Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and Breaks the Intestinal Stem Cell

SIMPLE SUMMARY: The intestinal epithelium—a single-cell layer lining the luminal surface of the small and large intestine—comprises an array of highly specialized cell types that perform diverse digestive functions while also forming a protective barrier against potentially toxic gut contents. As such, the intestinal epithelium is barraged by multiple extraneous stresses and undergoes constant renewal to replenish lost or damaged cells. This perpetual renewal is orchestrated by LGR5(+) stem cells in response to multiple convergent instructive signals, emanating from cells in the immediate vicinity, collectively termed the intestinal stem cell niche. In addition, reserve stem-like cells and/or more mature cell types can assume the stem cell mantle and replenish the injured epithelium, if LGR5(+) stem cell function is compromised. Here, we discuss the niche signals that govern the stem cell state, and how these go awry in the development of colorectal cancer. ABSTRACT: The intestinal epithelium fulfils pleiotropic functions in nutrient uptake, waste elimination, and immune surveillance while also forming a barrier against luminal toxins and gut-resident microbiota. Incessantly barraged by extraneous stresses, the intestine must continuously replenish its epithelial lining and regenerate the full gamut of specialized cell types that underpin its functions. Homeostatic remodelling is orchestrated by the intestinal stem cell (ISC) niche: a convergence of epithelial- and stromal-derived cues, which maintains ISCs in a multipotent state. Following demise of homeostatic ISCs post injury, plasticity is pervasive among multiple populations of reserve stem-like cells, lineage-committed progenitors, and/or fully differentiated cell types, all of which can contribute to regeneration and repair. Failure to restore the epithelial barrier risks seepage of toxic luminal contents, resulting in inflammation and likely predisposing to tumour formation. Here, we explore how homeostatic niche-signalling pathways are subverted in tumorigenesis, enabling ISCs to gain autonomy from niche restraints (“ISC emancipation”) and transform into cancer stem cells capable of driving tumour initiation, progression, and therapy resistance. We further consider the implications of the pervasive plasticity of the intestinal epithelium for the trajectory of colorectal cancer, the emergence of distinct molecular subtypes, the propensity to metastasize, and the development of effective therapeutic strategies.