Homeostatic responses of colonic LGR5<sup>+</sup>stem cells following acute<i>in vivo</i>exposure to a genotoxic carcinogen

Kim, Eun-Joo; Davidson, Laurie A.; Zoh, Roger S.; Hensel, Martha E.; Patil, Bhimanagouda S.; Callaway, Evelyn S.; Allred, Clinton D.; Turner, Nancy D.; Weeks, Brad R.; Chapkin, Robert S.

doi:10.1093/carcin/bgv250

Cited by 21 publications

(16 citation statements)

References 57 publications

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“…24 Mice were fed with n-3 PUFA and curcumin alone or in combination for 3 weeks, injected with AOM and analyzed to measure DNA damage (gamma H2AX ( γ H2AX)), apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)), damage repair (methylguanine-methyl transferase (MGMT)) and proliferation (5-ethynyl-2′-deoxyuridine (EdU)) in crypts 12 and 24 h later as described previously. 4 Because the integration cassette in this mouse model is epigenetically silent in about 60–70% of crypts, 25 we analyzed only GFP-positive crypts using fluorescence microscopy. No differences between GFP high and GFP neg crypts in response to carcinogen and bioactive compounds were observed (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…It has been demonstrated that Lgr5 + stem cells are preferentially damaged by AOM in the distal colon compared with differentiated cells 4 and n-3 PUFA reduce AOM-induced DNA adducts, 26 which cause double-strand breaks (DSBs). 4 Therefore, to determine the chemoprotective effects of combinatorial bioactives on AOM-induced DNA damage in Lgr5 + stem cells as compared with differentiated cells in vivo , we measured γ H2AX, a marker of the double-strand breaks.…”

Section: Resultsmentioning

confidence: 99%

“…1 High fat diet (HFD)-induced obesity augments stemness and tumorigenicity of intestinal progenitors. 2 In addition, epithelial colonic leucine-rich repeat-containing G-protein-coupled receptor 5-positive (Lgr5) + stem cells respond to HFD 3 and genotoxic carcinogen, for example, AOM, 4 during the cancer initiation stage. It has also been demonstrated that colonic Lgr5 + stem cells are preferentially damaged by AOM compared with differentiated cells.…”

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confidence: 99%

“…It has also been demonstrated that colonic Lgr5 + stem cells are preferentially damaged by AOM compared with differentiated cells. 4 A functional consequence of this status could enhance tumorigenesis. Thus, induction of apoptosis in DNA-damaged Lgr5 + stem cells is likely to be a useful marker for successful cancer prevention, and may hold promise for identifying novel and improved cancer-chemopreventive agents.…”

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confidence: 99%

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

et al. 2016

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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

et al. 2016

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“…This response has been demonstrated with other carcinogens that stimulate apoptotic removal of DNA damaged cells, which occurs throughout the crypt, including at the base of the crypt where the adult colon stem cells reside. [41][42][43] Wang et al 40 followed up this experiment using the same design in which they discovered that expression of select genes (e.g., NADPH oxidase, Nox) is elevated. They also noted that downregulation of Nox expression reduced cell cycle activity and allowed apoptosis to occur.…”

Section: Cooking Effects On Pro-mutagenic Compoundsmentioning

confidence: 99%

Association between red meat consumption and colon cancer: A systematic review of experimental results

Turner

Lloyd

2017

Exp Biol Med (Maywood)

109

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A role for red and processed meat in the development of colorectal cancer has been proposed based largely on evidence from observational studies in humans, especially in those populations consuming a westernized diet. Determination of causation specifically by red or processed meat is contingent upon identification of plausible mechanisms that lead to colorectal cancer. We conducted a systematic review of the available evidence to determine the availability of plausible mechanistic data linking red and processed meat consumption to colorectal cancer risk. Forty studies using animal models or cell cultures met specified inclusion criteria, most of which were designed to examine the role of heme iron or heterocyclic amines in relation to colon carcinogenesis. Most studies used levels of meat or meat components well in excess of those found in human diets. Although many of the experiments used semi-purified diets designed to mimic the nutrient loads in current westernized diets, most did not include potential biologically active protective compounds present in whole foods. Because of these limitations in the existing literature, there is currently insufficient evidence to confirm a mechanistic link between the intake of red meat as part of a healthy dietary pattern and colorectal cancer risk. Impact statement Current recommendations to reduce colon cancer include the reduction or elimination of red or processed meats. These recommendations are based on data from epidemiological studies conducted among cultures where meat consumption is elevated and consumption of fruits, vegetables, and whole grains are reduced. This review evaluated experimental data exploring the putative mechanisms whereby red or processed meats may contribute to colon cancer. Most studies used levels of meat or meat-derived compounds that were in excess of those in human diets, even in cultures where meat intake is elevated. Experiments where protective dietary compounds were used to mitigate the extreme levels of meat and meat-derived compounds showed protection against colon cancer, with some essentially negating the impact of meat in the diet. It is essential that better-designed studies be conducted that use relevant concentrations of meat or meat-derived compounds in complex diets representative of the foods consumed by humans.

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The Role of Stem Cells in Colorectal Cancer Carcinogenesis and Treatment

Islam

Gopalan

Lam

2019

Stem Cell Biology and Regenerative Medicine

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Homeostatic responses of colonic LGR5⁺stem cells following acutein vivoexposure to a genotoxic carcinogen

Cited by 21 publications

References 57 publications

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

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

Association between red meat consumption and colon cancer: A systematic review of experimental results

The Role of Stem Cells in Colorectal Cancer Carcinogenesis and Treatment

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Homeostatic responses of colonic LGR5+stem cells following acutein vivoexposure to a genotoxic carcinogen

Cited by 21 publications

References 57 publications

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

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

Association between red meat consumption and colon cancer: A systematic review of experimental results

The Role of Stem Cells in Colorectal Cancer Carcinogenesis and Treatment

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Product

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Homeostatic responses of colonic LGR5⁺stem cells following acutein vivoexposure to a genotoxic carcinogen