Development of new treatments of non-viral hepatocellular carcinoma through targeting microbiota

• Project/Area Number: 20K17658
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kumamoto University
• Principal Investigator: Mima Kosuke 熊本大学, 病院, 特任助教 (00546559)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 肝細胞癌 / 肝転移 / 腸内細菌 / 免疫細胞 / フレイル / Fusobacterium nucleatum / 日常生活自立度 / 非B非C型 / 糖尿病 / 免疫

Outline of Research at the Start

熊本大学消化器外科では年間500例以上の消化器癌手術が行われ、600例以上の肝癌切除例の切除標本が凍結組織、パラフィン包埋組織として管理されている。さらに手術のみならず、患者背景、腫瘍因子、手術因子、化学療法、生活背景、予後がデータベースに管理されている。本研究では多数例のヒト非B非C型肝細胞癌組織中の細菌叢や腸内細菌叢を網羅的に解析し、臨床データと組み合わせて解析することで非B非C型肝細胞癌の進展や抗腫瘍免疫応答に関わる細菌の同定を試みる。さらにマウスモデルを用いて、そのメカニズムを解明する。本研究結果は細菌を標的とした非B非C肝細胞癌に対する新たな治療法の開発につながることが期待される。

Outline of Final Research Achievements

Evidence suggests that the gut microbiome inhibits antitumor immune responses and promotes the development of gastrointestinal cancer. The liver is exposed to bacteria via blood through the portal vein has many immune cells such as T-cells and macrophages. We found that high TAN (tumor associated neutrophils) (p=0.0398), low CD8+ cells (p=0.0275), and high TAM (tumor associated macrophages) (p=0.001) were significantly associated with worse overall survival (OS), and that high TAN (p=0.010), and high TAM (p=0.00125) were significantly associated with worse disease-free survival (DFS).

Academic Significance and Societal Importance of the Research Achievements

肝細胞癌は、本邦はもちろん国際的に罹患数・死亡数が多い癌で、予後不良の疾患である。近年本邦において　肝炎ウイルス感染を伴わない肝細胞癌が増加している。本研究により、肝細胞癌組織中の免疫細胞が肝細胞癌の発育進展に重要な役割を果たしていることが明らかとなり、本研究の成果は細菌を標的とした非B非C型肝細胞癌の新たな治療法の開発のための有益な情報となることが期待される。

