Molecular pathophysiological role of CX3CR1+ monocytes in the development of colitis-associated colon cancer

• Project/Area Number: 19K08442
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Mie University
• Principal Investigator: Masuya Masahiro 三重大学, 医学系研究科, 教授 (30281083)
• Project Period (FY): 2019-04-01 – 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); 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)
• Keywords: 単球 / マクロファージ / CX3CR1 / 大腸炎関連大腸癌 / AOM/DSS / 大腸癌 / 大腸腫瘍 / monocyte / fibrocyte / colon cancer

Outline of Research at the Start

CX3CR1GFP/+骨髄キメラマウスでは、CX3CR1の機能を有する造血細胞がGFP陽性細胞としてフローサイトメトリーや蛍光免疫組織染色で容易に同定できる。CX3CR1GFP/GFP骨髄キメラマウスではCX3CR1の機能が完全に喪失するので、この両骨髄キメラマウスにAOM/DSS傷害を与えて比較検討することで、（a）マクロファージ、線維細胞などの骨髄由来単球系細胞の変化、（b）Th1/Th17/TregなどのTリンパ球亜群の変化を大腸腫瘍と非腫瘍部で解析できるとともに、(c)CX3CR1の機能喪失により、AOM/DSS傷害に伴う大腸線維化や腫瘍形成が減弱するのか増強するのかを明らかにできる。

Outline of Final Research Achievements

We prepared bone marrow (BM) chimeric mice, which were reconstituted with BM cells derived from wild-type (WT) or C-X3-C motif chemokine receptor 1 (CX3CR1)-deficient mice. Azoxymethane/dextran sodium sulfate (AOM/DSS) treatment started 8 weeks after BM transplantation and the DSS treatment was repeated for three cycles. At 20 weeks after the initiation of AOM, in CX3CR1-deficient BM chimeric mice compared with in WT BM chimeric mice, (1) the number of colon tumors was significantly reduced, (2) the number of CX3CR1high macrophages in the colonic lamina propria and mRNA expression level of Tnfa, Il1b, and Tgfb in the colon tissue decreased, (3) serum levels of TNF-α, IL-1β, and TGF-β were significantly lower. Therefore, CX3CR1high macrophages derived from BM are thought to be associated with the development of colon tumors by the production of inflammatory and anti-inflammatory cytokines during the colon inflammation.

Academic Significance and Societal Importance of the Research Achievements

炎症性腸疾患患者の診療で重要な課題は、慢性炎症による大腸癌の発症・進展である。骨髄由来の単球から派生するM2マクロファージなどの免疫を負に調節する細胞は癌発症・進展に関与すると考えられている。がん治療の場では免疫チェックポイント阻害剤による細胞傷害性T細胞の抗腫瘍効果増強が注目されているが、我々はケモカインCX3CL1による単球の炎症部位への動員と炎症部位で分化したマクロファージからの炎症性及び抗炎症性サイトカイン産生を制御することが大腸炎関連大腸癌の発症を抑制することを明らかにした。このことは炎症性腸疾患患者の大腸癌発症予防法開発に繋がると期待される。

Research Products

• [Journal Article] Irbesartan, an angiotensin II type 1 receptor blocker, inhibits colitis-associated tumourigenesis by blocking the MCP-1/CCR2 pathway. (2021)
  • Author(s): Hachiya K, Masuya M, Kuroda N, Yoneda M, Tsuboi J, Nagaharu K, Nishimura K, Shiotani T, Ohishi K, Tawara I, Katayama N.
  • Journal Title: Sci Rep Volume: 11 Issue: 1 Pages: 19943-19943
  • DOI: 10.1038/s41598-021-99412-8
  • Peer Reviewed / Open Access
• [Journal Article] Tet1 is not required for myeloid leukemogenesis by MLL-ENL in novel mouse models. (2021)
  • Author(s): Ono R, Masuya M, Inoue N, Shinmei M, Ishii S, Maegawa Y, Maharjan BD, Katayama N, Nosaka T.
  • Journal Title: PLosONE Volume: 16 Issue: 3 Pages: e0248425-e0248425
  • DOI: 10.1371/journal.pone.0248425
  • Peer Reviewed / Open Access