Inflammation and colorectal cancer: colitis-associated neoplasia

Abstract

Connection between inflammation and cancer is a rapidly developing field. Epidemiological data suggests that inflammation along with distinct arms of host immune system plays a very important role in the development and progression of many different cancers. Inflammatory bowel disease (IBD) is an important risk factor for the development of colon cancer, namely, colitis-associated cancer (CAC). The molecular mechanisms by which inflammation promotes cancer development are still being uncovered and may differ between CAC and other forms of colorectal cancer. Recent work has shed light on the role of distinct immune cells, cytokines, and other immune mediators in virtually all of the steps of colonic tumorigenesis, including tumor initiation and promotion as well as progression and metastasis. The close proximity of colonic tumors to the myriad of intestinal microbes, as well as instrumental role of microbiota in IBD, introduces microbes as new players capable of triggering inflammation and possibly promoting tumorigenesis. Various mechanisms of CAC tumorigenesis as well as new possible hints for the future approaches for prevention and therapy are discussed in this review.

Figure 1. The role of chronic inflammation in tumor initiation

Genotoxic compounds produced by inflammatory cells can damage DNA. In addition, signaling by distinct inflammatory cytokines upregulates ROS and RNI levels inside the target epithelial cells. Chronic intestinal inflammation is also intimately associated with a breakdown of protective intestinal barriers, which causes increased accessibility of inflamed epithelium to food borne and other types of mutagens. Altogether these processes contribute to enhanced mutagenesis required for tumor initiation. Furthermore, inflammatory signaling (particularly through cytokines) upregulates chromatin modifiers, miRNA and other epigenetic changes. Inflammatory signals also provide additional activation of pro-survival and proliferative pathways such as Akt, STAT3 and NF-κB, as well as increased Wnt/β-catenin signaling pivotal for adenoma formation and growth.

Figure 2. Interplay between microbiota, chronic inflammation and CAC tumorigenesis

Under normal conditions “good” or commensal microbes prevail, mediate immune system maturation, tolerance and also inhibit growth of ‘bad’ microbes probably via competition for ecological niches. Infection with colitogenic pathogens or shift in microflora causes increased growth of ‘bad’ microbes, which can cause aberrant immune responses, barrier disruption, production of inflammatory and pro-tumorigenic cytokines and metabolic activation of various carcinogens cells are also pro-tumorigenic. Intestinal inflammation in CAC can in turn further shape ‘bad’ microflora, selecting for the overrepresentation of particular species. Tumor may be enriched in distinct microflora, either indicating that these microbes may serve tumor-promoting role or the fact that for some reasons due to the tissue alterations tumor now is the best site for colonization by some particular microbes. Whether identity of ‘good’ microbes is much different from ‘bad’ ones remains an open question, because even truly commensal bacteria can (upon disruption of the barriers) can trigger inflammatory response to aid CAC development.