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

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.

Characteristics of the cancer stem cell niche and therapeutic strategies

“…CSC niches have already been identified in several types of human cancers including brain, liver, breast, lung, head and neck, prostate, melanoma, gastric, pancreatic, renal, ovarian, esophageal and colorectal cancers [ 75 – 87 ]. Various studies have focused on the similarities and differences among the niches in different cancers and how cancer specific microenvironments can affect the formation and the development of CSC niches [ 4 , 6 , 88 – 90 ].…”

The role of intestinal stem cell within gut homeostasis: Focusing on its interplay with gut microbiota and the regulating pathways

“…Secretion of BMP ligands by crypt expressing oncogenic KRAS or PI3K, inhibition of ISC activity, and alteration of Wnt signaling by PDGFRloCD81 + stromal cells induced by crypt with oncogenic PI3K 176 . In conclusion, BMP signaling sustains homeostatic balance by suppressing Lgr5 + ISC proliferation at the base of the crypt while promoting the allocation of secretory cell lines 177 .…”

Microbiota-Associated Metabolites and Related Immunoregulation in Colorectal Cancer

“…Interestingly, butyrate also impacts tumorigenesis by regulating intestinal stem cells (ISC), the cells of origin of intestinal cancer [61,62]. A recent study showed butyrate suppressed the intestinal stem cell proliferation in crypts surrounding the ulcers in a mouse model of colitis by acting as an HDACi to promote the expression of the negative cell-cycle regulator Foxo3 [63].…”