Development of new colorectal cancer treatments through targeting the gut microbiota that influence antitumor immunity and the efficacy of cancer chemotherapies.

• Project/Area Number: 17H05094
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Digestive surgery
• Research Institution: Kumamoto University
• Principal Investigator: Mima Kosuke 熊本大学, 病院, 非常勤診療医師 (00546559)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2018: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2017: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
• Keywords: 大腸癌 / 肝転移 / 腸内細菌 / Fusobacterium nucleatum / 免疫 / MDSC / TAM / 免疫細胞 / CD8 / 腫瘍免疫 / 抗腫瘍免疫応答 / 大腸癌肝転移形成 / 縫合不全 / Bifidobacterium

Outline of Final Research Achievements

Accumulating evidence links the intestinal microbiota and colorectal carcinogenesis. Fusobacterium nucleatum (F. nucleatum) has been shown to potentiate colorectal tumor growth and inhibit antitumor immune responses. Emerging evidence demonstrates an enrichment of Fusobacterium species in colorectal cancer live metastasis (CRLM).
F. nucleatum was detected in 8 (4.4%) of 181 CRLM cases. Compared with F. nucleatum-negative cases, F. nucleatum-positive cases were significantly associated with low density of CD8+ T-cells (P =0.033), and higher density of myeloid-derived suppressor cell (P = 0.015) and tumor-associated macrophage (P = 0.027) in CRLM. Our data may have implications for preventing the formation of liver metastases from colorectal cancer through targeting intestinal microflora.

Academic Significance and Societal Importance of the Research Achievements

本邦における大腸癌の罹患率、死亡率は２０００年以降横ばいであるが依然として高く、癌種別死亡数は男性第３位、女性第１位である。大腸癌に関連した死亡の主な原因は遠隔転移であり、大腸癌の遠隔転移および再発形式として最も頻度が高い臓器が肝臓である。
本研究でFusobacterium nucleatumなどの腸内細菌が大腸癌肝転移巣における抗腫瘍免疫応答の抑制に関与している可能性があり、今後Fusobacterium nucleatumや腸内細菌を標的とした新しい大腸癌肝転移の予防および治療法の確立につながる可能性がある。

