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

April-2021 Volume 21 Issue 4

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April-2021 Volume 21 Issue 4

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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

Copyright: © Faluyi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 263
|
Published online on: February 8, 2021

https://doi.org/10.3892/ol.2021.12524
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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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1	Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global patterns and trends in colorectal cancer incidence and mortality. Gut. 66:683–691. 2017. View Article : Google Scholar : PubMed/NCBI
2	Fearon ER and Vogelstein B: A genetic model for colorectal tumorigenesis. Cell. 61:759–767. 1990. View Article : Google Scholar : PubMed/NCBI
3	Moon RT, Bowerman B, Boutros M and Perrimon N: The promise and perils of Wnt signaling through beta-catenin. Science. 296:1644–1646. 2002. View Article : Google Scholar : PubMed/NCBI
4	Ashton-Rickardt PG, Dunlop MG, Nakamura Y, Morris RG, Purdie CA, Steel CM, Evans HJ, Bird CC and Wyllie AH: High frequency of APC loss in sporadic colorectal carcinoma due to breaks clustered in 5q21-22. Oncogene. 4:1169–1174. 1989.PubMed/NCBI
5	Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, Koyama K, Utsunomiya J, Baba S and Hedge P: Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science. 253:665–669. 1991. View Article : Google Scholar : PubMed/NCBI
6	Moser AR, Pitot HC and Dove WF: A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science. 247:322–324. 1990. View Article : Google Scholar : PubMed/NCBI
7	Coletta PL, Müller AM, Jones EA, Mühl B, Holwell S, Clarke D, Meade JL, Cook GP, Hawcroft G, Ponchel F, et al: Lymphodepletion in the Apc^Min/+ mouse model of intestinal tumorigenesis. Blood. 103:1050–1058. 2004. View Article : Google Scholar : PubMed/NCBI
8	Lane SW, Sykes SM, Al-Shahrour F, Shterental S, Paktinat M, Lo Celso C, Jesneck JL, Ebert BL, Williams DA and Gilliland DG: The Apc(min) mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS. Blood. 115:3489–3497. 2010. View Article : Google Scholar : PubMed/NCBI
9	Wang J, Fernald AA, Anastasi J, Le Beau MM and Qian Z: Haploinsufficiency of Apc leads to ineffective hematopoiesis. Blood. 115:3481–3488. 2010. View Article : Google Scholar : PubMed/NCBI
10	Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 366:2443–2454. 2012. View Article : Google Scholar : PubMed/NCBI
11	Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, Geva R, Gottfried M, Penel N, Hansen AR, et al: Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: Results from the phase II KEYNOTE-158 study. J Clin Oncol. 38:1–10. 2020. View Article : Google Scholar : PubMed/NCBI
12	Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, Morse MA, Van Cutsem E, McDermott R, Hill A, et al: Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 36:773–779. 2018. View Article : Google Scholar : PubMed/NCBI
13	Toh JWT, de Souza P, Lim SH, Singh P, Chua W, Ng W and Spring KJ: The potential value of immunotherapy in colorectal cancers: Review of the evidence for programmed death-1 inhibitor therapy. Clin Colorectal Cancer. 15:285–291. 2016. View Article : Google Scholar : PubMed/NCBI
14	Schumacher TN and Schreiber RD: Neoantigens in cancer immunotherapy. Science. 348:69–74. 2015. View Article : Google Scholar : PubMed/NCBI
15	Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, et al: PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 515:568–571. 2014. View Article : Google Scholar : PubMed/NCBI
16	Spranger S, Bao R and Gajewski TF: Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature. 523:231–235. 2015. View Article : Google Scholar : PubMed/NCBI
17	Bain CC and Mowat AM: Macrophages in intestinal homeostasis and inflammation. Immunol Rev. 260:102–117. 2014. View Article : Google Scholar : PubMed/NCBI
18	Faust N, Varas F, Kelly LM, Heck S and Graf T: Insertion of enhanced green fluorescent protein into the lysozyme gene creates mice with green fluorescent granulocytes and macrophages. Blood. 96:719–726. 2000. View Article : Google Scholar : PubMed/NCBI
19	Dietrich WF, Lander ES, Smith JS, Moser AR, Gould KA, Luongo C, Borenstein N and Dove W: Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell. 75:631–639. 1993. View Article : Google Scholar : PubMed/NCBI
20	Smith PG, Coletta PL, Markham AF and Whitehouse A: In vivo episomal maintenance of a herpesvirus saimiri-based gene delivery vector. Gene Ther. 8:1762–1769. 2001. View Article : Google Scholar : PubMed/NCBI
