Rapidly cycling Lgr5+ stem cells are exquisitely sensitive to extrinsic dietary factors that modulate colon cancer risk

Abstract

The majority of colon tumors are driven by aberrant Wnt signaling in intestinal stem cells, which mediates an efficient route toward initiating intestinal cancer. Natural lipophilic polyphenols and long-chain polyunsaturated fatty acids (PUFAs) generally suppress Wnt- and NF-κB- (nuclear factor-κ light-chain enhancer of activated B-cell) related pathways. However, the effects of these extrinsic agents on colonic leucine-rich repeat-containing G-protein-coupled receptor 5-positive (Lgr5+) stem cells, the cells of origin of colon cancer, have not been documented to date. Therefore, we examined the effect of n-3 PUFA and polyphenol (curcumin) combination on Lgr5+ stem cells during tumor initiation and progression in the colon compared with an n-6 PUFA-enriched control diet. Lgr5-EGFP-IRES-creERT2 knock-in mice were fed diets containing n-6 PUFA (control), n-3 PUFA, n-6 PUFA+curcumin or n-3 PUFA+curcumin for 3 weeks, followed by 6 azoxymethane (AOM) injections, and terminated 17 weeks after the last injection. To further elucidate the effects of the dietary bioactives at the tumor initiation stage, Lgr5+ stem cells were also assessed at 12 and 24 h post AOM injection. Only n-3 PUFA+curcumin feeding reduced nuclear β-catenin in aberrant crypt foci (by threefold) compared with control at the progression time point. n-3 PUFA+curcumin synergistically increased targeted apoptosis in DNA-damaged Lgr5+ stem cells by 4.5-fold compared with control at 12 h and maximally reduced damaged Lgr5+ stem cells at 24 h, down to the level observed in saline-treated mice. Finally, RNAseq analysis indicated that p53 signaling in Lgr5+ stem cells from mice exposed to AOM was uniquely upregulated only following n-3 PUFA+curcumin cotreatment. These novel findings demonstrate that Lgr5+ stem cells are uniquely responsive to external dietary cues following the induction of DNA damage, providing a therapeutic strategy for eliminating damaged Lgr5+ stem cells to reduce colon cancer initiation.

Functional link between plasma membrane spatiotemporal dynamics, cancer biology, and dietary membrane-altering agents

“…Recent data from one of these phase IIa clinical trials indicates that consumption of curcumin at 4 g per day for 30 days significantly (40%) reduces the number of aberrant crypt foci (ACF) in a CRC model [304] and in men and women [305]. More recently, our laboratory examined the effect of n-3 PUFA and curcumin in a mouse colorectal cancer initiation model and found that these agents when combined synergistically reduced (75%) the number of ACF in a mouse CRC model [28]. Importantly, several studies have confirmed that curcumin is well tolerated and that the effect is potentially mediated by curcumin delivered to the target tissue, i.e., it is directly incorporated into the intestinal mucosa [28, 305, 306].…”

“…This suggests that select MTDBs could reduce cancer risk by attenuating oncogenic protein activity by modulating the membrane organization of essential proteins and lipids. Thus, MTDBs could potentially serve as chemoprotective agents for cancer therapy [28–30]. In this review, we describe the importance of the plasma membrane as a central cellular hub that integrates numerous cues to orchestrate the modulation of various signaling networks, which can become hyperactivated, resulting in tumorigenesis.…”

Emerging role of chemoprotective agents in the dynamic shaping of plasma membrane organization

“…n-3 PUFA and curcumin paradoxically increase injury scores in an inflamed animal model [52], while the same n-3 PUFA dose has beneficial effects in a colon cancer model [67]. Along these lines, it has been demonstrated that fish oil feeding increases colon inflammation in a genetically susceptible mouse model [68], while exhibiting a chemo-protective tumor suppressing effect in an inflamed colon cancer animal model [69].…”

Shaping functional gut microbiota using dietary bioactives to reduce colon cancer risk

“…Adding to the complexity, recent evidence indicates that multiple stem cell hierarchies exist in the intestine and that plasticity within stem cell hierarchies mediates cellular fate in response to extrinsic factors such as nutrition, inflammation, and physical stress signals [54–58]. Interestingly, a role for diet in the regulation of intestinal stem cells has been reported [59–62]. …”

“…For example, combining the dietary polyphenol curcumin with fish oil, rich in n-3 polyunsaturated fatty acids, was recently shown to reduce nuclear β -catenin in aberrant crypt foci in mice exposed to AOM [62]. Furthermore, this combination of dietary bioactives was shown to synergistically increase targeted apoptosis in Lgr5 + stem cells.…”