Clarification and control of immune cell-induced PSC substrate remodeling using KPCL mice

• Project/Area Number: 17K10700
• 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: ONIMARU Manabu 九州大学, 医学研究院, 共同研究員 (80529876)
• Co-Investigator(Kenkyū-buntansha): 三好 圭 九州大学, 大学病院, 助教 (70755272) ; 寅田 信博 九州大学, 大学病院, 臨床検査技師 (00398075) ; 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 / 膵星細胞 / リモデリング / 癌微小環境 / 膵微小環境 / 癌間質相互作用 / 免疫細胞

Outline of Final Research Achievements

Focusing on the fact that remodeling of extracellular matrix abundant in pancreatic cancer tissues is involved in cancer invasion and metastasis, we analyzed the substrate remodeling centering on PSC (pancreatic stellate cells).
For the PSC, we have clarified the relationship between Endo180 expression in PSC and extracellular matrix, between MMP2 secretion / MT1MMP expression and basement membrane infiltration / substrate remodeling, and between ERK1 / 2 and EMT, autophagy, and cancer cell infiltration.
In addition, we elucidated the effect of the adipose stem cell-derived stromal cells on substrate density or pancreatic cancer invasion, and the effect of S100P expression in pancreatic cancer cells on the formation of single-layer circular defects in lymphatic vessels.

Academic Significance and Societal Importance of the Research Achievements

膵癌は、罹患者数と死亡者数がほぼ同数の極めて難治性の癌で、5年生存率は約7%と極めて予後不良な疾患であり、その診断法や治療法の新規開発は、社会的要請度・緊急性が高い。
本研究においては、細胞外マトリックスの新たなリモデリング機構としての脂肪幹細胞の働きや、膵癌細胞のリンパ管浸潤の機序などにも着目し、解析を重ねた。
それぞれにおいて基質リモデリングや上皮間葉転換などを介する癌細胞浸潤の抑制を誘導しうる有望な治療標的を各種同定するに至ったことは、膵癌治療に対する学術的、社会的要請に応じる結果が得られたといえる。

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: J Exp Clin Cancer Res Volume: 38 Pages: 221-221
  • DOI: 10.1186/s13046-019-1226-8
  • Peer Reviewed / Open Access
• [Journal Article] S100P regulates the collective invasion of pancreatic cancer cells into the lymphatic endothelial monolayer (2019)
  • Author(s): Nakayama H, Ohuchida K, Yonenaga A, Sagara A, Ando Y, Kibe S, Takesue S, Abe T, Endo S, Koikawa K, Okumura T, Shido K, Miyoshi K, Nakata K, Moriyama T, Miyasaka Y, Inoue S, Ohtsuka T, Mizumoto K, Nakamura M
  • Journal Title: International Journal of Oncology Volume: 55 Pages: 211-222
  • DOI: 10.3892/ijo.2019.4812
  • Peer Reviewed
• [Journal Article] Adipose tissue-derived stromal cells are sources of cancer-associated fibroblasts and enhance tumor progression by dense collagen matrix (2019)
  • 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: International Journal of Cancer Volume: 144 Pages: 1401-1403
  • 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 Lett. Volume: 425 Pages: 65-77
  • DOI: 10.1016/j.canlet.2018.03.031
  • 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 Lett Volume: 412 Pages: 143-154
  • DOI: 10.1016/j.canlet.2017.10.010
  • Peer Reviewed / Open Access
• [Presentation] 膵癌リンパ節転移におけるcollective cell invasion 制御因子の検討 (2019)
  • Author(s): 中山宏道、大内田研宙、安藤陽平、岐部晋、武居晋、進藤幸治、森山大樹、仲田興平、大塚隆生、中村雅史
  • Organizer: 第74回日本消化器外科学会総会
• [Presentation] S100Pが癌細胞塊のリンパ管内皮層へのクリアランスに関与しリンパ節転移に関わる (2019)
  • Author(s): 中山宏道、大内田研宙、相良亜希子、米永晃子、安藤陽平、岐部晋、武居晋、進藤幸治、仲田興平、森山大樹、宮坂義浩、藤田逸人、永井俊太郎、岡部安博、大塚隆生、水元一博、中村雅史
  • Organizer: 第119回日本外科学会定期学術集会
• [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] Fat tissue and pancreatic parenchyma play different roles in pancreatic cancer invasion (2018)
  • Author(s): Ohuchida K, Kibe S, Okumura T, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Nakamura M
  • Organizer: Pancreas 2018
  • Int'l Joint Research
• [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