Ulcerative colitis: from inflammation to cancer. Do estrogen receptors have a role?

Abstract

Ulcerative colitis (UC) is a condition at increased risk for colorectal carcinoma (CRC) development. Nowadays, screening and follow-up programs are routinely performed worldwide to promote the early detection of CRCs in subjects with well known risk factors (extent, duration and severity of the disorder). The diffusion of these procedures is presumably the main reason for the marked reduction of cancer incidence and mortality in the course of UC. In addition, chemoprevention has been widely investigated and developed in many medical fields, and aspirin has shown a preventive effect against CRC, while mesalazine has been strongly invoked as a potential chemopreventive agent in UC. However, available studies show some limitations due to the obvious ethical implications of drug withdrawal in UC in order to design a control group. The estrogen receptors (ER) alpha/beta balance seems to have a relevant influence on colorectal carcinogenesis and ER beta appears to parallel apoptosis, and hence an anti-carcinogenic effect. Phytoestrogens are compounds acting as ER beta agonists and have shown a promising chemopreventive effect on sporadic as well as genetically inherited CRC. There is evidence suggesting a role for ERs in UC-related carcinogenesis. In this perspective, since these substances can be considered as dietary supplements and are completely free from side effects, phytoestrogens could be an interesting option for CRC prevention, even when the disease is a consequence of long-term chronic inflammation, as in the course of UC. Further studies of their effects are warranted in both the basic research and clinical fields.

Keywords: Chemoprevention; Colorectal cancer; Dietary supplementation; Epithelial dysplasia; Estrogen receptors; Inflammatory bowel disease; Phytoestrogens; Ulcerative colitis.

Figure 1

progressive steps of ulcerative colitis-related carcinogenesis, genetic pathways and estrogen receptors alpha and beta patterns.

Figure 2

Estrogen receptors beta and interactions with genes involved in the regulation of cell cycle. Estrogen receptors (ER) beta has an antagonist inhibitory function, mediated by the down-regulation of proto-oncogenes c-myc and cyclins (as indicated by minus sign next to the arrow on the left side) and up-regulation of oncosoppressants p21 and p27 (as indicated by plus sign next to the arrow on the right side). In the lowest part of the figure is indicated the cell cycle phases and the site of its interaction with ER beta induced mediators (G2 phase).

Figure 3

Alpha and beta estrogen receptors balance in normal and neoplastic colon.