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

Dixon, Steven William; Collard, Tracey Jane; Mortensson, Eleanor May Harrisdotter; Legge, Danny Nigel; Chambers, Adam Christian; Greenhough, Alexander; Creed, Tom Julian; Williams, Ann Caroline

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.

Citation

Dixon, S. W., Collard, T. J., Mortensson, E. M. H., Legge, D. N., Chambers, A. C., Greenhough, A., …Williams, A. C. (2021). 5-aminosalicylic acid inhibits stem cell function in human adenoma derived cells: Implications for chemoprophylaxis in colorectal tumorigenesis. British Journal of Cancer, 124, 1959–1969. https://doi.org/10.1038/s41416-021-01354-5

• Journal Article Type: Article
• Acceptance Date: Jan 27, 2021
• Online Publication Date: Mar 30, 2021
• Publication Date: Jun 8, 2021
• Deposit Date: Feb 1, 2021
• Publicly Available Date: Oct 1, 2021
• Journal: British Journal of Cancer
• Print ISSN: 0007-0920
• Electronic ISSN: 1532-1827
• Publisher: Springer Nature [academic journals on nature.com]
• Peer Reviewed: Peer Reviewed
• Volume: 124
• Pages: 1959–1969
• DOI: https://doi.org/10.1038/s41416-021-01354-5
• Public URL: https://uwe-repository.worktribe.com/output/7046387