21	Walter I, Fleischmann M, Klein D, Müller M, Salmons B, Günzburg WH, Renner M and Gelbmann W: Rapid and sensitive detection of enhanced green fluorescent protein expression in paraffin sections by confocal laser scanning microscopy. Histochem J. 32:99–103. 2000. View Article : Google Scholar : PubMed/NCBI
22	Newberry RD, Stenson WF and Lorenz RG: Cyclooxygenase-2-dependent arachidonic acid metabolites are essential modulators of the intestinal immune response to dietary antigen. Nat Med. 5:900–906. 1999. View Article : Google Scholar : PubMed/NCBI
23	Hull MA, Faluyi OO, Ko CW, Holwell S, Scott DJ, Cuthbert RJ, Poulsom R, Goodlad R, Bonifer C, Markham AF, et al: Regulation of stromal cell cyclooxygenase-2 in the Apc^Min/+ mouse model of intestinal tumorigenesis. Carcinogenesis. 27:382–391. 2006. View Article : Google Scholar : PubMed/NCBI
24	Leenen PJ, de Bruijn MF, Voerman JS, Campbell PA and van Ewijk W: Markers of mouse macrophage development detected by monoclonal antibodies. J Immunol Methods. 174:5–19. 1994. View Article : Google Scholar : PubMed/NCBI
25	Scott DJ, Hull MA, Cartwright EJ, Lam WK, Tisbury A, Poulsom R, Markham AF, Bonifer C and Coletta PL: Lack of inducible nitric oxide synthase promotes intestinal tumorigenesis in the Apc(Min/+) mouse. Gastroenterology. 121:889–899. 2001. View Article : Google Scholar : PubMed/NCBI
26	Keshav S, Chung P, Milon G and Gordon S: Lysozyme is an inducible marker of macrophage activation in murine tissues as demonstrated by in situ hybridization. J Exp Med. 174:1049–1058. 1991. View Article : Google Scholar : PubMed/NCBI
27	Lelouard H, Fallet M, de Bovis B, Méresse S and Gorvel JP: Peyer's patch dendritic cells sample antigens by extending dendrites through M cell-specific transcellular pores. Gastroenterology. 142:592–601.e3. 2012. View Article : Google Scholar : PubMed/NCBI
28	Joeris T, Müller-Luda K, Agace WW and Mowat AM: Diversity and functions of intestinal mononuclear phagocytes. Mucosal Immunol. 10:845–864. 2017. View Article : Google Scholar : PubMed/NCBI
29	Emile JF, Julié C, Le Malicot K, Lepage C, Tabernero J, Mini E, Folprecht G, Van Laethem JL, Dimet S, Boulagnon-Rombi C, et al PETACC8 Study Investigators; Austrian Breast and Colorectal cancer Study Group (ABCSG); Belgian Group of Digestive Oncology (BGDO); John Allen Bridgewater, : Prospective validation of a lymphocyte infiltration prognostic test in stage III colon cancer patients treated with adjuvant FOLFOX. Eur J Cancer. 82:16–24. 2017. View Article : Google Scholar : PubMed/NCBI
30	Bain CC, Bravo-Blas A, Scott CL, Perdiguero EG, Geissmann F, Henri S, Malissen B, Osborne LC, Artis D and Mowat AI: Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat Immunol. 15:929–937. 2014. View Article : Google Scholar : PubMed/NCBI
31	Shaw TN, Houston SA, Wemyss K, Bridgeman HM, Barbera TA, Zangerle-Murray T, Strangward P, Ridley AJL, Wang P, Tamoutounour S, et al: Tissue-resident macrophages in the intestine are long lived and defined by Tim-4 and CD4 expression. J Exp Med. 215:1507–1518. 2018. View Article : Google Scholar : PubMed/NCBI
32	Wang D and DuBois RN: The Role of Prostaglandin E(2) in Tumor-Associated Immunosuppression. Trends Mol Med. 22:1–3. 2016. View Article : Google Scholar : PubMed/NCBI
33	Faluyi OO, Fitch P and Howie SE: An increased CD25-positive intestinal regulatory T lymphocyte population is dependent upon Cox-2 activity in the Apc^min/+ model. Clin Exp Immunol. 191:32–41. 2018. View Article : Google Scholar : PubMed/NCBI
34	Bain CC, Scott CL, Uronen-Hansson H, Gudjonsson S, Jansson O, Grip O, Guilliams M, Malissen B, Agace WW and Mowat AM: Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors. Nat Immunol. 15:929–937. 2014. View Article : Google Scholar : PubMed/NCBI
35	Zelenay S, van der Veen AG, Böttcher JP, Snelgrove KJ, Rogers N, Acton SE, Chakravarty P, Girotti MR, Marais R, Quezada SA, et al: Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell. 162:1257–1270. 2015. View Article : Google Scholar : PubMed/NCBI
36	Grainger JR, Askenase MH, Guimont-Desrochers F, da Fonseca DM and Belkaid Y: Contextual functions of antigen-presenting cells in the gastrointestinal tract. Immunol Rev. 259:75–87. 2014. View Article : Google Scholar : PubMed/NCBI
37	de Jong JP, Voerman JS, van der Sluijs-Gelling AJ, Willemsen R and Ploemacher RE: A monoclonal antibody (ER-HR3) against murine macrophages. I. Ontogeny, distribution and enzyme histochemical characterization of ER-HR3-positive cells. Cell Tissue Res. 275:567–576. 1994. View Article : Google Scholar : PubMed/NCBI
38	de Jong JP, Leenen PJ, Voerman JS, van der Sluijs-Gelling AJ and Ploemacher RE: A monoclonal antibody (ER-HR3) against murine macrophages. II. Biochemical and functional aspects of the ER-HR3 antigen. Cell Tissue Res. 275:577–585. 1994. View Article : Google Scholar : PubMed/NCBI

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