Environmental Impact on Intestinal Stem Cell Functions in Mucosal Homeostasis and Tumorigenesis

Augenlicht, Leonard H.

doi:10.1002/jcb.25719

Cited by 12 publications

(16 citation statements)

References 83 publications

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“…For example, a purified mouse diet that provides common nutrients at the level of each equivalent to that in humans that is linked to high incidence of human colon cancer causes mouse intestinal tumors and has pronounced effects on which and how mouse intestinal stem cells function. This established that intestinal stem/ progenitor-like cell function can be recruited by the nutritional environment, not only by damage or genetic manipulation of Lgr5 hi cells (Augenlicht, 2017;Li et al, 2019Li et al, , 2020Peregrina et al, 2015). This has important implications for how intestinal homeostasis is maintained in humans where nutrient exposures vary among populations and vary for individuals daily.…”

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confidence: 99%

Effects of Diet Choice on Stem Cell Function Necessitate Clarity in Selection and Reporting

Houston

Peregrina

et al. 2020

Cell Stem Cell

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Augenlicht and colleagues raise concerns about the impact of diet on stem cell regulation and call for more careful reporting on dietary conditions used in mouse studies on this topic. We agree that specific conditions for animal housing and care should be reported, and we encourage this in our STAR Methods guidelines for all papers. However, moving forward we will require more detailed reporting on dietary information for mouse studies where the main scientific focus concerns stem cell functions, and especially metabolism. This will include vendor information, stock number, and feeding schedules within the STAR Methods section and Experimental Models section of the Key Resource Table. We hope this will provide further reproducibility, robustness, and clarity in the papers we publish.Investigators treat ''chow diet'' as a singular entity and many stem cell papers do not provide any, or they provide insufficient, information to discern components of different ''chows.'' However, chow diets are prepared from products such as corn and wheat husks, oats, alfalfa, and soybean and fish meals, inherently differing among manufacturers, varying among batches, and potentially containing mycotoxins, heavy metals, and pesticides. Their plant-based manufacture dictates that chow elevates mouse serum levels of biologically active phytoestrogens to exceed 1,000-50,000 times the level of endogenous estrogen (Brown and Setchell, 2001;Wang et al., 2005), but these are absent in mice fed purified diets and are at less than 5% of that in most humans. Thousands of publications establish that these compounds alter regulatory, signaling, oncogenic, and metabolic pathways that can affect stem cell function.

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confidence: 99%

Effects of Diet Choice on Stem Cell Function Necessitate Clarity in Selection and Reporting

Houston

Peregrina

et al. 2020

Cell Stem Cell

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“…It has been proposed that cancer development is an inevitable consequence of multiple stem cell divisions and stochastic processes that provoke DNA damage, increasing the probability for tumorigenesis ( 43 ). However, an extensive body of evidence has strongly implicated environmental and other lifestyle factors as significant modulators of cancer risk, including colon cancer ( 44 ). Obesity has proven to be particularly hazardous for cancer risk at many sites, as well as accelerated disease progression and related mortality ( 2 , 3 ).…”

Section: Discussionmentioning

confidence: 99%

Dietary Walnuts Protect Against Obesity-Driven Intestinal Stem Cell Decline and Tumorigenesis

