Stem cell dynamics in homeostasis and cancer of the intestine

Key Points Intestinal stem cells (ISCs) are not static entities but are instead involved in many dynamical processes. ISCs are equipotent and continuously replace each other in neutral events. The ISC phenotype is the sum of all markers and features that are commonly associated with stem cells in the intestine. Therefore, the ISC phenotype is continuously changing as new markers and features are being identified. ISC activity is the ability of cells to initiate clonal long-term, multipotent lineages and is typically assessed by lineage tracing experiments. ISC potential refers to the display of ISC activity solely in a specific context but not during homeostasis; for example, during regeneration after tissue injury. Examples of intestinal cells with ISC potential are label-retaining Paneth cell precursors and Delta-like 1-positive (DLL1 + ) secretory precursors. The functional ISC compartment is the number of cells with ISC activity corrected for their relative contribution to the total output of the stem cell compartment. Mutations that are commonly found in colorectal cancer (CRC), such as adenomatous polyposis coli ( APC ) inactivation and KRAS activation, act on ISC dynamics and give a competitive advantage to the cell in which they occur. The benefit of mutated ISCs over wild-type ISCs is not absolute, and mutated ISCs are frequently outcompeted by wild-type ISCs. CRCs contain cells with stem cell-like activity; however, the frequency of these cells remains unknown, as does the importance of these cells for the biology of CRCs. Differentiated cancer cells and cancer stem cells are in constant flux, which is influenced by signals that emanate from the tumour stroma. This Review discusses recent studies that offer quantitative insights into the dynamics of intestinal stem cell behaviour that govern homeostasis. These studies provide the necessary baseline parameters such that we can begin to understand stem cell behaviour during colorectal cancer development. Intestinal stem cells (ISCs) and colorectal cancer (CRC) biology are tightly linked in many aspects. It is generally thought that ISCs are the cells of origin for a large proportion of CRCs and crucial ISC-associated signalling pathways are often affected in CRCs. Moreover, CRCs are thought to retain a cellular hierarchy that is reminiscent of the intestinal epithelium. Recent studies offer quantitative insights into the dynamics of ISC behaviour that govern homeostasis and thereby provide the nece