Research Products

• [Journal Article] Clinical significance of preoperative inflammation-based score for the prognosis of patients with hepatocellular carcinoma who underwent hepatectomy (2022)
  • Author(s): Matsumoto Takashi、Kitano Yuki、Imai Katsunori、Kinoshita Shotaro、Sato Hiroki、Shiraishi Yuta、Mima Kosuke、Hayashi Hiromitsu、Yamashita Yo-ichi、Baba Hideo
  • Journal Title: Surgery Today Volume: - Issue: 7 Pages: 1008-1015
  • DOI: 10.1007/s00595-021-02427-x
  • Peer Reviewed
• [Journal Article] Relationship between Fusobacterium nucleatum and antitumor immunity in colorectal cancer liver metastasis (2021)
  • Author(s): Sakamoto Yuki、Mima Kosuke、Ishimoto Takatsugu、Ogata Yoko、Imai Katsunori、Miyamoto Yuji、Akiyama Takahiko、Daitoku Nobuya、Hiyoshi Yukiharu、Iwatsuki Masaaki、Baba Yoshifumi、Iwagami Shiro、Yamashita Yo‐ichi、Yoshida Naoya、Komohara Yoshihiro、Ogino Shuji、Baba Hideo
  • Journal Title: Cancer Science Volume: 112 Issue: 11 Pages: 4470-4477
  • DOI: 10.1111/cas.15126
  • Peer Reviewed
• [Journal Article] Preoperative iron status is a prognosis factor for stage II and III colorectal cancer (2021)
  • Author(s): Sawayama Hiroshi、Miyamoto Yuji、Mima Kosuke、Kato Rikako、Ogawa Katsuhiro、Hiyoshi Yukiharu、Shimokawa Mototsugu、Akiyama Takahiko、Kiyozumi Yuki、Iwagami Shiro、Iwatsuki Masaaki、Baba Yoshifumi、Yoshida Naoya、Baba Hideo
  • Journal Title: International Journal of Clinical Oncology Volume: 26 Issue: 11 Pages: 2037-2045
  • DOI: 10.1007/s10147-021-01995-9
  • Peer Reviewed
• [Journal Article] The Sulfur Microbial Diet and Risk of Colorectal Cancer by Molecular Subtypes and Intratumoral Microbial Species in Adult Men (2021)
  • Author(s): Sikavi DR, Nguyen LH, Haruki K, Ugai T, Ma W, Wang DD, Thompson KN, Yan Y, Branck T, Wilkinson JE, Akimoto N, Zhong R, Lau MC, Mima K, Kosumi K, Morikawa T, Rimm EB, Garrett WS, Izard J, Cao Y, Song M, Huttenhower C, Ogino S, Chan AT.
  • Journal Title: Clinical and Translational Gastroenterology Volume: 12 Issue: 8 Pages: e00338-e00338
  • DOI: 10.14309/ctg.0000000000000338
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Frailty is associated with poor prognosis after resection for pancreatic cancer (2021)
  • Author(s): Mima Kosuke、Hayashi Hiromitsu、Nakagawa Shigeki、Matsumoto Takashi、Kinoshita Shotaro、Matsumura Kazuki、Kitamura Fumimasa、Uemura Norio、Nakao Yosuke、Itoyama Rumi、Kaida Takayoshi、Imai Katsunori、Yamashita Yo-ichi、Baba Hideo
  • Journal Title: International Journal of Clinical Oncology Volume: 26 Issue: 10 Pages: 1938-1946
  • DOI: 10.1007/s10147-021-01983-z
  • Peer Reviewed
• [Journal Article] Impairment of Activities of Daily Living is an Independent Risk Factor for Recurrence and Mortality Following Curative Resection of Stage I?III Colorectal Cancer (2021)
  • Author(s): Mima Kosuke、Kosumi Keisuke、Miyanari Nobutomo、Tajiri Takuya、Kanemitsu Kosuke、Takematsu Toru、Inoue Mitsuhiro、Mizumoto Takao、Kubota Tatsuo、Baba Hideo
  • Journal Title: Journal of Gastrointestinal Surgery Volume: － Issue: 10 Pages: 2628-2636
  • DOI: 10.1007/s11605-021-04990-7
  • Peer Reviewed
• [Journal Article] Association of Fusobacterium nucleatum with Specific T-cell Subsets in the Colorectal Carcinoma Microenvironment (2021)
  • Author(s): Borowsky J, Mima K, Ogino S et al.
  • Journal Title: Clinical Cancer Research Volume: － Issue: 10 Pages: 2816-26
  • DOI: 10.1158/1078-0432.ccr-20-4009
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The efficacy of adjuvant chemotherapy for resected high-risk stage II and stage III colorectal cancer in frail patients (2021)
  • Author(s): Mima Kosuke、Miyanari Nobutomo、Kosumi Keisuke、Tajiri Takuya、Kanemitsu Kosuke、Takematsu Toru、Inoue Mitsuhiro、Mizumoto Takao、Kubota Tatsuo、Baba Hideo
  • Journal Title: International Journal of Clinical Oncology Volume: － Issue: 5 Pages: 903-912
  • DOI: 10.1007/s10147-021-01876-1
  • Peer Reviewed
• [Journal Article] Surgical resection of a ruptured transverse pancreatic artery aneurysm (2021)
  • Author(s): Takematsu Toru、Kosumi Keisuke、Tajiri Takuya、Kanemitsu Kosuke、Mima Kosuke、Inoue Mitsuhiro、Mizumoto Takao、Kubota Tatsuo、Miyanari Nobutomo、Baba Hideo
  • Journal Title: Surgical Case Reports Volume: 7 Issue: 1
