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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 …
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