Microbial Products Promote IL-23 and IL-17–Mediated Tumor Growth

Colorectal cancers exhibit increased immune infiltration and elevated expression of inflammatory genes, many of which are characteristic of colitis-associated cancer and are associated with tumor progression, such as the T-helper 17 (T_H17) signature. To investigate the mechanisms underlying activation of this protumor immune response, Grivennikov and colleagues used a mouse model of spontaneous colorectal cancer driven by loss of the adenomatous polyposis coli (APC) tumor suppressor. In a similar manner to human colorectal cancer samples, mouse adenomas showed upregulation of interleukin (IL)-23, a positive regulator of T_H17 cells, in tumor-associated myeloid cells and increased tumoral expression of its downstream target IL-17. Ablation of the genes encoding IL-23, the IL-23 receptor, or the IL-17 receptor impaired colorectal tumor formation, indicating that IL-23 signaling enhances tumor growth via activation of an IL-17 response. Interestingly, genetic inactivation of Toll-like receptors or the adaptor protein myeloid differentiation primary response gene 88 (MYD88), which sense microbial products, also attenuated tumor formation and decreased IL-23 expression, suggesting that IL-23 upregulation is dependent on intestinal microflora. Consistent with this notion, elimination of commensal bacteria using antibiotics suppressed IL-23 and IL-17 expression and diminished tumor incidence. Furthermore, tumor-bearing mice exhibited increased blood levels of endotoxin and invasion of bacteria into early adenomas, suggestive of defects in the colonic epithelial barrier. Indeed, junctional proteins and the barrier protein mucin 2 were downregulated in mouse and human colorectal tumors but not in healthy tissue, coincident with induction of IL-23 and IL-17. In addition, loss of barrier function was observed in early adenomas and aberrant crypts and was induced in transformed cells upon APC inactivation. These results identify a broad role for microbial-dependent inflammation in colorectal cancer and suggest an additional mechanism by which cancer-initiating genetic lesions promote tumor progression.

Grivennikov SI, Wang K, Mucida D, Stewart CA, Schnabl B, Jauch D, et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17–mediated tumour growth. Nature 2012 Oct 3 [Epub ahead of print].

Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.