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PWE-003 Loss of interleukin-4 receptor α function drives initiation, but not progression, of azoxymethane-induced colorectal carcinogenesis in BALB/c mice
  1. N Ingram1,
  2. S L Perry1,
  3. N Scott2,
  4. P L Coletta1,
  5. M A Hull1
  1. 1Section of Molecular Gastroenterology, Leeds Institute of Molecular Medicine, Leeds, UK
  2. 2Department of Histopathology, St James's University Hospital, Leeds, UK

Abstract

Introduction We have previously demonstrated that genetic deletion of interleukin-4 receptor α (IL-4Rα) in BALB/c mice leads to an increase in azoxymethane (AOM)-induced aberrant crypt focus (ACF) multiplicity. Therefore, we tested the hypothesis that absence of IL-4Rα signalling also promotes adenoma growth and development in AOM-induced colorectal carcinogenesis.

Methods BALB/c IL-4Rα/ and IL-4Rα+/+ mice (wild-type) were injected twice with 10 mg/kg AOM, for methylene blue stained ACF counting at 6 weeks or with 6 injections, for tumour phenotype analysis at 32 weeks. Lymphocyte (CD4+, CD8+, CD25+ and FoxP3+) and myeloid-derived suppressor cell (CD11b+, GR-1+; MDSC) splenocyte populations were analysed by flow cytometry. Blood cell populations were measured using a Vet abc blood analyser.

Results Loss of IL-4Rα signalling was associated with an increase in ACF multiplicity (median 8.5, IQR 7.25–12, n=8) compared with wild-type mice (median 3, IQR 1–3.5, n=9) (p=0.007 Mann Whitney U-test) confirming our previous observation of an anti-neoplastic role of IL-4Rα signalling in AOM-induced tumour initiation. At 32 weeks, the number of ACFs detected in AOM-treated IL-4Rα/ mice (median 8, IQR 6–10, n=16) remained higher than wild-type mice (median 3, IQR 2–7, n=19) (p=0.0017). However, loss of IL-4Rα signalling did not promote macroscopic tumour development (incidence=25%, mean number per tumour-bearing mouse=2 tumours/colon) compared with wild-type animals (incidence=26.3%, mean=1.4 tumours/colon). All tumours apart from one case of mild dysplasia were adenomas that exhibited severe dysplasia. Adenomas were only detected in female mice. Adenomas were smaller in IL-4Rα/ mice (mean (SD) 2.3 (1.0) mm) compared with wild-type tumours (3.7 (1.3) mm, p=0.06). There was no significant difference in routine haematological parameters between IL-4Rα/ mice and wild-type animals at both time points. However, there was an increase in CD4+ and FoxP3+ splenocytes (but not MDSCs) in IL-4Rα/ mice compared with wild-type animals at 32 weeks after AOM treatment.

Conclusion IL-4Rα signalling has stage-specific roles during AOM-induced colorectal carcinogenesis in BALB/c mice. Although absence of IL-4Rα signalling promotes initiation, it does not appear to be protective for progression to adenoma and may even have a pro-tumorigenic role during adenoma growth. Smaller tumour size in IL-4Rα/ mice is associated with an increase in splenic regulatory T cells.

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