Silent Waters Run Deep. Quiescent stem cells in homeostasis and cancer

Abstract

The Introduction summarizes the current literature on quiescence in adult stem cell niches and the various methods for the isolation of quiescent stem cells, outlines the complexity of the intestinal stem cell niche, and formulates the hypothesis that quiescent stem cells are involved in inflammation-associated tumours. Moreover, quiescent cancer stem cells and their clinical relevance are reviewed. In Chapter 1 and 2 we describe the generation of tightly regulated doxycyclineinducible models for studying mouse intestinal and esophageal biology respectively. The mouse model developed and characterized in Chapter 1 was employed in Chapter 3 to isolate and characterize a quiescent label-retaining cell population present within the intestinal epithelium. Chapters 4 to 6 describe the role of quiescent cells during tissue injury and their presence in full-blown tumors. In Chapter 4, we describe the induction of colonic inflammation in tumor-prone Apc1638N/+/villin-KRASG12V animals. These mice develop colon cancer characterized by the presence of Paneth-like cells. In Chapter 5, a rare villin-expressing, quiescent population of tumor cells is shown to be present in stomach tumors of the intestinal type from Apc1638N/+ animals. Moreover, we characterized quiescent, label-retaining tumor cells in small intestinal adenocarcinomas of Apc1638N/+/villin-KRASG12V animals, as outlined in Chapter 6. Finally, the Discussion summarizes the main finding of this thesis and gives directions for future research.