Update and latest advances in mechanisms and management of colitis-associated colorectal cancer

Abstract

Colitis-associated colorectal cancer (CAC) is defined as a specific cluster of colorectal cancers that develop as a result of prolonged colitis in patients with inflammatory bowel disease (IBD). Patients with IBD, including ulcerative colitis and Crohn's disease, are known to have an increased risk of developing CAC. Although the incidence of CAC has significantly decreased over the past few decades, individuals with CAC have increased mortality compared to individuals with sporadic colorectal cancer, and the incidence of CAC increases with duration. Chronic inflammation is generally recognized as a major contributor to the pathogenesis of CAC. CAC has been shown to progress from colitis to dysplasia and finally to carcinoma. Accumulating evidence suggests that multiple immune-mediated pathways, DNA damage pathways, and pathogens are involved in the pathogenesis of CAC. Over the past decade, there has been an increasing effort to develop clinical approaches that could help improve outcomes for CAC patients. Colonoscopic surveillance plays an important role in reducing the risk of advanced and interval cancers. It is generally recommended that CAC patients undergo endoscopic removal or colectomy. This review summarizes the current understanding of CAC, particularly its epidemiology, mechanisms, and management. It focuses on the mechanisms that contribute to the development of CAC, covering advances in genomics, immunology, and the microbiome; presents evidence for management strategies, including endoscopy and colectomy; and discusses new strategies to interfere with the process and development of CAC. These scientific findings will pave the way for the management of CAC in the near future.

Keywords: Colitis-associated colorectal cancer; Colonoscopic surveillance; Epidemiology; Inflammatory bowel disease; Management; Mechanisms.

Figure 1

Different mechanisms of colitis-associated colorectal carcinogenesis. Recent advances underlying colitis-associated colorectal carcinogenesis include a variety of mechanisms, including genetics and epigenetics, immunity and inflammation, and microbiota. Their subtle and complex interactions contribute to the development of colorectal cancer (CAC): (1) DNA mutations, oxidative damage, DNA methylation and histone modifications promote colitis-associated colorectal carcinogenesis; (2) Classical signaling pathways such as NF-κB, Wnt/β-catenin, STAT3/IL-6 promote colitis-associated colorectal carcinogenesis. In addition, TIMs and macrophage polarization are also involved in carcinogenesis; and (3) Several bacteria (e.g., E. coli, ETBF, and Fn) and metabolites may cause DNA damage, inflammation, activation of several oncogenic signaling pathways and EMT, thereby promoting CAC. BFT: Bacteroides fragilis toxin; DSBs: Double-strand breaks; EMT: Epithelial-mesenchymal transition; E. coli: Escherichia coli; ETBF: Enterotoxigenic Bacteroides fragilis; Fn: Fusobacterium nucleatum; IKK: IκB kinase; MEL18: Polycomb group ring finger 2; NFATc3: Nuclear factor of activated T cells 3; NF-Κb: Nuclear factor-κB; ODC: Ornithine decarboxylase; PI3K: Phosphoinositide 3-kinase; Pou3f1: POU class 3 homeobox 1; STAT3: Signal transducer and activator of transcription 3; TIMs: Tumor-infiltrating myeloid cells; TLR4: Toll-like receptor 4.