Reduction in the resident intestinal myelomonocytic cell population occurs during Apc<em><sup>Min/+</sup></em> mouse intestinal tumorigenesis

Faluyi,Olusola O.; Hull,Mark A.; Markham,Alexander F.; Bonifer,Constanze; Coletta,P. Louise

doi:10.3892/ol.2021.12524

Reduction in the resident intestinal myelomonocytic cell population occurs during Apc^Min/+ mouse intestinal tumorigenesis

Authors:
- Olusola O. Faluyi
- Mark A. Hull
- Alexander F. Markham
- Constanze Bonifer
- P. Louise Coletta
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Affiliations: Section of Molecular Gastroenterology, Leeds Institute of Medical Research, University of Leeds, St. James's University Hospital, Leeds, Yorkshire LS9 7TF, UK, Section of Experimental Haematology, Leeds Institute of Medical Research, University of Leeds, St. James's University Hospital, Leeds, Yorkshire LS9 7TF, UK
Published online on: February 8, 2021 https://doi.org/10.3892/ol.2021.12524
Article Number: 263
Copyright: © Faluyi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

With its significant contribution to cancer mortality globally, advanced colorectal cancer (CRC) requires new treatment strategies. However, despite recent good results for mismatch repair (MMR)‑deficient CRC and other malignancies, such as melanoma, the vast majority of MMR‑proficient CRCs are resistant to checkpoint inhibitor (CKI) therapy. MMR‑proficient CRCs commonly develop from precursor adenomas with enhanced Wnt‑signalling due to adenomatous polyposis coli (APC) mutations. In melanomas with enhanced Wnt signalling due to stabilized β‑catenin, immune anergy and resistance to CKI therapy has been observed, which is dependent on micro‑environmental myelomonocytic (MM) cell depletion in melanoma models. However, MM populations of colorectal adenomas or CRC have not been studied. To characterize resident intestinal MM cell populations during the early stages of tumorigenesis, the present study utilized the Apc^Min/+ mouse as a model of MMR‑proficient CRC, using enhanced green fluorescent protein (EGFP) expression in the mouse lysozyme (M‑lys)^lys‑EGFP/+ mouse as a pan‑myelomonocytic cell marker and a panel of murine macrophage surface markers. Total intestinal lamina propria mononuclear cell (LPMNC) numbers significantly decreased with age (2.32±1.39x10⁷ [n=4] at 33 days of age vs. 1.06±0.24x10⁷ [n=8] at 109 days of age) during intestinal adenoma development in Apc^Min/+ mice (P=0.05; unpaired Student's t‑test), but not in wild‑type littermates (P=0.35). Decreased total LPMNC numbers were associated with atrophy of intestinal lymphoid follicles and the absence of MM/lymphoid cell aggregates in Apc^Min/+ mouse intestine, but not spleen, compared with wild‑type mice. Furthermore, during the early stage of intestinal adenoma development, there was a two‑fold reduction of M‑lys expressing cells (P=0.05) and four‑fold reduction of ER‑HR3 (macrophage sub‑set) expressing cells (P=0.05; two tailed Mann‑Whitney U test) in mice with reduced total intestinal LPMNCs (n=3). Further studies are necessary to determine the relevance of these findings to immune‑surveillance of colorectal adenomas or MMR‑proficient CRC CKI therapy resistance.

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