Metformin may improve the outcome of patients with colorectal cancer and type 2 diabetes mellitus partly through effects on neutrophil extracellular traps

Akira Saito; Koji Koinuma; Rie Kawashima; Hideyo Miyato; Hideyuki Ohzawa; Hisanaga Horie; Hironori Yamaguchi; Hiroshi Kawahira; Toshiki Mimura; Joji Kitayama; Naohiro Sata

doi:10.1038/s44276-023-00022-w

Metformin may improve the outcome of patients with colorectal cancer and type 2 diabetes mellitus partly through effects on neutrophil extracellular traps

BJC Rep. 2023 Dec 12;1(1):20. doi: 10.1038/s44276-023-00022-w.

Authors

Affiliations

¹ Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan.
² Department of Oral and Maxillofacial Surgery, Jichi Medical University, Shimotsuke, Japan.
³ Department of Clinical Oncology, Jichi Medical University, Shimotsuke, Japan.
⁴ Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan. [email protected].

Abstract

Background: Although metformin reduces the risk of cancer-related mortality in patents with type 2 diabetes, the mechanism of its anti-cancer effects has not been fully understood.

Method: Impact of metformin on survival was examined in patients who underwent curative colectomy for colorectal cancer (CRC). The effects of metformin in neutrophil extracellular traps (NETs) were examined with in-vitro experiments and multiplex immunohistochemistry of surgically resected CRC specimens.

Results: Prior intake of metformin prolonged relapse-free (P = 0.036) and overall survival (P = 0.041) in 289 patients with T2DM to the comparable levels to those of 1576 non-diabetic patients. Metformin reduced the production of NETs stimulated with lipopolysaccharide or HT-29 colon cancer cells to 60% of control. Neutrophils markedly suppressed the chemotactic migration of activated T cells in an NET-dependent manner, which was reversed by metformin treatment up to approximately half of the migration without neutrophils. Immunohistochemical analysis revealed a significant association between metformin intake and a reduction in the numbers of tumor-associated neutrophils (TANs) and NETs. Simultaneously, metformin intake was found to increase the presence of CD3(+) and CD8(+) tumor-infiltrating T cells (TILs), particularly at the tumor-invasion front, especially in areas with fewer TANs and NETs.

Conclusion: Metformin suppresses the diabetes-associated enhancement of NET formation, which can augment the infiltration of TILs in CRC tissues. The anti-tumor effect of metformin in patients with T2DM may be, at least partly, attributable to the inhibition of NETs.