5-Aminosalicylic acid inhibits stem cell function in human adenoma-derived cells: implications for chemoprophylaxis in colorectal tumorigenesis

Abstract

Background Most colorectal cancers (CRC) arise sporadically from precursor lesions: colonic polyps. Polyp resection prevents progression to CRC. Risk of future polyps is proportional to the number and size of polyps detected at screening, allowing identification of high-risk individuals who may benefit from effective chemoprophylaxis. We aimed to investigate the potential of 5-aminosalicylic acid (5-ASA), a medication used in the treatment of ulcerative colitis, as a possible preventative agent for sporadic CRC. Methods Human colorectal adenoma (PC/AA/C1, S/AN/C1 and S/RG/C2), transformed adenoma PC/AA/C1/SB10 and carcinoma cell lines (LS174T and SW620) were treated with 5-ASA. The effect on growth in two- and three-dimensional (3D) culture, β-catenin transcriptional activity and on cancer stemness properties of the cells were investigated. Results 5-ASA was shown, in vitro, to inhibit the growth of adenoma cells and suppress β-catenin transcriptional activity. Downregulation of β-catenin was found to repress expression of stem cell marker LGR5 (leucine-rich G protein-coupled receptor-5) and functionally suppress stemness in human adenoma and carcinoma cells using 3D models of tumorigenesis. Conclusions 5-ASA can suppress the cancer stem phenotype in adenoma-derived cells. Affordable and well-tolerated, 5-ASA is an outstanding candidate as a chemoprophylactic medication to reduce the risk of colorectal polyps and CRC in those at high risk.

Inflammation-Driven Colorectal Cancer Associated with Colitis: From Pathogenesis to Changing Therapy

“…It has been hypothesised that the chemopreventive properties of the main classes of drugs available for IBD treatment are due to their direct (anticarcinogenic mechanisms) and indirect activity (reducing inflammatory activity) [ 47 , 48 ]. The scientific community has recently questioned the risk of developing colorectal cancer in IBD patients after being treated with immunomodulator therapy.…”

“…In addition, 5-ASA also suppresses the Wnt/β-catenin pathway, which is an effective anticarcinogenic mechanism. Finally, it has also been found to induce a cell cycle stop or apoptosis in carcinomatous cells with deficient/mutated β-catenin or mutated COX-2 [ 47 ].…”

Molecular Mechanisms of the Antitumor Effects of Mesalazine and Its Preventive Potential in Colorectal Cancer

“…The 5-ASA antineoplastic mechanism of action in CRC is strongly related to suppressing the Wnt/β-catenin pathway [ 74 ]. Mutation of the suppressor gene adenomatous polyposis coli (APC) is a common cause of genetic changes leading to the development of colorectal cancer by nuclear accumulation of β-catenin.…”

“…β-catenin then translocates into the cell nucleus, where it activates the transcription factor TCF/LEF (T-cell factor/lymphocyte enhance factor), which increases cell proliferation by activating the transcription of target genes encoding proteins such as c-Myc, cyclin D1, and CD44 [ 75 , 79 ]. Mutations resulting in upregulated Wnt/β-catenin signaling have been demonstrated to be sufficient for early adenoma formation [ 74 , 80 ].…”

Editorial: 5‐ASA in IBD patients on biologics—‘stop or continue’?

“…In the present study, the authors 1 provided, for the first time, consistent data on this issue and found no evidence for 5‐ASA reducing the weighted incidence of CRC in IBD patients on 5‐ASA versus those who had never used them. This is despite the potential protective effects of 5‐ASA from its intrinsic anti‐neoplastic properties on colon dysplasia seen in several studies in both UC and colonic CD 5 . So, to the question ‘is it time to systematically stop 5‐ASA when introducing biologics in IBD?’.…”