Abstract SY40-01: Tumor elicited inflammation and malignant progression in colorectal cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Colorectal cancer (CRC) is the third leading cause of cancer related deaths in the US and other Western countries. Whereas 2% of CRC arises in the context of pre-existing inflammatory bowel disease (IBD), especially ulcerative colitis (UC), and is known as colitis associated cancer (CAC), most CRC, including familial and sporadic cases, is found in individuals that do not show any signs of IBD. Yet, expression profiling has revealed the same inflammatory gene signature, which depends on activation of NF-κB and STAT3, in both CAC and CRC, findings that generate a question regarding the origin of the CRC-elicited inflammatory response. In early experiments we have shown that activation of NF-κB, which leads to production of the pro-inflammatory cytokine IL-6, a potent activator of STAT3, plays a critical role in the development of CAC. More recently we investigated the origin and role of inflammation in the development and progression of sporadic CRC, most of which is driven by loss of the tumor suppressor APC and activation of the β catenin signaling pathway. We focused our studies on IL-23, a heterodimeric cytokine, composed of a unique p19 subunit and a p40 subunit which it shares with IL-12. As observed by others, we also found that IL-23 expression is strongly elevated in CRC relative to adjacent non-tumor tissue and have extended these findings to the CPC-APC mouse model of colorectal tumorigenesis. In CPC-APC mice, the major source of IL-23 expression in colorectal adenomas are tumor associated macrophages (TAM). Importantly, ablation of IL-23 p19 either in all cells or only in bone marrow (BM)-derived cells attenuates the development and slows down the progression of CRC in CPC-APC mice and similar results were observed upon ablation of IL-23 receptor (IL-23R). As IL-23R is not expressed on adenoma epithelial cells, IL-23 must exert its pro-tumorigenic effect via an indirect mechanism. Indeed, IL-23 signaling promotes the polarization of IL-17 producing T cells (Th17) and the production of IL-6, both of which contribute to the development and progression of sporadic colorectal tumors in mice. Importantly, molecular epidemiological studies carried out by Galon, Fridman and their co-workers have revealed that an “IL-23-Th17” signature that is upregulated in about 10% of human CRC patients, and that the presence of this signature in stage I/II CRC is associated with very poor prognosis and a marked decrease in disease free survival. We investigated the mechanism responsible for the specific induction of IL-23 in TAM and found it to depend on Toll like receptor (TLR) - MyD88 signaling, which appears to be activated in response to components of the colonic microflora that permeate the adenomas. We also detected eubacterial 16S RNA in both mouse and human colonic adenomas, as well as increased penetrance of bacterial endotoxin (LPS) into adenomas relative to surrounding non-cancerous tissue. The development of colorectal adenomas in both mice and men is associated with loss of protective mucins and junctional adhesion proteins and this is likely to be the primary mechanism that accounts for the selective entry of microbial products into the tumor and induction of the tumor promoting “IL-23-Th17” signature. Future studies should focus on the therapeutic value of anti-IL-23 or anti-IL-17 interventions and the genetic or environmental causes of the large variation in the magnitude of IL-17 production amongst human CRC patients. References 1. Greten, F.R., Eckmann, L., Greten, T.F., Park, J.M., Li, Z-W, Egan, L.J., Kagnoff, M.F. and Karin, M. (2004) IKKβ links inflammation and tumorigenesis in a mouse model of colitis associated cancer. Cell 118:285-296. 2. 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Tumor elicited inflammation and malignant progression in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY40-01. doi:10.1158/1538-7445.AM2014-SY40-01