New therapeutic strategy against neutrophil in the tumor microenvironment of colon cancer

• Project/Area Number: 18K07196
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kyoto University
• Principal Investigator: Itatani Yoshiro 京都大学, 医学研究科, 助教 (80814029)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 大腸癌 / 腫瘍微小環境 / 好中球 / 血管新生 / マウスモデル / .腫瘍微小環境

Outline of Final Research Achievements

In this study, we tried to reveal tumor promotive function of neutrophils in the tumor microenvironment of colon cancer, using mouse models of colon cancer. Neutrophil is one of the important host immune cells. However, it is also known that neutrophils promote tumor progression in the tumor microenvironment. It becomes an attractive therapeutic strategy to suppress only tumor promotive function of the neutrophils without affecting protective function against infection. CMS4 colon cancer shows poor prognosis, with resistance to anti-VEGF treatment. We found that neutrophils accumulated in the tumor microenvironment of CMS4 mouse colon cancer, secreting Bv8 angiogenic factor. When treating anti-Bv8 antibody in addition to anti VEGF antibody, tumor formation of CMS4 mouse colon cancer was suppressed.

Academic Significance and Societal Importance of the Research Achievements

CMS4大腸癌は予後不良で、大腸癌治療のキードラッグの抗VEGF治療に抵抗性を示すことが知られている。今回我々の研究では、CMS4大腸癌の抗VEGF治療耐性に好中球が深く関与すること、好中球由来の血管新生因子Bv8をVEGFとともに阻害することで、抗VEGF治療耐性が解除されることを、自然発生大腸癌マウスモデルを用いることで、より実臨床に近い環境で解明した。本邦において、大腸癌はがん死亡数では肺癌に次ぐ２番目の死亡数で、最新がん統計によると2019年は約5万人が大腸癌で死亡したとされる。本研究結果が臨床応用されれば、これらの患者の治療に有用である可能性がある。

Research Products

• [Journal Article] Combination of lymphocyte count and albumin concentration as a new prognostic biomarker for rectal cancer (2021)
  • Author(s): Yamamoto Takehito、Kawada Kenji、Hida Koya、Matsusue Ryo、Itatani Yoshiro、Mizuno Rei、Yamaguchi Takashi、Ikai Iwao、Sakai Yoshiharu
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 5027-5027
  • DOI: 10.1038/s41598-021-84475-4
  • Peer Reviewed / Open Access
• [Journal Article] Suppressing neutrophil-dependent angiogenesis abrogates resistance to anti-VEGF antibody in a genetic model of colorectal cancer (2020)
  • Author(s): Itatani Yoshiro、Yamamoto Takamasa、Zhong Cuiling、Molinolo Alfredo A.、Ruppel Jane、Hegde Priti、Taketo M. Mark、Ferrara Napoleone
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 117 Issue: 35 Pages: 21598-21608
  • DOI: 10.1073/pnas.2008112117
  • Peer Reviewed / Open Access
• [Journal Article] Disruption of CCR1-mediated myeloid cell accumulation suppresses colorectal cancer progression in mice (2020)
  • Author(s): Kiyasu Yoshiyuki、Kawada Kenji、Hirai Hideyo、Ogawa Ryotaro、Hanada Keita、Masui Hideyuki、Nishikawa Gen、Yamamoto Takamasa、Mizuno Rei、Itatani Yoshiro、Kai Masayuki、Taketo Makoto Mark、Sakai Yoshiharu
  • Journal Title: Cancer Letters Volume: 487 Pages: 53-62
  • DOI: 10.1016/j.canlet.2020.05.028
  • NAID: 120006878497
  • Peer Reviewed
• [Journal Article] Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression via CCR5. (2019)
  • Author(s): Nishikawa G, Kawada K, Nakagawa J, Toda K, Ogawa R, Inamoto S, Mizuno R, Itatani Y, Sakai Y.
  • Journal Title: Cell Death & Disease Volume: 10 Issue: 4 Pages: 264-264
  • DOI: 10.1038/s41419-019-1508-2
  • NAID: 120006596558
  • Peer Reviewed / Open Access
• [Journal Article] F-Box/WD Repeat Domain-Containing 7 Induces Chemotherapy Resistance in Colorectal Cancer Stem Cells. (2019)
  • Author(s): Honma S, Hisamori S, Nishiuchi A, Itatani Y, Obama K, Shimono Y, Sakai Y.
  • Journal Title: Cancers Volume: 11 Issue: 5 Pages: 635-635
  • DOI: 10.3390/cancers11050635
  • NAID: 120006644046
  • Peer Reviewed / Open Access
• [Journal Article] Transforming Growth Factor-β Signaling Pathway in Colorectal Cancer and Its Tumor Microenvironment. (2019)
  • Author(s): Itatani Y, Kawada K, Sakai Y.
  • Journal Title: Int J Mol Sci Volume: 20 Issue: 23 Pages: 5822-5822
  • DOI: 10.3390/ijms20235822
  • NAID: 120006895434
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-9-5p-CDX2 Axis: A Useful Prognostic Biomarker for Patients with Stage II/III Colorectal Cancer. (2019)
  • Author(s): Nishiuchi A, Hisamori S, Sakaguchi M, Fukuyama K, Hoshino N, Itatani Y, Honma S, Maekawa H, Nishigori T, Tsunoda S, Obama K, Miyoshi H, Shimono Y, Taketo MM, Sakai Y.
  • Journal Title: Cancers (Basel) Volume: 11 Issue: 12 Pages: 1891-1891
  • DOI: 10.3390/cancers11121891
  • NAID: 120006846477
  • Peer Reviewed / Open Access
• [Journal Article] The Role of Tumor-Associated Neutrophils in Colorectal Cancer (2019)
  • Author(s): Mizuno Rei、Kawada Kenji、Itatani Yoshiro、Ogawa Ryotaro、Kiyasu Yoshiyuki、Sakai Yoshiharu
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 3 Pages: 529-529
  • DOI: 10.3390/ijms20030529
  • NAID: 120006552928
• [Journal Article] Resistance to Anti-Angiogenic Therapy in Cancer?Alterations to Anti-VEGF Pathway (2018)
  • Author(s): Itatani Yoshiro、Kawada Kenji、Yamamoto Takamasa、Sakai Yoshiharu
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 4 Pages: 1232-1232
  • DOI: 10.3390/ijms19041232
  • NAID: 120006510294
• [Presentation] 大腸癌腫瘍微小環境でのサイトカイン/ケモカインネットワークと腫瘍免疫 (2019)
  • Author(s): 板谷喜朗
  • Organizer: 日本外科学会