Nobel role of liver endothelial cells in liver metastasis formation

• Project/Area Number: 16K10599
• 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: MAEYAMA Ryo 九州大学, 医学研究院, 共同研究員 (10611668)
• Co-Investigator(Kenkyū-buntansha): 藤田 逸人 九州大学, 医学研究院, 助教 (40611281) ; 大内田 研宙 九州大学, 大学病院, 講師 (20452708)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 膵癌 / 肝転移 / 血管内皮細胞 / leading cell / 肝内血管内皮細胞

Outline of Final Research Achievements

We have reported that cancer-associated fibroblasts have a role as “leading cells” which lead cancer cell invasion in the tumor microenvironment. Same as cancer-associated fibroblasts, we hypothesized that endothelial cells can function as leading cells because of their high migratory activity in angiogenesis. Although co-culture of pancreatic cancer cells (PCCs) and human umbilical vascular endothelial cells (HUVECs) under 3D condition could not reveal the role of HUVECs as leading cells, HUVECs promoted migration of PCCs. Furthermore, neutrophil extracellular traps promoted the formation of liver metastasis through activation of cancer-associated fibroblasts in the metastatic foci.

Academic Significance and Societal Importance of the Research Achievements

膵癌は、非常に予後不良な癌腫であり、その原因の一つとして高い転移能が挙げられる。
転移先の臓器は主に肝・肺・腹膜・骨であり、中でも肝転移は膵癌患者の予後に大きく関わる。近年、さまざまな癌腫において肝転移のメカニズムが徐々に解明されてきているが、肝転移における肝内血管内皮細胞の役割については未知の部分が多い。
本研究において、癌の肝転移形成に関わる現象として好中球細胞外トラップに着目し、好中球細胞外トラップが肝転移巣での癌関連線維芽細胞の誘導を促進することで肝転移形成を促進している可能性が示唆された。このことは今後の新たな膵癌肝転移の制御法を開発する一助となると思われる。

Research Products

• [Journal Article] CD110 promotes pancreatic cancer progression and its expression is correlated with poor prognosis. (2019)
  • Author(s): Yan Z, Ohuchida K, Zheng B, Okumura T, Takesue S, Nakayama H, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Hashizume M, Nakamura M
  • Journal Title: J Cancer Res Clin Oncol. Volume: 145 Issue: 5 Pages: 1147-1164
  • DOI: 10.1007/s00432-019-02860-z
  • 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
• [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
• [Journal Article] （The） Calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer-stromal interactions in a mouse xenograft model (2016)
  • Author(s): Yoshida M, Miyasaka Y, Ohuchida Kenoki, Okumura T, Zheng B, Torata N, Fujita H, Nabae T, Manabe T, Shimamoto M, Ohtsuka T, Mizumoto K, Nakamura M
  • Journal Title: Cancer Sci Volume: 107 Issue: 10 Pages: 1443-1452
  • DOI: 10.1111/cas.13024
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Role of neutrophil extracellular traps(NETs) in pancreatic cancer liver metastasis (2018)
  • Author(s): Takesue S, Ohuchida K, Nakayama H, Koikawa K, Shindo K, Nakata K, Moriyama T, Miyasaka Y, Ohtsuka T, Nakamura M
  • Organizer: Pancreas2018
  • 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: Pancreas2018
  • Int'l Joint Research
• [Presentation] CD110の阻害は、マウスの膵癌肝転移を抑制する (2018)
  • Author(s): 厳子龍、大内田研宙、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77回日本癌学会学術総会
• [Presentation] マウスモデルを用いた膵癌微小転移形成機序の解析 (2017)
  • Author(s): 武居晋、大内田研宙、安藤陽平、岐部晋、中山宏道、阿部俊也、肥川和寛、遠藤翔、厳子龍、奥村隆志、仲田興平、森山大樹、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] 膵癌におけるTPO-CD110-ERK-MYCシグナル経路の生物学的意義の解析 (2017)
  • Author(s): Zilong Yan,大内田研宙、奥村隆志、遠藤翔、阿部俊也、肥川和寛、武居晋、中山宏道、安藤陽平、岐部晋、仲田興平、宮坂義浩、森山大樹、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] 膵癌における肝・肺転移形成機序の相違に関する検討 (2017)
  • Author(s): 武居晋、鄭彪、大内田研宙、森泰寿、仲田興平、宮坂義浩、大塚隆生、永井英司、中村雅史
  • Organizer: 第72回日本消化器外科学会総会