et al. 2018

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Obesity can negatively impact intestinal homeostasis, and increase colon cancer risk and related mortality. Thus, given the alarmingly high rates of obesity in the US and globally, it is critical to identify practical strategies that can break the obesity-cancer link. Walnuts have been increasingly recognized to mitigate cancer risk, and contain many bioactive constituents with antioxidant and anti-inflammatory properties that could potentially counteract pathways thought to be initiators of obesity-related cancer. Therefore, the purpose of this study was to determine if walnuts could preserve intestinal homeostasis, and attenuate tumorigenesis and growth in the context of obesity and a high calorie diet. To this end, we studied effects of walnuts on these parameters under different dietary conditions in wildtype mice, two independent Apc models (Apc1638N/+ and ApcΔ14), and in MC38 colon cancer cells in vivo, respectively. Walnuts did not alter the metabolic phenotype or intestinal morphology in normal mice fed either a low-fat diet (LFD), LFD with 6% walnuts (LFD+W), high-fat diet (HFD), or HFD with 7.6% walnuts (HFD+W). However, walnuts did lead to a significant reduction in circulating CCL5 and preserved intestinal stem cell (ISC) function under HFD-fed conditions. Furthermore, walnuts reduced tumor multiplicity in Apc1638N/+ male HFD+W animals, as compared to HFD controls (3.7 ± 0.5 vs. 2.5 ± 0.3; P = 0.015), tended to reduce the number of adenocarcinomas (0.67 ± 0.16 vs. 0.29 ± 0.12; P = 0.07), and preferentially limited tumor growth in ApcΔ14 male mice (P = 0.019) fed a high-calorie western-style diet. In summary, these data demonstrate that walnuts confer significant protection against intestinal tumorigenesis and growth and preserve ISC function in the context of a high-calorie diet and obesity. Thus, these data add to the accumulating evidence connecting walnuts as a potentially effective dietary strategy to break the obesity-colon cancer link.

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“…As occurs in colon tissue [ 134 ], 1,25(OH) 2 D 3 upregulates LGR5 , LRIG1 , SMOC2 and MSI1 stemness genes and downregulates the differentiation genes MUC2 and TFF2 in normal rectum organoids, but not in rectal tumor organoids, which indicates a homeostatic action of 1,25(OH) 2 D 3 on the normal stem cell population in both intestinal areas (colon and rectum) [ 135 ]. Accordingly, studies by Augenlicht’s group have revealed that feeding mice with a low vitamin D 3 and calcium diet or specific-inactivation of Vdr in Lgr5 + intestinal stem cells compromises stem cell properties and function, and thus alters the maturation of Lgr5 + progeny and intestinal homeostasis [ 136 , 137 , 138 ]. Interestingly, in human colon carcinoma cell lines, the miR-372/373 cluster, which is upregulated by the Wnt/β-catenin pathway and enhances stemness, has been found to downregulate VDR RNA and a panel of differentiation genes [ 139 ].…”

Section: Effects Of 125(oh) 2 D 3 mentioning

confidence: 99%

Vitamin D Effects on Cell Differentiation and Stemness in Cancer

Fernández‐Barral

Bustamante-Madrid

Ferrer-Mayorga

et al. 2020

Cancers

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Vitamin D3 is the precursor of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), a pleiotropic hormone that is a major regulator of the human genome. 1,25(OH)2D3 modulates the phenotype and physiology of many cell types by controlling the expression of hundreds of genes in a tissue- and cell-specific fashion. Vitamin D deficiency is common among cancer patients and numerous studies have reported that 1,25(OH)2D3 promotes the differentiation of a wide panel of cultured carcinoma cells, frequently associated with a reduction in cell proliferation and survival. A major mechanism of this action is inhibition of the epithelial–mesenchymal transition, which in turn is largely based on antagonism of the Wnt/β-catenin, TGF-β and EGF signaling pathways. In addition, 1,25(OH)2D3 controls the gene expression profile and phenotype of cancer-associated fibroblasts (CAFs), which are important players in the tumorigenic process. Moreover, recent data suggest a regulatory role of 1,25(OH)2D3 in the biology of normal and cancer stem cells (CSCs). Here, we revise the current knowledge of the molecular and genetic basis of the regulation by 1,25(OH)2D3 of the differentiation and stemness of human carcinoma cells, CAFs and CSCs. These effects support a homeostatic non-cytotoxic anticancer action of 1,25(OH)2D3 based on reprogramming of the phenotype of several cell types.

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Environmental Impact on Intestinal Stem Cell Functions in Mucosal Homeostasis and Tumorigenesis

Cited by 12 publications

References 83 publications

Effects of Diet Choice on Stem Cell Function Necessitate Clarity in Selection and Reporting

Effects of Diet Choice on Stem Cell Function Necessitate Clarity in Selection and Reporting

Dietary Walnuts Protect Against Obesity-Driven Intestinal Stem Cell Decline and Tumorigenesis

Vitamin D Effects on Cell Differentiation and Stemness in Cancer

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