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.

• 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