Research Products

• [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] Association of autophagy status with amount of Fusobacterium nucleatum in colorectal cancer (2020)
  • Author(s): Haruki K, Kosumi K, Hamada T, Twombly TS, Väyrynen JP, et al.
  • Journal Title: The Journal of Pathology Volume: 250 Issue: 4 Pages: 397-408
  • DOI: 10.1002/path.5381
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Metabolic Profiling of Formalin-Fixed Paraffin-Embedded Tissues Discriminates Normal Colon from Colorectal Cancer (2020)
  • Author(s): Arima K, Lau MC, Zhao M, Haruki K, Kosumi K, Mima K, Gu M, Väyrynen JP, Twombly TS, Baba Y, Fujiyoshi K, Kishikawa J, Guo C, Baba H, Richards WG, Chan AT, Nishihara R, Meyerhardt JA, Nowak JA, Giannakis M, Fuchs CS, Ogino S
  • Journal Title: Molecular Cancer Research Volume: - Issue: 6 Pages: 883-890
  • DOI: 10.1158/1541-7786.mcr-19-1091
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mucosal cancer-associated microbes and anastomotic leakage after resection of colorectal carcinoma (2020)
  • Author(s): Mima Kosuke、Sakamoto Yuki、Kosumi Keisuke、Ogata Yoko、Miyake Keisuke、Hiyoshi Yukiharu、Ishimoto Takatsugu、Iwatsuki Masaaki、Baba Yoshifumi、Iwagami Shiro、Miyamoto Yuji、Yoshida Naoya、Ogino Shuji、Baba Hideo
  • Journal Title: Surgical Oncology Volume: 32 Pages: 63-68
  • DOI: 10.1016/j.suronc.2019.11.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Advanced Age Is a Risk Factor for Recurrence After Resection in Stage II Colorectal Cancer (2019)
  • Author(s): MIMA KOSUKE、KURASHIGE JUNJI、MIYANARI NOBUTOMO、MORITO ATSUSHI、YUMOTO SHINSEI、MATSUMOTO TAKASHI、KOSUMI KEISUKE、INOUE MITSUHIRO、MIZUMOTO TAKAO、KUBOTA TATSUO、BABA HIDEO
  • Journal Title: In Vivo Volume: 34 Issue: 1 Pages: 339-346
  • DOI: 10.21873/invivo.11779
  • Peer Reviewed
• [Journal Article] Interval laparoscopic appendectomy after antibiotic therapy for appendiceal abscess in elderly patients (2019)
  • Author(s): Mima Kosuke、Miyanari Nobutomo、Itoyama Rumi、Nakao Yosuke、Kato Rikako、Shigaki Hironobu、Kurashige Junji、Inoue Mitsuhiro、Iwagami Shiro、Mizumoto Takao、Kubota Tatsuo、Baba Hideo
  • Journal Title: Asian Journal of Endoscopic Surgery Volume: - Issue: 3 Pages: 311-318
  • DOI: 10.1111/ases.12758
  • Peer Reviewed
• [Journal Article] The gut microbiome, antitumor immunity, and liver cancer (2019)
  • Author(s): Mima Kosuke、Baba Hideo
  • Journal Title: HepatoBiliary Surgery and Nutrition Volume: 8 Issue: 1 Pages: 67-68
  • DOI: 10.21037/hbsn.2018.11.09
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic association of PTGS2 (COX-2) over-expression according to BRAF mutation status in colorectal cancer: Results from two prospective cohorts and CALGB 89803 (Alliance) trial (2019)
  • Author(s): Kosumi K, Hamada T, Zhang S, Liu L, da Silva A, Koh H, Twombly TS, Mima K, Morikawa T, Song M, Nowak JA, Nishihara R, Saltz LB, Niedzwiecki D, Ou FS, Zemla T, Mayer RJ, Baba H, Ng K, Giannakis M, Zhang X, Wu K, Giovannucci EL, Chan AT, Fuchs CS, Meyerhardt JA, Ogino S
  • Journal Title: European Journal of Cancer Volume: 111 Pages: 82-93
  • DOI: 10.1016/j.ejca.2019.01.022
  • Peer Reviewed
