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Defects in epithelial barriers drive colorectal cancer growth

by ecancer reporter Clare Sansom


Many solid tumour types have been linked to or associated with inflammatory processes. 


About 2% of colorectal tumours arise in patients who have already been diagnosed with an inflammatory bowel disease, a subtype that is referred to as colitis-associated cancer.


Interestingly, however, genetic and cellular characteristics of inflammation have been found to be associated with the large majority of colorectal cancers that are not associated with pre-existing, clinically recognised inflammation.


The genetic events that lead to the formation of these typical colorectal tumours are now quite well understood.


 They often arise following loss of function of the APC tumour suppressor gene; activation of beta-catenin; and then mutations in further proto-oncogenes and tumour suppressor genes including K-Ras and TP53


Pro-inflammatory genes are up-regulated in these tumours, which are also often infiltrated by immune cells. The nature of these responses can give a guide to prognosis; in particular, infiltration by T-helper cells that express the cytokine interleukin-17 (IL-17) and a gene expression signature that is characteristic of these cells is an indicator of poor prognosis in Stage I/II colorectal cancer. However, the mechanisms through which tumour-associated inflammation occurs and develops are as yet poorly understood.


Michael Karin from the University of California San Diego, CA, USA and his co-workers have now investigated the mechanisms of this tumour-elicited inflammation in a mouse model of colorectal cancer.


The transgenic mice selected (CPC-APC mice) mainly develop tumours in the distal colon, and these, like human colorectal tumours, very often show up-regulation of the cytokines IL-17 and IL-23. There are no significant differences between tumour and normal tissue in levels of other cytokines. Karin and his co-workers then showed that tumour growth and proliferation was reduced in CPC-APC mice in which the genes encoding IL-23 or its receptor had been knocked out. Reduction or removal of IL-23 dependent signalling reduced the production of some downstream cytokines, including IL-17.


Epithelial tumours, including colorectal cancers, often develop close to commensal microbial communities, which are physically separated from cells of the immune system by a protective epithelial barrier. As IL-23 is known to be activated by microbial products, Karin and his co-workers suggested that invasion of the tumour by these products might trigger the production of this cytokine and thus tumour growth.


They tested this hypothesis by transplanting bone marrow in which genes associated with sensing and responding to the presence of microbial products had been knocked out into CPC-APC mice. Expression of IL-23 and downstream cytokines was reduced in these mice, and also in mice in which the gut microflora were temporarily depeleted using antibiotics; tumour growth was reduced in the knockout mice.


Bacteria are prevented from crossing the epithelial barrier by mucus produced by goblet cells, and mice in which the mucin gene Muc2 has been knocked out develop inflammatory disease and colitis-associated cancer.


This, and the fact that mucins are barely detectable in human colorectal cancer cells, suggests a link between barrier defects, microbial infiltration and cancer development. The researchers found that genes associated with the maintenance of the epithelial barrier, such as those for the junctional proteins JAM-A and JAM-B, were down-regulated in both human and mouse colorectal tumours. Similar gene expression patterns were observed in human pre-cancerous lesions, including adenomas.


The observation that non-steroidal anti-inflammatory drugs can protect against colorectal cancer first suggested a close link between inflammation and this tumour type. Karin and his co-workers now propose a mechanism through which the breakdown of epithelial barriers and the consequent infiltration of components of the gut microflora into tumours lead to an inflammatory response involving the up-regulation of IL-23 and IL-17 that promotes tumour growth. They suggest that early treatment with IL-23 and IL-17 antagonists might be effective for colorectal cancer patients whose tumours over-express these cytokines.





Grivennikov, S.I., Wang, K., Mucida, D. and 18 others (2012). Adenoma-linked barrier defects and microbial products drive IL-23/IL-17 mediated tumour growth. Nature, published online ahead of print 3 October 2012. doi:10.1038/nature11465



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