Inflammation and Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the fourth most common cancer in both men and women in the United States, resulting in over 55,000 deaths annually. Environmental and genetic factors influence the development of CRC, and inflammation is a critical hallmark of cancer that may arise from a variety of factors.

Purpose of review: While patients with inflammatory bowel disease (IBD) have a higher risk of developing CRC, sporadic CRCs may engender or be potentiated by inflammation as well. In this review, we focus on recent advances in basic and translational research utilizing murine models to understand the contribution of inflammatory signaling pathways to CRC.

Recent findings: We discuss advances in the utility of three-dimensional enteroid/colonoid/tumoroid cultures to understand immune-epithelial interactions in CRC, as well as the potential for utilizing patient-derived tumoroids for personalized therapies.

Summary: This review underscores the importance of understanding the complex molecular mechanisms underlying inflammation in sporadic CRC and highlights up-and-coming or new avenues for CRC biomarkers or therapies.

Keywords: colitis-associated cancer; colonoids; cytokines; enteroids; inflammation; inflammatory bowel disease; mouse models of colorectal cancer; sporadic colorectal cancer; tumoroids.

Figure 1

Steps to utilize 3D enteroids/colonoids/tumoroids for co-culture experiments. A. Enteroid/colonoid/tumoroid cultures can be grown readily from normal crypt (stem-cell containing) epithelium or tumors from mouse models or patient tissue. B. Studies demonstrating co-cultures of enteroid/colonoid/tumoroid with various inflammatory components are rapidly emerging. Considerations for co-culturing include: which immune/stromal cell co-culture experiment will answer my experimental question? Can this immune/stromal cell type be readily purified from mice/humans for use in co-culture experiments? Will the co-cultured cells survive in 3D enteroid growth conditions? If possible, will the co-culture cells express a fluorescent reporter? C. Co-culture platform must be considered and can include co-mingling of enteroid cells with immune/stromal cells (permitting direct interaction), growing adherent cells (such as fibroblasts) and then layering enteroids in 3D matrix on top of the layer of adherent cells, or evaluating dissociated enteroids grown as monolayers on semi-permeable supports with co-culture cells added to the upper (apical) or lower (basolateral) chamber. D. Analyses of co-cultures can include using biochemical or immunohistochemical analyses of morphology, proliferation, and cell death, gene expression studies, drug sensitivity, and functional tests including transepithelial migration and barrier function.