Prevention of preneoplastic lesions by dietary vitamin D in a mouse model of colorectal carcinogenesis

Hummel, Doris M.; Thiem, Ursula; Höbaus, Julia; Mesteri, Ildikó; Gober, Lukas; Stremnitzer, Caroline; Graça, João; Obermayer–Pietsch, Barbara; Kállay, Enikö

doi:10.1016/j.jsbmb.2012.09.003

Cited by 52 publications

(40 citation statements)

References 22 publications

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“…Several studies utilizing mouse models of colitis have shown that vitamin D can be beneficial in preventing or ameliorating inflammation and clinical disease (30–32); however, these models do not typically progress to neoplasia. Recently, the DSS/AOM model, another model of inflammation associated cancer which does progress to dysplasia and tumor formation, was used to demonstrate that increasing concentrations of dietary vitamin D are protective against preneoplasic lesions in a dose-dependent manner (33). Consistent with these findings, we have shown that increased dietary vitamin D is effective at not only preventing inflammation and dysplasia, but subsequent invasive tumor formation as well.…”

Section: Discussionmentioning

confidence: 99%

Increased Dietary Vitamin D Suppresses MAPK Signaling, Colitis, and Colon Cancer

et al. 2014

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Epidemiologic studies associate low serum vitamin D levels with an increased risk of colon cancer and inflammatory diseases such as inflammatory bowel disease (IBD). 129-Smad3tm1Par/J (Smad3−/−) mice are a model of bacterial-driven colitis and colon cancer when infected with Helicobacter bilis. Thus, we used this mouse model to determine whether increased dietary vitamin D would reduce inflammation and colon cancer. Smad3−/− mice were fed purified diet with either maintenance (1 IU vitamin D/g diet; maintenance) or increased concentrations of vitamin D (5 IU vitamin D/g diet; high vitamin D). One week after diet initiation, mice were inoculated with broth or H. bilis and were necropsied at several time points post-inoculation to assess inflammation, dysplasia, and neoplasia incidence. At 16 weeks post infection, 11% of mice fed high vitamin D diet had cancer compared to 41% of mice fed maintenance diet (p=0.0121). Evaluation at an early time point (1 week post-infection) showed that animals fed high vitamin D had decreased MAPK (p-p38 and p-JNK) activation in lamina propria leukocytes as well as decreased NFκB activation in colonic epithelial cells. Reduction in MAPK and NFκB activation correlated with decreased IBD scores (2.7 vs 15.5, p<0.0001) as well as decreased inflammatory cell infiltrates and reduced expression of proinflammatory cytokines in cecal tissue. These findings suggest that increased dietary vitamin D is beneficial in preventing inflammation-associated colon cancer through suppression of inflammatory responses during initiation of neoplasia or early stage carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Increased Dietary Vitamin D Suppresses MAPK Signaling, Colitis, and Colon Cancer

et al. 2014

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“…This could be explained by the finding that the VDR controls nuclear β-catenin levels in colon cancer cells and can thus attenuate the effect of mutations that activate the Wnt/β-catenin pathway (12). Additionally, Hummel et al (13) showed that increasing dietary vitamin D intake prevents chemically induced preneoplastic lesions in mice colon. However, a large-scale randomized controlled trial, the Women's Health Initiative, found that calcium and vitamin D supplementation had no effect on the incidence of colorectal cancer compared with the placebo arm after a 7-year follow-up; this follow-up period is possibly insufficient for detecting the effect (14).…”

Section: Vitamin D Receptor Polymorphisms Are Associated With Reducedmentioning

confidence: 99%

Vitamin D Receptor Polymorphisms Are Associated with Reduced Esophageal Vitamin D Receptor Expression and Reduced Esophageal Adenocarcinoma Risk

Janmaat

Winkel

Peppelenbosch

et al. 2015

Mol Med

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“…How much vitamin D repletion is optimal? Studies in the AOM/DSS murine colon cancer model suggest that a dose-response relationship does exist; colonic dysplasia decreases as serum 25D3 levels increase from approximately 12 ng/mL to 60 ng/mL (43). The most striking effect was seen when mice with serum 25D3 levels of 12 ng/mL (100 IU/kg diet) were compared to those having a level of 30 ng/mL (400 IU/kg diet).…”

Section: Discussionmentioning

confidence: 99%

Vitamin D Repletion Reduces the Progression of Premalignant Squamous Lesions in the NTCU Lung Squamous Cell Carcinoma Mouse Model

Mazzilli

Hershberger

Reid

et al. 2015

Cancer Prevention Research

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The chemopreventive actions of vitamin D were examined in the N-nitroso-tris-chloroethylurea (NTCU) mouse model, a progressive model of lung squamous cell carcinoma (SCC). SWR/J mice were fed a deficient diet (D) containing no vitamin D3, a sufficient diet (S) containing 2000 IU/kg vitamin D3, or the same diets in combination with the active metabolite of vitamin D, calcitriol (C) (80 μg/kg, weekly). The percentage (%) of the mucosal surface of large airways occupied by dysplastic lesions was determined in mice after treatment with a total dose of 15 or 25 μmol NTCU (N). After treatment with 15 μmol NTCU, the % of the surface of large airways containing high-grade dysplastic (HGD) lesions were vitamin D-deficient +NTCU (DN), 22.7 % (p<0.05 compared to vitamin D-sufficient +NTCU (SN)); DN + C, 12.3%; SN, 8.7%; and SN + C, 6.6%. The extent of HGD increased with NTCU dose in the DN group. Proliferation, assessed by Ki-67 labeling, increased upon NTCU treatment. The highest Ki-67 labeling index was seen in the DN group. As compared to SN mice, DN mice exhibited a 3-fold increase (p <0.005) in circulating white blood cells (WBC), a 20% (p <0.05) increase in IL-6 levels, and a 4 -fold (p <0.005) increase in WBC in bronchial lavages. Thus, vitamin D repletion reduces the progression of premalignant lesions, proliferation, and inflammation, and may thereby suppress development of lung SCC. Further investigations of the chemopreventive effects of vitamin D in lung SCC are warranted.

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Prevention of preneoplastic lesions by dietary vitamin D in a mouse model of colorectal carcinogenesis

Abstract: Highlights► High dietary vitamin D was able to prevent premalignant lesions caused by AOM/DSS. ► Increasing vitamin D intake raised serum 25-D3 levels reaching a plateau ≥1000 IU/kg. ► Serum 25-D3 levels over 30 ng/ml are needed to prevent tumorigenesis.

Cited by 52 publications

References 22 publications

Increased Dietary Vitamin D Suppresses MAPK Signaling, Colitis, and Colon Cancer

Increased Dietary Vitamin D Suppresses MAPK Signaling, Colitis, and Colon Cancer

Vitamin D Receptor Polymorphisms Are Associated with Reduced Esophageal Vitamin D Receptor Expression and Reduced Esophageal Adenocarcinoma Risk

Vitamin D Repletion Reduces the Progression of Premalignant Squamous Lesions in the NTCU Lung Squamous Cell Carcinoma Mouse Model

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