The mechanism of promoting liver metastasis caused by CXCL 12 and fundamental research for innovative therapeutic development in intrahepatic cholangiocarcinoma

• Project/Area Number: 18K08709
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kumamoto University
• Principal Investigator: MASUDA Tosirou 熊本大学, 病院, 非常勤診療医師 (50551256)
• Co-Investigator(Kenkyū-buntansha): 山下 洋市 熊本大学, 大学院生命科学研究部(医), 准教授 (00404070) ; 岡部 弘尚 熊本大学, 病院, 非常勤診療医師 (40573621) ; 今井 克憲 熊本大学, 大学院生命科学研究部(医), 助教 (60555746) ; 中川 茂樹 熊本大学, 病院, 非常勤診療医師 (10594872) ; 日比 泰造 熊本大学, 大学院生命科学研究部(医), 教授 (10338072)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 肝内胆管癌 / CXCL12 / 転移 / cDNAマイクロアレイ / 免疫化学組織染色 / vivo / 予後不良 / Vivo / 胆管癌

Outline of Final Research Achievements

Intrahepatic cholangiocarcinoma (ICC) accounts for about 5-10% of primary liver cancers in Japan and is one of the poorest prognostic cancers with a high rate of recurrence after curative hepatic resection. The aim of this study was to elucidate the mechanism of metastasis and recurrence in ICC and to identify novel therapeutic targets. We evaluated resected specimens of primary and metastatic ICCs by cDNA microarray and immunohistochemical staining, and showed that CXCL12, which is one of chemokines, was significantly upregulated in liver metastases compared to primary tumors, and that the prognosis after liver resection was significantly worse in patients with high CXCL12 expression. In addition, we also showed that CXCL12 suppression in human cholangiocarcinoma cell lines suppressed their invasive and migratory potential, indicating that CXCL12 may be a potential therapeutic target in ICC.

Academic Significance and Societal Importance of the Research Achievements

肝内胆管癌 (ICC)は肝癌の約5－10%を占めており、肝切除後も高率に再発をきたす予後不良な癌の一つです。　我々は、ケモカインCXCL12が転移巣の切除標本で有意に高発現すること、肝切除後の予後に関与していること、ヒト胆管癌細胞株におけるCXCL12抑制による浸潤能及び遊走能が抑制効果を示し、CXCL12がICCにおける治療ターゲットになりうる可能性を示しました。

