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

• Published in: British journal of cancer 2021-06, Vol.124 (12), p.1959-1969
• Main Authors: Dixon, Steven William, Collard, Tracey Jane, Mortensson, Eleanor May Harrisdotter, Legge, Danny Nigel, Chambers, Adam Christian, Greenhough, Alexander, Creed, Tom Julian, Williams, Ann Caroline
• Format: Article
• Language: English
• Subjects: 631/67/1504/1885; 631/67/2195; 692/308/2778; Adenoma; Adenoma - drug therapy; Adenoma - genetics; Adenoma - pathology; Adenoma - prevention & control; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinogenesis - drug effects; Carcinogenesis - genetics; Carcinogenesis - pathology; Carcinoma - genetics; Carcinoma - pathology; Carcinoma - prevention & control; Cell culture; Cell Line, Tumor; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Chemoprevention - methods; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - genetics; Colitis, Ulcerative - pathology; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Colorectal Neoplasms - prevention & control; Drug Resistance; Epidemiology; Gene Expression Regulation, Neoplastic - drug effects; Humans; Mesalamine - pharmacology; Mesalamine - therapeutic use; Molecular Medicine; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - physiology; Oncology; Phenotypes; Polyps; Stem cells; Transcription; Tumor cell lines; Tumorigenesis; Tumors; Ulcerative colitis; Wnt Signaling Pathway - drug effects; Wnt Signaling Pathway - genetics; β-Catenin
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-021-01354-5

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.