Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia

Dynamic intestinal stem cell plasticity and lineage remodeling by a nutritional environment relevant to human risk for tumorigenesis

“…Fifth, the extensive remodeling of stem cells and the mucosa by NWD1 demonstrate that complex remodeling characterizing the very earliest benign human tumors [25], and both the involved and uninvolved mucosa in human IBD, is already underway much earlier in the mucosa at risk. Finally, human colon tumors consist of both Lgr5 positive and negative stem cells with the balance determined by the mutational signature and environmental signals from other cell types or drugs [26], similar to what is reported here regarding the mucosa at nutritional risk that gives rise to these tumors.…”

“…Adjusting key nutrient exposures in the mouse to mimic those linked to elevated risk for human colon tumors causes rapid, reversible and hence dynamic adaptation of stem cells and the lineages that also alter pathogenic pathways establishing a pro-tumorigenic environment. Specific elements of this remodeling parallel the pathogenic mechanisms in human inflammatory bowel disease that is pro-tumorigenic, and the dynamic adaptation also reflects that there is dynamic plasticity in the balance of Lgr5 positive and negative stem cells that support tumor growth [26]. Thus, the mucosa at dietary risk for tumor development has already undergone complex remodeling, as documented in for both the inflamed and uninvolved mucosa in human IBD [23] and in the earliest human benign tumors [25].…”

“…The novel results with NWD1 establish that dietary elevation of risk involves dynamic and complex remodeling of stem, progenitor and lineage differentiated cells early in the mucosa, a complexity of alteration documented in the uninvolved as well as involved mucosa of human IBD [23], and for the very earliest benign human tumors [25]. There is an overall adaptive response that includes determining which cells function as stem cells, similar to a recent finding that the environment provides selective pressure for whether Lgr5 positive or negative which stem cells dominate in mouse and human tumors [26]. Therefore, while oncogenic mutations provide a stem cell with a competitive advantage to expand in favoring tumor development [17], this competition is carried out on a playing field sculpted and continually remodeled by the nutritional environment, with a major effect on outcome.…”

Innate immune receptor C5aR1 regulates cancer cell fate and can be targeted to improve radiotherapy in tumours with immunosuppressive microenvironments

“…Upregulation is shown in red as per z-score indicated below. Data for 3 independent samples is shown from data deposited at the ArrayExpress database under accession number E-MTAB-11769 (Gil Vazquez et al, 2022).…”

Balancing the scales: Do healthy lifestyle choices offset the colorectal cancer risk of unhealthy choices?

“…Intestinal stem cells (ISCs), marked by expression of Lgr5 , reside at the base of intestinal crypts and are thought to be the cell of origin (Barker et al, 2009), supporting a bottom‐up model of tumorigenesis (Preston et al, 2003). However, the latest work describing cell plasticity (Gil Vazquez et al, 2022; Tian et al, 2011) indicates that differentiated cells, potentially carrying a mutation, further up the crypt can dedifferentiate into ISCs if the ISC pool undergoes trauma (Gil Vazquez et al, 2022). As mutated cells near the crypt surface normally undergo anoikis and are shed into the lumen, this evidence supports a top‐down model of CRC initiation that can arise if the ISC pool is depleted by dietary or inflammatory means (Ngo et al, 2022).…”