Research Products

• [Journal Article] Efficacy of delayed primary closure with intrawound continuous negative pressure and irrigation treatment after surgery for colorectal perforation (2021)
  • Author(s): Ogawa Katsuhiro、Nitta Hidetoshi、Masuda Toshiro、Matsumoto Katsutaka、Okino Tetsuya、Miyamoto Yuji、Baba Hideo、Takamori Hiroshi
  • Journal Title: Acute Medicine & Surgery Volume: 8 Issue: 1
  • DOI: 10.1002/ams2.633
  • Peer Reviewed / Open Access
• [Journal Article] Perforated Marginal Ulcer after Subtotal Stomach Preserving Pancreaticoduodenectomy-Report of Five Cases. (2020)
  • Author(s): Ogawa K, Shiraishi Y, Maruno M, Shimizu K, Karashima R, Nitta H, Masuda T, Matsumoto K, Ikuta Y, Okino T, Takamori H.
  • Journal Title: Gan To Kagaku Ryoho Volume: 47(1) Pages: 156-158
  • Peer Reviewed
• [Journal Article] Impact of resection margin status on survival in pancreatic cancer patients after neoadjuvant treatment and pancreatoduodenectomy (2020)
  • Author(s): Maeda Shimpei、Moore Alexandra M.、Yohanathan Lavanya、Hata Tatsuo、Truty Mark J.、Smoot Rory L.、Cleary Sean P.、Nagorney David M.、Grotz Travis E.、Park Eugene J.、Girgis Mark D.、Reber Howard A.、Motoi Fuyuhiko、Masuda Toshiro、Unno Michiaki、Kendrick Michael L.、Donahue Timothy R.
  • Journal Title: Surgery Volume: 167 Issue: 5 Pages: 803-811
  • DOI: 10.1016/j.surg.2019.12.008
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CXCL 12 expression in intrahepatic cholangiocarcinoma is associated with metastasis and poor prognosis (2019)
  • Author(s): Miyata Tatsunori、Yamashita Yo‐Ichi、Yoshizumi Tomoharu、Shiraishi Masayuki、Ohta Masayuki、Eguchi Susumu、Aishima Shinichi、Fujioka Hikaru、Baba Hideo
  • Journal Title: Cancer Science Volume: 110 Issue: 10 Pages: 3197-3203
  • DOI: 10.1111/cas.14151
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Usefulness of Perioperative C-reactive Protein/Albumin Ratio in Patients With Intrahepatic Cholangiocarcinoma: A Retrospective Single Institutional Study. (2019)
  • Author(s): Nakao Y, Yamashita YI, Arima K, Miyata T, Itoyama R, Yusa T, et al.
  • Journal Title: Anticancer research Volume: 39(5) Issue: 5 Pages: 2641-2646
  • DOI: 10.21873/anticanres.13388
  • Peer Reviewed
• [Presentation] International Observership Report (2018)
  • Author(s): Toshiro Masuda、Kenichi Ogata,Taishi Yamane,Hideaki Takeyama,Katsuhiro Ogawa,Hiromitsu Hayashi,Shinichi Akahoshi,Katsutaka Matsumoto,Yoshiaki Ikuta,Hiroshi Takamori
  • Organizer: 第30回日本肝胆膵外科学会学術集会
• [Presentation] Endoscopic Retrograde Gall Bladder Drainage followed by cholecystectomy for acute cholecystitis with more than 72 hours after its onset (2018)
  • Author(s): Toshiro Masuda、Kenichi Ogata,Taishi Yamane,Hideaki Takeyama,Katsuhiro Ogawa,Hiromitsu Hayashi,Shinichi Akahoshi,Katsutaka Matsumoto,Yoshiaki Ikuta,Hiroshi Takamori
  • Organizer: 第30回日本肝胆膵外科学会学術集会
• [Presentation] A benefit of laparoscopic approach in hepatic posterior sectionectomy (2018)
  • Author(s): Hiromitsu Hayashi、Yoshiaki Ikuta,Toshiro Masuda,Kenichi Ogata,Katsutaka Matsumoto,Shinichi Akaboshi,Katsuhiro Ogawa,Hideaki Takeyama,Taishi Yamane,Hiroshi Takamori
  • Organizer: 第30回日本肝胆膵外科学会学術集会
• [Presentation] 肝細胞癌再発に対して経横隔膜アプローチによる胸腔鏡下肝切除を行った1例 (2018)
  • Author(s): 林 洋光、生田義明、増田稔郎、緒方健一、松本克孝、赤星慎一、小川克大、武山秀晶、山根大侍、高森啓史：肝細胞癌再発に対して経横隔膜アプローチによる胸腔鏡下肝切除を行った1例
  • Organizer: 第111回日本消化器病学会九州支部例会・第105回日本消化器内視鏡学会九州支部例会
• [Presentation] 高齢者肝切除における栄養評価CONUTの臨床的意義 (2018)
  • Author(s): 光浦智証、林洋光、生田義明、赤星慎一、増田稔郎、緒方健一、松本克孝、小川克大、武山秀晶、山根大侍、高森啓史
  • Organizer: 第54回日本肝癌研究会
• [Presentation] 腔鏡下肝後区域切除のコツとピットホール ～定型化へ向けて～ (2018)
  • Author(s): 林 洋光、生田義明、増田稔郎、緒方健一、松本克孝、赤星慎一、小川克大、武山秀晶、山根大侍、高森啓史
  • Organizer: 第73回日本消化器外科学会総会
• [Presentation] 胆嚢管結石嵌頓による急性胆嚢炎に対する緊急手術症例の検討 (2018)
  • Author(s): 沖野哲也、松村和季、東孝暁、清水健次、小川克大、新田英利、赤星慎一、増田稔郎、松本克孝、生田義明、高森啓史、馬場秀夫
  • Organizer: 第80回日本臨床外科学会総会
• [Presentation] 抗血栓内服薬が膵頭十二指腸切除術の術後早期アウトカムに及ぼす影響 (2018)
  • Author(s): 生田義明、松村和季、東孝暁、清水健次、小川克大、新田英利、赤星慎一、増田稔郎、松本克孝、沖野哲也、高森啓史
  • Organizer: 第80回日本臨床外科学会総会
• [Presentation] 成人における小腸腫瘍33例の臨床病理学的検討 (2018)
  • Author(s): 清水健次、土居浩一、松村和季、東孝暁、小川克大、新田英利、増田稔郎、赤星慎一、松本克孝、生田義明、沖野哲也、高森啓史
  • Organizer: 第80回日本臨床外科学会総会
• [Presentation] 腹部手術歴を有する例に対する鏡視下肝切除の問題点と胸腔を活用したアプローチの工夫 (2018)
  • Author(s): 林 洋光、高森啓史、山下洋市、生田義明、増田稔郎、岡部弘尚、中川茂樹、今井克憲、近本亮、馬場秀夫
  • Organizer: 第31回日本内視鏡外科学会総会
• [Presentation] CXCL12 is involved in liver metastasis of intrahepatic cholangiocarcinoma (2018)
  • Author(s): Miyata T, Yamashita Y, Yoshizumi T, Shiraishi M, Ota M, Eguchi S, Aishima S, Baba H, Fujioka H
  • Organizer: The 27th Meeting of the Japanese Association of Metastasis and Research
• [Presentation] CXCL12 is involved in liver metastasis of intrahepatic cholangiocarcinoma (2018)
  • Author(s): Miyata T, Yamashita Y, Yoshizumi T, Shiraishi M, Ota M, Eguchi S, Aishima S, Baba H, Fujioka H
  • Organizer: The 72nd General Meeting of the Japanese Society of Gastroenterological Surgery
• [Presentation] CXCL12 is involved in liver metastasis of intrahepatic cholangiocarcinoma. (2018)
  • Author(s): Miyata T, Yamashita Y, Yoshizumi T, Shiraishi M, Ota M, Eguchi S, Aishima S, Baba H, Fujioka H
  • Organizer: The 30th Meeting of the Japanese Society of HBP Surgery
• [Presentation] CXCL12 is involved in liver metastasis of intrahepatic cholangiocarcinoma (2018)
  • Author(s): 4.Miyata T, Yamashita Y, Yoshizumi T, Shiraishi M, Ota M, Eguchi S, Aishima S, Baba H, Fujioka H
  • Organizer: The 77th Annual Meeting of the Japanese Cancer Association