Abstract LB-200: IL-1beta promotes the development of intestinal epithelial stem cells

Abstract

Abstract Although iflammation has been linked to stem cell-mediated tumorigenesis, the inflammatory factors responsible for the induction of abnormal proliferation of stem cells remain to be identified. Up-regulation of IL-1β has been associated with colon tumor initiation and progression. The objective of this study is to determine whether IL-1β alone may contribute to intestinal stem cells (ISC)-mediated tumorigenesis by promoting the development of ISCs. In a preliminary study, it was shown that rat normal intestinal epithelia cell line IEC-18 cells proliferated as a monolayer culture under serum-free conditions, demonstrating that either IEC-18-ISCs are not active in these conditions or ISCs are absent in IEC-18 cell line. However, we have found that addition of IL-1β to the cell culture medium caused monolayer IEC-18 cells to form spheres with up-regulated expression of stem cell markers including Bmi-1, β-catenin, Lgr5, c-Myc, and Nanog. This shows that IL-1β can induce the development and/or self-renewal of ISCs to form spheres. IL-1β-mediated ISC self-renewal is further demonstrated by a colony-forming assay when IEC-18 cells were cultured in soft agar under serum-free conditions. Interestingly, IL-1β promoted only a relatively small population (about 0.03%) of IEC-18 cells to form colonies, suggesting that the majority of IEC-18 cells are terminally differentiated cells. Furthermore, we have found that, when cultured in collagen-coated plates in serum-free medium, IL-1β-treated IEC-18 cells demonstrated a loss of cell-cell contact inhibition, growth to relatively high cell densities as evidenced by the presence of foci, and up-regulated expression of stem cell markers. Overall, results from our studies provide the first evidence that IL-1β alone can promote the development and self-renewal of ISCs. IL-1β-activated ISCs possess typical characteristics of malignant cells including colony formation in soft agar and loss of cell-cell contact inhibition of growth. Thus, aberrant production of IL-1β in intestinal inflammation may contribute to the initiation and progression of colon cancer by inducing the abnormal development of intestinal epithelial stem cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-200. doi:1538-7445.AM2012-LB-200