F4/80+Ly6Chigh Macrophages Lead to Cell Plasticity and Cancer Initiation in Colitis

Alice E Shin; Yodit Tesfagiorgis; Frederikke Larsen; Mathieu Derouet; Peter Y F Zeng; Hayley J Good; Liyue Zhang; Mara R Rubinstein; Yiping W Han; Steven M Kerfoot; Anthony C Nichols; Yoku Hayakawa; Christopher J Howlett; Timothy C Wang; Samuel Asfaha

doi:10.1053/j.gastro.2023.01.002

F4/80⁺Ly6C^high Macrophages Lead to Cell Plasticity and Cancer Initiation in Colitis

Gastroenterology. 2023 Apr;164(4):593-609.e13. doi: 10.1053/j.gastro.2023.01.002. Epub 2023 Jan 10.

Authors

Affiliations

¹ Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada.
² Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
³ Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Otolaryngology and Head and Neck Surgery, Western University, London, Ontario, Canada.
⁴ Department of Medicine, Western University, London, Ontario, Canada.
⁵ Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University Irving Medical Center, New York, New York.
⁶ Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University Irving Medical Center, New York, New York; Departments of Microbiology & Immunology and Medicine (Medical Sciences), Columbia University Irving Medical Center, New York, New York.
⁷ Department of Otolaryngology and Head and Neck Surgery, Western University, London, Ontario, Canada.
⁸ Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
⁹ Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
¹⁰ Department of Medicine, Columbia University Irving Medical Center, New York, New York.
¹¹ Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada. Electronic address: sasfaha2@uwo.ca.

Abstract

Background & aims: Colorectal cancer is a leading cause of cancer death, and a major risk factor is chronic inflammation. Despite the link between colitis and cancer, the mechanism by which inflammation leads to colorectal cancer is not well understood.

Methods: To investigate whether different forms of inflammation pose the same risk of cancer, we compared several murine models of colitis (dextran sodium sulfate [DSS], 2,4,6-trinitrobenzene sulfonic acid, 4-ethoxylmethylene-2-phenyloxazol-5-one, Citrobacter rodentium, Fusobacterium nucleatum, and doxorubicin) with respect to their ability to lead to colonic tumorigenesis. We attempted to correlate the severity of colitis and inflammatory profile with the risk of tumorigenesis in both azoxymethane-dependent and Dclk1/APC^fl/fl murine models of colitis-associated cancer.

Results: DSS colitis reproducibly led to colonic tumors in both mouse models of colitis-associated cancer. In contrast, all other forms of colitis did not lead to cancer. When compared with the colitis not associated with tumorigenesis, DSS colitis was characterized by significantly increased CD11b⁺F4/80⁺Ly6C^high macrophages and CD11b⁺Ly6G⁺ neutrophils. Interestingly, depletion of the CD11b⁺F4/80⁺Ly6C^high macrophages inhibited tumorigenesis, whereas depletion of CD11b⁺Ly6G⁺ neutrophils had no effect on tumorigenesis. Furthermore, the macrophage-derived cytokines interleukin-1β, tumor necrosis factor-α, and interleukin-6 were significantly increased in DSS colitis and promoted stemness of Dclk1⁺ tuft cells that serve as the cellular origin of cancer.

Conclusions: We have identified CD11b⁺F4/80⁺Ly6C^high macrophages as key mediators of cancer initiation in colitis-associated cancer. Development of new therapies that target these cells may provide an effective preventative strategy for colitis-associated cancer.

Keywords: AOM/DSS; Colitis; Colitis-Associated Cancer; Colorectal Cancer; Dclk1; Macrophages; Tuft Cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Azoxymethane
Carcinogenesis / metabolism
Cell Plasticity
Colitis* / chemically induced
Colitis* / complications
Colitis* / metabolism
Colitis-Associated Neoplasms* / metabolism
Dextran Sulfate / toxicity
Disease Models, Animal
Inflammation / metabolism
Macrophages / metabolism
Mice
Mice, Inbred C57BL

Substances

Azoxymethane
Dextran Sulfate
Ly-6C antigen, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding