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Loss of intestinal barrier function in colorectal neoplasia
▸ Grivennikov SI, Wang K, Mucida D, et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 2012;491:254–8.
Human colorectal cancers demonstrate increased levels of IL-23p19, the IL-23 subunit responsible for activation of TH17 and other IL-17-producing cells. Using the CPC-APC mouse model of distal colonic tumourigenesis, Grivennikov and colleagues observed that colon tumours in these mice exhibited overexpression of IL-23 and IL-17. IL-23 expression was found to be localised to tumour infiltrating cells including CD11b+ leukocytes and F4/80+ myeloid cells, while IL-17-producing cells were detected in tumours and mesenteric lymph nodes. Ablation of IL-23, or its receptor, resulted in reduced tumour multiplicity and growth in the CPC-APC mice, accompanied by a reduction in epithelial STAT3 phosphorylation. Similarly, CPC-APC mice lacking IL-17 receptor also displayed reduced tumour growth. Since the commensal microflora appears to regulate gut IL-23 expression, the researchers examined IL-23 expression in lethally irradiated CPC-APC mice, which had been transplanted with knockout bone marrow, lacking the innate immune components MyD88 or TLRs 2, 4 and 9. In the transplanted mice, tumoural IL-23 expression by myeloid cells was decreased; IL-17 expression in tumours also appears to depend on MyD88 in bone marrow-derived cells. Broad spectrum antibiotic treatment, resulting in depletion of the gut microflora, resulted in diminished tumoural IL-23, IL-17 and STAT3. In a separate series of experiments, colonic loops of CPC-APC mice were injected with fluorescently labelled lipopolysaccharide. The researchers observed translocation of the LPS into tumours, but not normal adjacent mucosa. The LPS appeared to co-localise with tumour associated macrophages. Using fluorescent in situ hybridisation, bacteria were detected within tumours from CPC-APC mice, and early human adenomas. Using an inducible APC knockout model, it appeared that APC loss was associated with mucin loss, defective barrier function, and …
Contributors Dr Paul Lochhead, Dr Miranda Hanson, Dr Prakash Ramachandran, Dr Norma McAvoy, Dr Mairi McLean, Dr John Leeds.
Journals reviewed Nature, Immunity, Gastroenterology, Endoscopy.
Competing interests None.
Provenance and peer review Not commissioned; internally peer reviewed.
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