Joint Research
• [Presentation] BM-derived cells differentiated into multilineage hematopoietic cells regulate invasion and proliferation of pancreatic cancer (2018)
  • Author(s): Iwamoto C, Ohuchida K, Okumura T, Koikawa K, Takesue S, Nakayama H, Endo S, Kibe S, Ando Y, Shindo K, Nakata K, Miyawaki K, Murata M, Akashi K, Nakamura M, Hashizume M
  • Organizer: Pancreas 2018
  • Int'l Joint Research
• [Presentation] 癌関連腹膜中皮細胞は膵癌腹膜播腫形成を促進する (2017)
  • Author(s): 阿部俊也、大内田研宙、肥川和寛、遠藤翔、奥村隆志、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117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): Koikawa K, Ohuchida K, Ando Y, Kibe S, Nakayama H, Takesue S, Yan Z, Abe T, Okumura T, Iwamoto C, Moriyama T, Nakata K, Miyasaka Y, Okabe Y, Ohtsuka T, Mizumoto K, Nakamura M
  • Organizer: The 48th Annual Meeting of The American Pancreatic Association
  • Int'l Joint Research
• [Presentation] Novel role of peritoneal mesothelial cells that lead to pancreatic cancer peritoneal dissemination formation (2016)
  • Author(s): Abe T, Ohuchida K, Kibe S, Ando Y, Nakayama H, Takesue S, Endo S, Koikawa K, Okumura T, Moriyama T, Nakata K, Miyasaka Y, Manabe T, Ohtsuka T, Nagai E, Mizumoto K, Nakamura M.
  • Organizer: 47th Annual Meeting of the American Pancreatic Association
  • Place of Presentation: Boston(USA)
  • Year and Date: 2016-10-28
  • Int'l Joint Research