Colorectal Cancer in Ulcerative Colitis: Mechanisms, Surveillance and Chemoprevention

Abstract

Patients with ulcerative colitis (UC) are at a two- to three-fold increased risk of developing colorectal cancer (CRC) than the general population based on population-based data. UC-CRC has generated a series of clinical problems, which are reflected in its worse prognosis and higher mortality than sporadic CRC. Chronic inflammation is a significant contributor to the development of UC-CRC, so comprehending the relationship between the proinflammatory factors and epithelial cells together with downstream signaling pathways is the core to elucidate the mechanisms involved in developing of CRC. Clinical studies have shown the importance of early prevention, detection and management of CRC in patients with UC, and colonoscopic surveillance at regular intervals with multiple biopsies is considered the most effective way. The use of endoscopy with targeted biopsies of visible lesions has been supported in most populations. In contrast, random biopsies in patients with high-risk characteristics have been suggested during surveillance. Some of the agents used to treat UC are chemopreventive, the effects of which will be examined in cancers in UC in a population-based setting. In this review, we outline the current state of potential risk factors and chemopreventive recommendations in UC-CRC, with a specific focus on the proinflammatory mechanisms in promoting CRC and evidence for personalized surveillance.

Keywords: cell signaling; chromoendoscopy; risk factors; surveillance; ulcerative colitis-associated colorectal cancer.

Figure 1

The involvement of cytokine-related signaling pathways in colitis-associated CRC. (A) Binding of IL-23 to IL-23R activates the downstream JAK/STAT pathway to release IL-17A, IL-21, IL-22 from Th17 cells, exerting proinflammatory and protumor effects. (B–E) Several factors such as S1P, IL-22, IL-6, VEGF contribute to phosphorylation of STAT3 that upregulates Bcl-x and Caspase 3, downregulate Bcl-xl to inhibit apoptosis. (F) Kynurenine pathway metabolites rapidly activate PI3K/AKT signaling which then promotes β-catenin translocate to the nucleus, where β-catenin can form transcription complex with YAP and TCF4. (G–I) Proinflammatory stimuli including TNF-α, IL-1β and LPS can participate in tumor initiation and development through boosting the downstream molecule NF-κB activity. (J) PGE2 activates PI3K/AKT/PPAR-δ signaling to promote cell survival, thus increasing tumor burden.