A role for the vitamin D pathway in non-intestinal lesions in genetic and carcinogen models of colorectal cancer and in familial adenomatous polyposis

Bong, Yong-Sik; Assefnia, Shahin; Tuohy, Thérèse M.F.; Neklason, Deborah W.; Burt, Randall W.; Ahn, Jaeil; Mesquita, Paul Jacob Bueno de; Byers, Stephen W.

doi:10.18632/oncotarget.12768

Cited by 5 publications

(2 citation statements)

References 52 publications

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“…Vitamin D is not only a vitamin, but also a multifunctional pro-hormone and a precursor to calcitriol [1,25-dihydroxy-vitamin D3 (1,25(OH) 2 D 3 )], which is a potent steroid hormone [ 18 ]. The etiology of vitamin D deficiency-mediated cancers is characterized by an alteration in the oncogenic Wnt/β-catenin signaling pathway or the APC/β-catenin/TCF tumor suppressor pathway [ 5 , 19 , 20 ]. So et al [ 21 ] found that administration of 1,25(OH) 2 D 3 or its analogs decreased Notch ligand levels, inhibited Notch 1 signaling, and reduced the CSC numbers among breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D-induced vitamin D receptor expression induces tamoxifen sensitivity in MCF-7 stem cells via suppression of Wnt/β-catenin signaling

et al. 2018

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Objective: Cancer stem cells (CSCs) are responsible for the drug resistance of breast cancers. Vitamin D deficiency promotes tumor resistance. The present study examined the effect of vitamin D and vitamin D receptor (VDR) expression on the tamoxifen resistance of CSCs. Methods: MCF-7 cells were treated with 1,25(OH)2D3 and their levels of VDR expression, viability, and apoptosis were detected. CD133+ MCF-7 stem cells were identified and transfected with a VDR-overexpression plasmid. The tamoxifen concentration that reduced MCF-7 cell viability by 50% (IC50) was determined. The activation of Wnt/β-catenin signaling was also investigated. Results: Vitamin D reduced the viability of MCF-7 cells and promoted their apoptosis. Vitamin D enhanced VDR expression and induced DNA damage. When CD133+ stem cells were separated from MCF-7 cells, the IC50 of tamoxifen for stem cells was significantly higher than that of parental MCF-7 cells, suggesting a higher tamoxifen resistance in MCF-7 stem cells. Levels of VDR expression and Wnt/β-catenin signaling in CD133+ cells were markedly lower and higher than those in CD133− cells, respectively. Stem cells transfected with VDR overexpression plasmids showed decreased tamoxifen IC50 values, viability, spheroid formation, and expression of Wnt and β-catenin proteins when compared with control cells. Cell apoptosis was increased by transfection with a VDR overexpression plasmid. Finally, the inhibitory effects induced by VDR overexpression could be reversed by the VDR inhibitor, calcifediol. Conclusion: Stem cells contributed to the tamoxifen resistance of MCF-7 cells. Vitamin D-induced VDR expression increased the sensitivity of MCF-7 stem cells to tamoxifen by inhibiting Wnt/β-catenin signaling.

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Section: Introductionmentioning

confidence: 99%

Vitamin D-induced vitamin D receptor expression induces tamoxifen sensitivity in MCF-7 stem cells via suppression of Wnt/β-catenin signaling

et al. 2018

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“…Although colon tumors develop in Apc 1638N/+ mice, their incidence and number is low and their formation takes 10–12 months (2, 6, 8). Treating Apc 1638N/+ mice with “Western style” diet (9) or crossing them with other genetically engineered mutant or knockout mice (6, 10–17) promotes multiplicity and sometimes progression of tumors in SI and/or colon. Similarly, conditional knockout of Apc in colonic epithelial cells leads to selective colon tumor formation (18, 19).…”

Section: Introductionmentioning

confidence: 99%

Increased Incidence of Colon Tumors in AOM-Treated Apc1638N/+ Mice Reveals Higher Frequency of Tumor Associated Neutrophils in Colon Than Small Intestine

Metzger¹,

Maruskova²,

Krebs³

et al. 2019

Front. Oncol.

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Colorectal cancer (CRC) is one of the most common cancers and a major cause of mortality. Mice with truncating Apc germline mutations have been used as a standard model of CRC, but most of the Apc-mutated lines develop multiple tumors in the proximal small intestine and rarely in the colon precluding detailed analysis of colon tumor microenvironment. Our aim was to develop a model with higher resemblance to human CRC and to characterize tumor infiltrating immune cells in spontaneously developing colon tumors compared to small intestinal tumors. Therefore, the Apc1638N/+ line was treated repeatedly with azoxymethane (AOM) and 90% colon tumor incidence and 4 to 5 colon tumors per mouse were achieved. Of note, AOM treatment specifically increased the tumor burden in the colon, but not in the small intestine. Histological grading and WNT-signaling activity did not differ significantly between small intestinal and colon tumors with some lesions progressing to invasive adenocarcinoma in both locations. However, characterization of the intratumoral myeloid cell compartment revealed a massive infiltration of colon tumors with neutrophils − 6-fold higher than in small intestinal tumors. Moreover, CCL17-expressing macrophages and dendritic cells accumulated in the tumors indicating the establishment of a tumor-promoting immunosuppressive environment. Thus, Apc1638N/+ mice treated with AOM are a suitable and straightforward model to study the influence of immune cells and chemokines on colon carcinogenesis.

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Roles of amino acids in preventing and treating intestinal diseases: recent studies with pig models

et al. 2017

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Animal models are needed to study and understand a human complex disease. Because of their similarities in anatomy, structure, physiology, and pathophysiology, the pig has proven its usefulness in studying human gastrointestinal diseases, such as inflammatory bowel disease, ischemia/reperfusion injury, diarrhea, and cancer. To understand the pathogenesis of these diseases, a number of experimental models generated in pigs are available, for example, through surgical manipulation, chemical induction, microbial infection, and genetic engineering. Our interests have been using amino acids as therapeutics in pig and human disease models. Amino acids not only play an important role in protein biosynthesis, but also exert significant physiological effects in regulating immunity, anti-oxidation, redox regulation, energy metabolism, signal transduction, and animal behavior. Recent studies in pigs have shown that specific dietary amino acids can improve intestinal integrity and function under normal and pathological conditions that protect the host from different diseases. In this review, we summarize several pig models in intestinal diseases and how amino acids can be used as therapeutics in treating pig and human diseases.

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A role for the vitamin D pathway in non-intestinal lesions in genetic and carcinogen models of colorectal cancer and in familial adenomatous polyposis

Cited by 5 publications

References 52 publications

Vitamin D-induced vitamin D receptor expression induces tamoxifen sensitivity in MCF-7 stem cells via suppression of Wnt/β-catenin signaling

Vitamin D-induced vitamin D receptor expression induces tamoxifen sensitivity in MCF-7 stem cells via suppression of Wnt/β-catenin signaling

Increased Incidence of Colon Tumors in AOM-Treated Apc1638N/+ Mice Reveals Higher Frequency of Tumor Associated Neutrophils in Colon Than Small Intestine

Roles of amino acids in preventing and treating intestinal diseases: recent studies with pig models

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