• [Journal Article] Dysbiosis of the gut microbiota and colorectal cancer: the key target of molecular pathological epidemiology (2018)
  • Author(s): Kosumi Keisuke、Mima Kosuke、Baba Hideo、Ogino Shuji
  • Journal Title: Journal of Laboratory and Precision Medicine Volume: 3 Pages: 76-76
  • DOI: 10.21037/jlpm.2018.09.05
  • Peer Reviewed / Open Access
• [Journal Article] Fusobacterium nucleatum in Colorectal Cancer Relates to Immune Response Differentially by Tumor Microsatellite Instability Status (2018)
  • Author(s): Hamada T, Zhang X, Mima K, Bullman S, Sukawa Y, Nowak JA, Kosumi K, Masugi Y, Twombly TS, Cao Y, Song M, Liu L, da Silva A, Shi Y, Gu M, Li W, Koh H, Nosho K, Inamura K, Keum N, Wu K, Meyerhardt JA, Kostic AD, Huttenhower C, Garrett WS, Meyerson M, Giovannucci EL, Chan AT, Fuchs CS, Nishihara R, Giannakis M, Ogino S
  • Journal Title: Cancer Immunology Research Volume: 6 Issue: 11 Pages: 1327-1336
  • DOI: 10.1158/2326-6066.cir-18-0174
  • Peer Reviewed
• [Journal Article] Vitamin D status after colorectal cancer diagnosis and patient survival according to immune response to tumour (2018)
  • Author(s): Hamada T, Liu L, Nowak JA, Mima K, Cao Y, Ng K, Twombly TS, Song M, Jung S, Dou R, Masugi Y, Kosumi K, Shi Y, da Silva A, Gu M, Li W, Keum N, Wu K, Nosho K, Inamura K, Meyerhardt JA, Nevo D, Wang M, Giannakis M, Chan AT, Giovannucci EL, Fuchs CS, Nishihara R, Zhang X, Ogino S
  • Journal Title: European Journal of Cancer Volume: 103 Pages: 98-107
  • DOI: 10.1016/j.ejca.2018.07.130
  • Peer Reviewed
• [Journal Article] Smoking and Risk of Colorectal Cancer Sub-Classified by Tumor-Infiltrating T Cells (2018)
  • Author(s): Hamada T, Nowak JA, Masugi Y, Drew DA, Song M, Cao Y, Kosumi K, Mima K, Twombly TS, Liu L, Shi Y, da Silva A, Gu M, Li W, Nosho K, Keum N, Giannakis M, Meyerhardt JA, Wu K, Wang M, Chan AT, Giovannucci EL, Fuchs CS, Nishihara R, Zhang X, Ogino S
  • Journal Title: JNCI: Journal of the National Cancer Institute Volume: 111 Issue: 1 Pages: 42-51
  • DOI: 10.1093/jnci/djy137
  • Peer Reviewed
• [Journal Article] Continuity of transcriptomes among colorectal cancer subtypes based on meta-analysis (2018)
  • Author(s): Ma Siyuan、Ogino Shuji、Parsana Princy、Nishihara Reiko、Qian Zhirong、Shen Jeanne、Mima Kosuke、Masugi Yohei、Cao Yin、Nowak Jonathan A.、Shima Kaori、Hoshida Yujin、Giovannucci Edward L.、Gala Manish K.、Chan Andrew T.、Fuchs Charles S.、Parmigiani Giovanni、Huttenhower Curtis、Waldron Levi
  • Journal Title: Genome Biology Volume: 19 Issue: 1 Pages: 142-142
  • DOI: 10.1186/s13059-018-1511-4
  • Peer Reviewed
• [Journal Article] The Amount of Bifidobacterium Genus in Colorectal Carcinoma Tissue in Relation to Tumor Characteristics and Clinical Outcome (2018)
  • Author(s): Kosumi K,Hamada T,Koh H,Borowsky J,Bullman S,Twombly TS,Nevo D,Masugi Y,Liu L,da Silva A,Chen Y,Du C,Gu M,Li C,Li W,Liu H,Shi Y,Mima K,Song M,Nosho K,Nowak JA,Nishihara R,Baba H,Zhang X,Wu K,Wang M,Huttenhower C,Garrett WS,Meyerson ML,Lennerz JK,Giannakis M,Chan AT,Meyerhardt JA,Fuchs CS,Ogino S
  • Journal Title: The American Journal of Pathology Volume: 188 Issue: 12 Pages: 2839-2852
  • DOI: 10.1016/j.ajpath.2018.08.015
  • Peer Reviewed
