To elucidate niche factors promoting micro liver metastasis of pancreatic cancer using genetically engineered model mice.

• Project/Area Number: 17K16566
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Kyushu University
• Principal Investigator: SADA Masafumi 九州大学, 医学研究院, 共同研究員 (10783508)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 膵癌 / 微小環境 / 微小転移 / 癌関連線維芽細胞 / 好中球 / NETs / CD110 / 膵癌肝転移 / ニッチ因子 / 微小環境因子 / 門脈循環腫瘍細胞

Outline of Final Research Achievements

Present study using pancreatic cancer spontaneous mice (KPC mice) and a splenic instilled liver metastasis model revealed that cancer-associated fibroblasts (CAF) are concentrated around cancer cells in the liver metastasis. It was suggested that CAFs construct micro environment which promoting liver metastasis formation. Furthermore, we focused on the concentration of neutrophils prior to CAFs and found that a mechanism called neutrophil extra-traps (NETs) work to promote liver metastasis formation.
In addition, liver metastasis was significantly increased when CD110 expression in cancer cells was high level, and it was shown that CD110 expression may be involved in liver metastasis formation of pancreatic cancer.
From these results, it is suggested that CAFs and neutrophils are involved on the host side and CD110 expression on the cancer side as factors that promote the formation of micro liver metastases of pancreatic cancer.

Academic Significance and Societal Importance of the Research Achievements

固形癌の多くは、進行すると遠隔臓器への転移をきたして致命的となることが多い。中でも膵癌は5年生存率が10％に満たず、その治療成績改善は急務である。
膵癌の進行過程において、肝転移をはじめとした遠隔転移の形成は非常に重要な局面であり、転移形成を制御することができれば、予後改善のための大きな一歩となり得る。本研究では膵癌の肝転移におけるごく初期段階に関する詳細な検討を行い、宿主側と癌側での新たな促進因子を見出すことができた。これらの結果は、今後の膵癌の治療成績向上に繋がると考えられる。

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
• [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] 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] 膵癌微小肝転移における癌関連線維芽細胞の誘導と好中球細胞外トラップ(NETs) (2018)
  • Author(s): 武居晋、大内田研宙、中山宏道、肥川和寛、進藤幸治、仲田興平、森山大樹、宮坂義浩、大塚隆生、中村雅史
  • Organizer: 第73回日本消化器外科学会総会
• [Presentation] オートファジーは膵星細胞の活性化に関与しており、その抑制は膵癌の進展を制御する (2017)
  • Author(s): 仲田興平、遠藤翔、大内田研宙、水元一博、小田義直、橋爪誠、中村雅史
  • Organizer: 第76回日本癌学会学術総会