Elucidation of leading cell and cancer microenvironment normalization of pancreatic cancer

• Project/Area Number: 26293305
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kyushu University
• Principal Investigator: OHUCHIDA Kenoki 九州大学, 大学病院, 助教 (20452708)
• Co-Investigator(Kenkyū-buntansha): 大塚 隆生 九州大学, 大学病院, 講師 (20372766) ; 村田 正治 九州大学, 先端融合医療レドックスナビ研究拠点, 准教授 (30304744) ; 前山 良 九州大学, 医学(系)研究科(研究院), 共同研究員 (10611668) ; 田中 雅夫 九州大学, 医学(系)研究科(研究院), 教授 (30163570) ; 江上 拓哉 九州大学, 医学(系)研究科(研究院), 共同研究員 (40507787) ; 宮坂 義浩 九州大学, 医学(系)研究科(研究院), 助教 (40507795) ; 真鍋 達也 九州大学, 医学(系)研究科(研究院), 助教 (60546464) ; 坂井 寛 九州大学, 医学(系)研究科(研究院), 共同研究員 (80611665)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2016: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2015: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: Pancreatic cancer / PSCs / Leading cell / ECM remodeling / Cancer micro environment / Normalization / 膵癌 / 膵星細胞 / 細胞外マトリックス / leading cell / 基質リモデリング

Outline of Final Research Achievements

We established 3D in vitro collagen invasion assay to investigate leading cell. We found that Pancreatic stellate cells (PSCs) frequently invaded a collagen matrix with cancer cells, which invaded behind the invading PSCs, and an increase in the number of invading cancer cells in co-cultures with PSCs. Invading PSCs changed the alignment of collagen fibers, resulting in ECM remodeling and an increase in the parallel fibers along the direction of invading PSCs. We elucidate that one of the ECM remodeling factor of PSCs is Endo180. Endo180 knockdown in PSCs attenuated the invasive abilities of PSCs and co-cultured cancer cells, and decreased the expression level of phosphorylated myosin light chain 2 (MLC2). Our findings suggest that PSCs lead the local invasion of pancreatic cancer cells by physically remodeling the ECM, possibly via the function of Endo180, which reconstructs the actin cell skeleton by phosphorylation of MLC2.