• [Journal Article] The role of intestinal bacteria in the development and progression of gastrointestinal tract neoplasms. (2017)
  • Author(s): Mima K, Ogino S, Nakagawa S, Sawayama H, Kinoshita K, Krashima R, Ishimoto T, Imai K, Iwatsuki M, Hashimoto D, Baba Y, Sakamoto Y, Yamashita YI, Yoshida N, Chikamoto A, Ishiko T, Baba H
  • Journal Title: Surg Oncol Volume: 26(4) Issue: 4 Pages: 368-376
  • DOI: 10.1016/j.suronc.2017.07.011
  • Peer Reviewed / Open Access
• [Presentation] Tissue Microbes and Anastomotic Leakage after Resection of Colorectal Carcinoma. (2019)
  • Author(s): Kosuke Mima, Keisuke Kosumi, Yuki Sakamoto, Yoko Ogata, Keisuke Miyake, Yukiharu Hiyoshi, Takatsugu Ishimoto, Masaaki Iwatsuki, Yoshifumi Baba, Shiro Iwagami, Yuji Miyamoto, Naoya Yoshida, Shuji Ogino, Hideo Baba
  • Organizer: SSO 2019-Society of Surgical Oncology Annual Cancer Symposium
  • Int'l Joint Research
• [Presentation] 大腸癌肝転移巣における細菌Fusobacterium nucleatumとCD8陽性T細胞数との関連 (2019)
  • Author(s): 美馬浩介、坂本悠樹、江藤弘二郞、日吉幸晴、今井克憲、岩槻政晃、石本崇胤、岩上志朗、馬場祥史、宮本裕士、山下洋市、吉田直矢、馬場秀夫
  • Organizer: 第４０回癌免疫外科研究会
• [Presentation] Microbiota and gastrointestinal cancer (2019)
  • Author(s): Kosuke Mima, Yuki Sakamoto, Hideo Baba
  • Organizer: The microbiome Cancer and Cancer Therapy
  • Int'l Joint Research / Invited
• [Presentation] 実地臨床における75歳以上の後期高齢者に対する膵頭十二指腸切除術の安全性の検討 (2019)
  • Author(s): 美馬 浩介、松本 千尋、加藤 梨佳子、藏重 淳二、井上 光弘、水元 孝郎、久保田 竜生、宮成 信友、馬場秀夫
  • Organizer: 第31回日本肝胆膵外科学会学術集会
• [Presentation] 本邦実地臨床おける高齢者Stage II大腸癌の臨床的特徴と予後の検討 (2019)
  • Author(s): 美馬 浩介、松本 千尋、加藤 梨佳子、藏重 淳二、井上 光弘、水元 孝郎、久保田 竜生、宮成 信友、馬場 秀夫
  • Organizer: 第74回日本消化器外科学会総会
• [Presentation] 腹腔鏡下鼠径ヘルニア修復術を契機に発見され、切除し得た高分化型後腹膜脂肪肉腫の１例 (2019)
  • 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、馬場 秀夫、宮成 信友
  • Organizer: 第32回日本内視鏡外科学会総会
• [Presentation] Relationship between Fusobacterium nucleatum and formation and immune response in colorectal cancer liver metastasis. (2019)
  • Author(s): Yuki Sakamoto, Kosuke Mima, Nobuya Daitoku, Yukiharu Hiyoshi, Katsunori Imai, Masaaki Iwatsuki, Takatsugu Ishimoto, Yoshifumi Baba, Shiro Iwagami, Yuji Miyamoto, Yoichi Yamashita, Naoya Yoshida, Hideo Baba
  • Organizer: AACR Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] Fusobacterium nucleatum in colorectal cancer liver metastasis and patient prognosis. (2018)
  • Author(s): Yuki Sakamoto, Kosuke Mima, Nobuya Daitoku, Yukiharu Hiyoshi, Katsunori Imai, Masaaki Iwatsuki, Shiro Iwagami, Yoshifumi Baba, Yuji Miyamoto, Yoichi Yamashita, Naoya Yoshida, Hideo Baba
  • Organizer: 第29回日本消化器癌発生学会
• [Presentation] Fusobacterium nucleatum in colorectal cancer liver metastasis is associated with poor prognosis. (2018)
  • Author(s): Yuki Sakamoto, Kosuke Mima, Nobuya Daitoku, Yukiharu Hiyoshi, Katsunori Imai, Masaaki Iwatsuki, Shiro Iwagami, Yoshifumi Baba, Yuji Miyamoto, Yoichi Yamashita, Naoya Yoshida, Hideo Baba
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 腸内細菌を標的とした大腸癌切除後の縫合不全予防の可能性 (2018)
  • Author(s): 美馬浩介、坂本悠樹、澤山 浩、日吉幸晴、岩槻政晃、石本崇胤、馬場祥史、宮本裕士、吉田直矢、馬場秀夫
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] 大腸癌における細菌Fusobacterium nucleatumと腫瘍発生部位、分子異常との関係 (2017)
  • Author(s): 美馬浩介、Reiko Nishihara、Zhi Rong Qian、荻野周史 、馬場秀夫
  • Organizer: 第72回日本消化器外科学会総会