  • DOI: 10.1186/s40792-021-01128-4
  • Peer Reviewed
• [Journal Article] Patient Age and Long-term Survival in Colorectal Cancer Patients Who Undergo Emergency Surgery (2021)
  • Author(s): KOSUMI KEISUKE、MIMA KOSUKE、MORITO ATSUSHI、YUMOTO SHINSEI、MATSUMOTO TAKASHI、INOUE MITSUHIRO、MIZUMOTO TAKAO、KUBOTA TATSUO、MIYANARI NOBUTOMO、BABA HIDEO
  • Journal Title: Anticancer Research Volume: 41 Issue: 2 Pages: 1069-1076
  • DOI: 10.21873/anticanres.14864
  • Peer Reviewed
• [Journal Article] Frailty is an independent risk factor for recurrence and mortality after curative resection in patients with stage I-III colorectal cancer (2020)
  • Author(s): Mima K, Kurashige J, Miyanari N, Morito A, Yumoto S, Matsumoto T, Kosumi K, Inoue M, Mizumoto T, Kubota T, Baba H
  • Journal Title: Ann Gastroenterol Surg Volume: - Issue: 4 Pages: 405-412
  • DOI: 10.1002/ags3.12337
  • Peer Reviewed / Open Access
• [Journal Article] The microbiome, genetics, and gastrointestinal neoplasms: the evolving field of molecular pathological epidemiology to analyze the tumor?immune?microbiome interaction (2020)
  • Author(s): Mima Kosuke、Kosumi Keisuke、Baba Yoshifumi、Hamada Tsuyoshi、Baba Hideo、Ogino Shuji
  • Journal Title: Human Genetics Volume: － Issue: 5 Pages: 725-746
  • DOI: 10.1007/s00439-020-02235-2
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Usefulness of laparoscopy in the management of incidentally discovered retroperitoneal liposarcoma mimicking inguinal hernia: A case report and literature review (2020)
  • Author(s): Matsumoto Takashi、Mima Kosuke、Ono Asuka、Miyanari Nobutomo、Morito Atsushi、Yumoto Shinsei、Kosumi Keisuke、Inoue Mitsuhiro、Mizumto Takao、Kubota Tatsuo、Baba Hideo
  • Journal Title: International Journal of Surgery Case Reports Volume: 72 Pages: 79-84
  • DOI: 10.1016/j.ijscr.2020.05.064
  • Peer Reviewed
• [Journal Article] Preoperative C-reactive protein-to-albumin ratio and clinical outcomes after resection of colorectal liver metastases (2020)
  • Author(s): Sakamoto Yuki、Mima Kosuke、Imai Katsunori、Miyamoto Yuji、Tokunaga Ryuma、Akiyama Takahiko、Daitoku Nobuya、Hiyoshi Yukiharu、Iwatsuki Masaaki、Nagai Yohei、Baba Yoshifumi、Iwagami Shiro、Yamashita Yo-ichi、Yoshida Naoya、Baba Hideo
  • Journal Title: Surgical Oncology Volume: 35 Pages: 243-248
  • DOI: 10.1016/j.suronc.2020.09.014
  • Peer Reviewed
• [Presentation] 腸内細菌や口腔細菌を標的とした大腸癌術後の縫合不全予防と免疫微小環境を介した肝転移に対する新規予防・治療の可能性 (2022)
  • Author(s): 美馬 浩介、坂本 悠樹、今井 克憲、石本 崇胤、甲斐田 剛圭、中川 茂樹、澤山 浩、林 洋光、宮本 裕士、吉田 直矢、山下 洋市、馬場 秀夫
  • Organizer: 第122回日本外科学会定期学術集会
• [Presentation] 肝細胞癌における免疫細胞の局在と相互関与が予後に与える影響についての検討 (2022)
  • Author(s): 遊佐 俊彦、山下 洋市、甲斐田 剛圭、美馬 浩介、中川 茂樹、林 洋光、今井 克憲、馬場 秀夫
  • Organizer: 第122回日本外科学会定期学術集会
• [Presentation] Preoperative impairment of activities of daily living is a risk factor for mortality following resection of hepatocellular carcinoma (2021)
  • Author(s): Kosuke Mima, Katsunori Imai, Shigeki Nakagawa, Takashi Matsumoto, Shotaro Kinoshita, Kazuki Matsumura, Fumimasa Kitamura, Norio Uemura, Takayoshi Kaida, Hiromitsu Hayashi, Yo-ichi Yamashita, Hideo Baba
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] Frailを有するStage II/III大腸癌患者の臨床的特徴と予後の検討 (2020)
  • Author(s): 美馬 浩介、森戸 淳、湯本 信成、松本 嵩史、小澄 敬祐、井上 光弘、水元 孝郎、久保田 竜生、宮成 信友、馬場 秀夫
  • Organizer: 第120回日本外科学会定期学術集会
• [Presentation] 高齢者やフレイルを有する患者に対する膵切除の安全性の検討 (2020)
  • Author(s): 美馬 浩介、宮成 信友、森戸 淳、湯本 信成、松本 嵩史、小澄 敬祐、井上 光弘、水元 孝郎、久保田 竜生、馬場 秀夫
  • Organizer: 第32回日本肝胆膵外科学会学術集会
• [Presentation] フレイルを有するStage II/III大腸癌患者に対する術後補助化学療法の有効性の検討 (2020)
  • Author(s): 美馬 浩介、森戸 淳、湯本 信成、松本 嵩史、小澄 敬祐、井上 光弘、水元 孝郎、久保田 竜生、宮成 信友、馬場 秀夫
  • Organizer: 第75回日本消化器外科学会総会
• [Presentation] 75歳以上の高齢者大腸癌における再発危険因子、予後不良因子の検討 (2020)
  • Author(s): 美馬 浩介、森戸 淳、湯本 信成、松本 嵩史、小澄 敬祐、井上 光弘、水元 孝郎、久保田 竜生、宮成 信友、馬場 秀夫
  • Organizer: 第18回日本消化器外科学会大会（JDDW 2020）
• [Presentation] Surgical and oncological outcomes of laparoscopic surgery for colorectal cancer in frail patients (2020)
  • Author(s): Kosuke Mima, Nobutomo Miyanari, Atsushi Morito, Shinsei Yumoto, Takashi Matsumoto, Keisuke Kosumi, Mitsuhiro Inoue, Takao Mizumoto, Tatsuo Kubota, Hideo Baba
  • Organizer: 第17回世界内視鏡外科学会、第33回日本内視鏡外科学会
  • Int'l Joint Research