Vitamin D is a determinant of mouse intestinal Lgr5 stem cell functions

Peregrina, Karina; Houston, Michele; Daroqui, Cecilia; Dhima, Elena; Sellers, Rani S.; Augenlicht, Leonard H.

doi:10.1093/carcin/bgu221

Cited by 66 publications

(118 citation statements)

References 44 publications

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“…Taken together, we believe that the reduction in stem cell proliferation is likely to contribute to the observed decrease in polyp formation in celecoxib treated APC Min/+ mice. Importantly, our study fits with other recent evidence that exogenous factors, e.g., diet can modulate GI stem cell proliferation (43, 44). …”

Section: Discussionsupporting

confidence: 92%

Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden

Montrose

Zhou

McNally

et al. 2016

Cancer Prevention Research

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Treatment with celecoxib, a selective COX-2 inhibitor, reduces formation of premalignant adenomatous polyps in the gastrointestinal tracts of humans and mice. In addition to its chemopreventive activity, celecoxib can exhibit anti-microbial activity. Differing bacterial profiles have been found in feces from colon cancer patients compared with that of normal subjects. Moreover, preclinical studies suggest that bacteria can modulate intestinal tumorigenesis by secreting specific metabolites. In the current study, we determined whether celecoxib treatment altered the luminal microbiota and metabolome in association with reducing intestinal polyp burden in mice. Administration of celecoxib for 10 weeks markedly reduced intestinal polyp burden in APCMin/+ mice. Treatment with celecoxib also altered select luminal bacterial populations in both APCMin/+ and wild-type mice including decreased Lactobacillaceae and Bifidobacteriaceae as well as increased Coriobacteriaceae. Metabolomic analysis demonstrated that celecoxib caused a strong reduction in many fecal metabolites linked to carcinogenesis including glucose, amino acids, nucleotides and lipids. Ingenuity Pathway Analysis suggested that these changes in metabolites may contribute to reduced cell proliferation. To this end, we showed that celecoxib reduced cell proliferation in the base of normal appearing ileal and colonic crypts of APCMin/+ mice. Consistent with this finding, lineage tracing indicated that celecoxib treatment reduced the rate at which Lgr5-positive stem cells gave rise to differentiated cell types in the crypts. Taken together, these results demonstrate that celecoxib alters the luminal microbiota and metabolome along with reducing epithelial cell proliferation in mice. We hypothesize that these actions contribute to its chemopreventive activity.

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Section: Discussionsupporting

confidence: 92%

Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden

Montrose

Zhou

McNally

et al. 2016

Cancer Prevention Research

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“…Previously, a signature of genes specifically expressed in their stem cell function, as also previously observed in other stem cell niches (7,8). This was confirmed by feeding mice with a purified western style diet (NWD1) characterised by low vitamin D levels mirroring individuals at high risk for colon cancer (9). Accordingly, in vivo inactivation of the Vdr gene in Lgr5 hi cells compromises their ability to lineage trace whereas lower dietary vitamin D3 affects both their stem cell function and their capacity to form tumours upon targeted mutation of the Apc gene (9).…”

Section: Commentary On Nutritionsupporting

confidence: 55%

“…This was confirmed by feeding mice with a purified western style diet (NWD1) characterised by low vitamin D levels mirroring individuals at high risk for colon cancer (9). Accordingly, in vivo inactivation of the Vdr gene in Lgr5 hi cells compromises their ability to lineage trace whereas lower dietary vitamin D3 affects both their stem cell function and their capacity to form tumours upon targeted mutation of the Apc gene (9). In view of these data and of previous observations substantiating the "top-down" model of intestinal tumour formation, other stem cell compartments, as well as differentiated cell types are likely capable, upon stress factors of various nature, of re-entering the cell cycle and of acquiring stem cell characteristics as part of the tissue adaptive response to this particular environmental factor, as well as perhaps others (10,11).…”

Section: Commentary On Nutritionmentioning

confidence: 91%

Modelling western dietary habits in the mouse: easier said than done

Fodde

Schmitt

Schewe

et al. 2017

Hepatobiliary Surg. Nutr.

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The recent debate on the relative importance of environmental vs. intrinsic factors in the onset of malignancy has raised major concerns that the general public might conclude that cancer prevention programmes are not worthwhile. In their original report (1), Tomasetti and Vogelstein concluded that a majority of cancers can be explained by the high number of stem cell divisions in tissues with a high cell turn-over, due to generation of random mutations and their accumulation each time DNA replicates. In a subsequent report (2), Wu and colleagues employed a different mathematical model and extended the data set to reach the opposing conclusion that spontaneous mutations occurring during stem cell division rarely reach the level necessary to underlie cancer development. In the majority of cases, exposure to environmental risk factors represents a fundamental requirement for the onset of malignant disease. Of note, in the mathematical approach of the former study (1), the intrinsic rate of stem cell division and the environmental risk factors were regarded as entirely independent variables whereas it is plausible to think that extrinsic factors do affect stem cell homeostasis.From this perspective, the study by Beyaz et al. The relevance of mouse studies for our understanding of the cellular and molecular mechanisms through which specific nutrients underlie colon cancer onset is largely dependent on our capacity to model western-style dietary habits in vivo with appropriate controls. From this perspective the diets employed in the Beyaz study raise a number of serious concerns.First, the control diet is a conventional "chow" (LabDiet, RMH3400) whereas the HFD is a purified product (Research Diets, D12492) produced by a different manufacturer and entirely different in nutrient levels when compared with the control diet. Of note, chow diets are typically used for 'maintenance' purposes because they provide complete and adequate nutrition at a relatively inexpensive price. However, they encompass plant-derived ingredients and are inappropriate for nutrition studies because of the high-dosage and variable levels of plant phytoestrogens. In chow-fed mice, serum phytoestrogens reach levels several orders of magnitude higher than endogenous estrogen, but are undetectable in animals fed with a purified diet (4,5). The substantial increase Commentary on NutritionModelling western dietary habits in the mouse: easier said than done

