Oestrogens promote tumorigenesis in a mouse model for colitis-associated cancer

Autor: Daniel W. Hommes, Patrick G. Groothuis, Mattheus C. B. Wielenga, Eveline S.M. de Jonge-Muller, James C. H. Hardwick, Joris J. T. H. Roelofs, Gijs R. van den Brink, Izak Biemond, Vanesa Muncan, Antwan G. Ederveen, Sanne L. Rosekrans, Jarom Heijmans, Geert D'Haens, Jooske F. van Lidth de Jeude
Přispěvatelé: Tytgat Institute for Liver and Intestinal Research, Graduate School, Gastroenterology and Hepatology, Amsterdam Cardiovascular Sciences, Amsterdam institute for Infection and Immunity, Pathology, Amsterdam Gastroenterology Endocrinology Metabolism, Cancer Center Amsterdam
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Zdroj: Gut, 63(2), 310-316. BMJ Publishing Group
Gut, 63(2), 310-316
ISSN: 0017-5749
Popis: Background Hormone replacement therapy increases the risk of developing ulcerative colitis in postmenopausal women. Chronic intestinal inflammation predisposes to colon cancer development, but effects of female hormones on colitis-associated cancer development have not been examined. Aim To investigate the role of female hormones in the dextran sodium sulfate (DSS)-azoxymethane (AOM) mouse model for colitis-associated cancer. Design We performed ovariectomies, or sham operations, on mice, and supplemented these animals with indicated hormones. Additionally, we used oestrogen receptor α or β ( Erα or Erβ ) mutant mice. To study colitis or colitis-associated cancer, we used DSS only, or DSS and AOM, respectively. Results Ovariectomy protects female mice against colitis-associated tumour development. Hormone replacement in ovariectomised mice with either oestradiol (E2), medroxyprogesterone acetate or a combination of both suggests that oestrogens are the ovary-derived factor that promotes tumour development in the context of inflammatory damage. E2-treated animals showed increased clinical symptoms and Il-6 production upon DSS-induced colitis and enhanced epithelial proliferation. Treatment with E2 markedly increased the numbers of polyps in ovariectomised mice and also strongly promoted tumour progression with all E2-treated animals developing at least one invasive adenocarcinoma, whereas, placebo-treated animals developed adenomas only. Using Er mutant mice, we find that the protumorigenic effect of oestrogen depends on both Erα and Erβ. Conclusions Our results suggest that oestrogens promote inflammation-associated cancer development by impairing the mucosal response to inflammatory damage.
Databáze: OpenAIRE