Research Products

• [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 Pages: 1443-1452
  • DOI: 10.1111/cas.13024
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hypoxic stellate cells of pancreatic cancer stroma regulate extracellular matrix fiber organization and cancer cell motility (2016)
  • Author(s): Sada M, Ohuchida K, Horioka K, Okumura T, Moriyama T, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Nakamura M
  • Journal Title: Cancer letter Volume: 372 Pages: 1499-1508
  • DOI: 10.1016/j.canlet.2016.01.016
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Suppression of CD51 in pancreatic stellate cells inhibits tumor growth by reducing stroma and altering tumor-stromal interaction in pancreatic cancer (2016)
  • Author(s): Horioka K, Ohuchida K, Sada M, Zheng B, Moriyama T, Fujita H, Manabe T, Ohtsuka T, Shimamoto M, Miyazaki T, Mizumoto K, Oda Y, Nakamura M.
  • Journal Title: International Journal of Oncology Volume: 48 Pages: 1499-1508
  • DOI: 10.3892/ijo.2016.3374
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 膵癌の浸潤・転移における癌微小環境の新たな役割 (2015)
  • Author(s): 大内田研宙、大塚隆生、橋爪誠、中村雅史
  • Journal Title: 胆と膵 Volume: 36 Pages: 1181-1187
• [Journal Article] Pancreatic Cancer: Clinical Significance of Biomarkers (2014)
  • Author(s): Mori M, Chiba T, Nakamizo A, Kumashiro R, Murata M, Akahoshi T, Tomikawa M, Ohuchida K, Ohtsuka T,Mizumoto K, Hashizume M,Tanaka M
  • Journal Title: GastroIntestinal Tumors Volume: 1 Pages: 33-40
  • DOI: 10.1159/000354996
  • Peer Reviewed
• [Journal Article] Peritoneal myofibroblasts at metastatic foci promote dissemination of pancreatic cancer. (2014)
  • Author(s): Akagawa S, Ohuchida K, Torata N, Hattori M, Eguchi D, Fujiwara K, Kozono S, Cui L, Ikenaga N, Ohtsuka T, Oishima S, Mizumoto K, Oda Y, Tanaka M
  • Journal Title: International Journal of Oncology Volume: 45 Pages: 113-120
  • DOI: 10.3892/ijo.2014.2391
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Micro RNA-373 is Down-regulated in Pancreatic Cancer and Inhibits Cancer Cell Invasion (2014)
  • Author(s): Nakata K, Ohuchida K, Mizumoto K, Aishima S, Oda Y, Nagai E, Tanaka M
  • Journal Title: Annals of Surgical Oncology Volume: 21
  • DOI: 10.1245/s10434-014-3676-8
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] CD166/ALCAM expression is characteristic of tumorigenicity and invasive and migratory activities of pancreatic cancer cells. (2014)
  • Author(s): Fujiwara K, Ohuchida K, Sada M, Horioka K, Ulrich CD 3rd, Shindo K, Ohtsuka T, Takahata S, Mizumoto K, Oda Y, Tanaka M.
  • Journal Title: CD166/ALCAM expression is characteristic of tumorigenicity and invasive and migratory activities of pancreatic cancer cells Volume: 9 Pages: 1-11
  • DOI: 10.1371/journal.pone.0107247
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Endo180 regulate phosphorylation of myosin light chain 2 activity and increase the ability of extracellular matrix remodeling in leading pancreatic stellate cells. (2016)
  • Author(s): Koikawa K, Ohuchida K, Kibe S, Ando Y, Takesue S, Nakayama H, Abe T, Endo S, Okumura T, Moriyama T, Nakata K, Miyasaka Y, Manabe T, Ohtsuka T, Nagai E, Mizumoto K, Nakamura M.
  • Organizer: The 47th Annual meeting of American Pancreatic Association
  • Place of Presentation: Boston(USA)
  • Year and Date: 2016-10-27
  • Int'l Joint Research
• [Presentation] 膵癌浸潤を先導するleading cell‐膵星細胞の基質リモデリング機能と浸潤機序の解明‐ (2016)
  • Author(s): 肥川和寛
  • Organizer: 第７１回日本消化器外科学会総会
  • Place of Presentation: アスティ徳島(徳島市）
  • Year and Date: 2016-07-15
• [Presentation] 低酸素下膵星細胞による癌間質マトリックス・リモデリングは膵癌浸潤能を増強する (2016)
  • Author(s): 佐田政史、大内田研宙、阿部俊也、遠藤翔、肥川和寛、奥村隆志、千々岩芳朗、吉田真樹、堀岡宏平、森山大樹、宮坂義浩、大塚隆生、植木隆, 永井英司、水元一博、 小田義直、中村雅史
  • Organizer: 第116回日本外科学会定期学術集会
  • Place of Presentation: リーガロイヤルホテル大阪(大阪市）
  • Year and Date: 2016-04-16
• [Presentation] 膵星細胞は基質リモデリングにより、leading cell として膵癌浸潤を先導する (2016)
  • Author(s): 肥川和寛、大内田研宙、佐田政史、阿部俊也、遠藤翔、奥村隆志、堀岡宏平、森山大樹、宮坂義浩、真鍋達也、大塚隆生、大内田理一、植木隆、永井英司、水元一博、中村雅史
  • Organizer: 第116回日本外科学会定期学術集会
  • Place of Presentation: リーガロイヤルホテル大阪(大阪市）
  • Year and Date: 2016-04-14
• [Presentation] Pancreatic Stellate Cells Lead and Promote the Local Invasion of Cancer Cells, by Physically Remodeling the Extracellular Matrix with Collagen Fiber Alignment in Pancreatic Cancer (2015)
  • Author(s): Koikawa K, Ohuchida K, Sada M, Abe T, Endo S, Horioka K, Moriyama T, Miyasaka Y, Ohtsuka T, Ohuchida R, Ueki T, Nagai E, Mizumoto K, Nakamura M
  • Organizer: American Pancreatic Association 46th Annual Meeting
  • Place of Presentation: San Diego(USA)
  • Year and Date: 2015-11-04
  • Int'l Joint Research
• [Presentation] Suppression of CD51 in Pancreatic Stellate Cells Inhibits Tumor Growth by Reducing Stroma and Altering Tumor-Stromal Interaction in Pancreatic Cancer (2015)
  • Author(s): Horioka K, Ohuchida K, Sada M, Zheng B, Ohtsuka T, Ueki T, Nagai E, Mizumoto K, Oda Y, Nakamura M
  • Organizer: American Pancreatic Association 46th Annual Meeting
  • Place of Presentation: San Diego(USA)
  • Year and Date: 2015-11-04
  • Int'l Joint Research
• [Presentation] 低酸素環境下膵星細胞はPLOD2誘導性間質リモデリングによって膵癌の浸潤を促進する (2015)
  • Author(s): 佐田政史、大内田研宙、奥村隆志、千々岩芳朗、吉田真樹、田中友晴、堀岡宏平、鄭彪、水内祐介、藤原謙次、森山大樹、宮坂義浩、大塚隆生、高畑俊一、小田義直、水元一博、田中雅夫
  • Organizer: 第115回日本外科学会定期学術集会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-04-16
• [Presentation] 膵癌細胞は腹膜中皮細胞と相互作用により腹膜播種を促進する (2015)
  • Author(s): 阿部俊也、大内田研宙、遠藤翔、肥川和寛、吉田真樹、千々岩芳朗、奥村隆志、田中友晴、佐田政史、堀岡宏平、藤原謙次、森山大樹、宮坂義浩、大塚隆生、高畑俊一、水元一博、田中雅夫
  • Organizer: 第115回日本外科学会定期学術集会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-04-16
• [Presentation] 膵癌細胞からの作用により膵星細胞中のNPAS1が増加する (2014)
  • Author(s): 藤原謙次、大内田研宙、赤川進、大塚隆夫、高畑俊一、水元一博、田中雅夫
  • Organizer: 第45回日本膵臓学会大会
  • Place of Presentation: 北九州市
  • Year and Date: 2014-07-11
• [Presentation] 膵癌間質の線維配列が癌細胞の形態と浸潤方向に与える影響 (2014)
  • Author(s): 佐田政史、大内田研宙、堀岡宏平、田中友晴、鄭彪、Cases AI、赤川進、藤原謙次、仲田興平、宮坂義浩、前山良、大塚隆生、高畑俊一、水元一博、田中雅夫
  • Organizer: 第114回日本外科学会定期学術集会
  • Place of Presentation: 京都市
  • Year and Date: 2014-04-04
• [Book] 【膵炎・膵がん】膵がん浸潤・転移における微小環境の病態 (2016)
  • Author(s): 大内田研宙、中村雅史
  • Total Pages: 250
  • Publisher: 最新医学社
• [Book] Annual Review 2014 消化器 (2014)
  • Author(s): 佐田政史、水元一博、大内田研宙、大塚隆生、田中雅夫
  • Total Pages: 306
  • Publisher: 中外医学社