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“…Apc 580S/580S mice on a C57BL/6 background were a kind gift of Dr. Leonard Augenlicht (Peregrina, et al 2015). To generate Pten deficiency and/or Apc deficiency in Lgr5+ ISCs, Lgr5+-GFP– Apc 580S/− – Pten flox/− mice were bred with Apc 580S/− – Pten flox/− animals to generate Lgr5+-GFP (Control), Lgr5+-GFP– Apc 580S/− ( Apc Het), Lgr5+-GFP Pten flox/flox ( Pten KO), Lgr5+-GFP– Apc 580S/− – Pten flox/flox ( Apc het –Pten KO), Lgr5+-GFP– Apc 580S/580S ( Apc KO), and Lgr5+-GFP– Apc 580S/580S – Pten flox/flox ( Apc KO –Pten KO) mice.…”

Section: Methodsmentioning

confidence: 99%

“…To generate Pten deficiency and/or Apc deficiency in Lgr5+ ISCs, Lgr5+-GFP– Apc 580S/− – Pten flox/− mice were bred with Apc 580S/− – Pten flox/− animals to generate Lgr5+-GFP (Control), Lgr5+-GFP– Apc 580S/− ( Apc Het), Lgr5+-GFP Pten flox/flox ( Pten KO), Lgr5+-GFP– Apc 580S/− – Pten flox/flox ( Apc het –Pten KO), Lgr5+-GFP– Apc 580S/580S ( Apc KO), and Lgr5+-GFP– Apc 580S/580S – Pten flox/flox ( Apc KO –Pten KO) mice. Mice were genotyped as described (Barker et al 2009; Byun et al 2011; Peregrina et al 2015), and males were weaned at 3 wks of age and provided a purified low fat diet (D12450H; Research Diets Inc, New Brunswick, NJ). Animals were maintained under standard temperature and photoperiod as described (Huffman et al 2013).…”

Section: Methodsmentioning

confidence: 99%

Apc inactivation, but not obesity, synergizes with Pten deficiency to drive intestinal stem cell-derived tumorigenesis

Tabrizian

Wang

Guan

et al. 2017

Endocrine-Related Cancer

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Obesity is a major risk factor for colorectal cancer and can accelerate Lgr5+ intestinal stem cell (ISC)-derived tumorigenesis following inactivation of Apc. However, whether non-canonical pathways involving PI3K-Akt signaling in ISCs can lead to tumor formation, and if this can be further exacerbated by obesity is unknown. Despite the synergy between Pten and Apc inactivation in epithelial cells on intestinal tumor formation, their combined role in Lgr5+-ISCs, which are the most rapidly dividing ISC population in the intestine, is unknown. Lgr5+-GFP mice were provided low-fat diet (LFD) or high-fat diet (HFD) for 8 mo and the transcriptome was evaluated in Lgr5+-ISCs. For tumor studies, Lgr5+-GFP and Lgr5+-GFP Ptenflox/flox mice were tamoxifen treated to inactivate Pten in ISCs and provided LFD or HFD until 14–15 mo of age. Finally, various combinations of Lgr5+-ISC specific, Apc and Pten-deleted mice were generated, and evaluated for histopathology and survival. HFD did not overtly alter Akt signaling in ISCs, but did increase other metabolic pathways. Pten deficiency, but not HFD, increased BrdU positive cells in the small intestine (P<0.05). However, combining Pten and Apc deficiency synergistically increased proliferative markers, tumor pathology and mortality, in a dose-dependent fashion (P<0.05). In summary, we show that HFD alone fails to drive Akt signaling in ISCs and that Pten deficiency, is dispensable as a tumor suppressor in Lgr5+-ISCs. However, combining Pten and Apc deficiency in ISCs synergistically increases proliferation, tumor formation, and mortality. Thus, aberrant Wnt/β-catenin, rather than PI3K-Akt signaling, is requisite for obesity to drive Lgr5+ISC-derived tumorigenesis.

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Vitamin D is a determinant of mouse intestinal Lgr5 stem cell functions

Cited by 66 publications

References 44 publications

Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden

Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden

Modelling western dietary habits in the mouse: easier said than done

Apc inactivation, but not obesity, synergizes with Pten deficiency to drive intestinal stem cell-derived tumorigenesis

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