Targeting cancer stem cells in solid tumors by vitamin D

So, Jae Young; Suh, Nanjoo

doi:10.1016/j.jsbmb.2014.10.007

Cited by 48 publications

(33 citation statements)

References 104 publications

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“…The cancer inhibitory effects of vitamin D compounds, including 1α,25(OH) 2 D 3 and a Gemini vitamin D analog BXL0124, are mediated through signaling pathways involved in cancer stem cell signaling, cell cycle suppression and differentiation pathways (35). TNBC cell lines, such as SUM159, exhibit predominantly patterns of basal cell surface markers with some minor subpopulations of stem-like or luminal type (6).…”

Section: Discussionmentioning

confidence: 99%

Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer

Shan

Wahler

Lee

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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Triple-negative breast cancer is one of the least responsive breast cancer subtypes to available targeted therapies due to the absence of hormonal receptors, aggressive phenotypes, and the high rate of relapse. Early breast cancer prevention may therefore play an important role in delaying the progression of triple-negative breast cancer. Cancer stem cells are a subset of cancer cells that are thought to be responsible for tumor progression, treatment resistance, and metastasis. We have previously shown that vitamin D compounds, including a Gemini vitamin D analog BXL0124, suppress progression of ductal carcinoma in situ in vivo and inhibit cancer stem-like cells in MCF10DCIS mammosphere cultures. In the present study, the effects of vitamin D compounds in regulating breast cancer stem-like cells and differentiation in triple-negative breast cancer were assessed. Mammosphere cultures, which enriches for breast cancer cells with stem-like properties, were used to assess the effects of 1α,25(OH)2D3 and BXL0124 on cancer stem cell markers in the triple-negative breast cancer cell line, SUM159. Vitamin D compounds significantly reduced the mammosphere forming efficiency in primary, secondary and tertiary passages of mammospheres compared to control groups. Key markers of cancer stem-like phenotype and pluripotency were analyzed in mammospheres treated with 1α,25(OH)2D3 and BXL0124. As a result, OCT4, CD44 and LAMA5 levels were decreased. The vitamin D compounds also down-regulated the Notch signaling molecules, Notch1, Notch2, Notch3, JAG1, JAG2, HES1 and NFκB, which are involved in breast cancer stem cell maintenance. In addition, the vitamin D compounds up-regulated myoepithelial differentiating markers, cytokeratin 14 and smooth muscle actin, and down-regulated the luminal marker, cytokeratin 18. Cytokeratin 5, a biomarker associated with basal-like breast cancer, was found to be significantly down-regulated by the vitamin D compounds. These results suggest that vitamin D compounds may serve as potential preventive agents to inhibit triple negative breast cancer by regulating cancer stem cells and differentiation.

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Section: Discussionmentioning

confidence: 99%

Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer

Shan

Wahler

Lee

et al. 2017

The Journal of Steroid Biochemistry and Molecular Biology

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“…They possess the capacity of unlimited self-renewal through symmetric cell division, the ability to give rise to progeny cells through asymmetric division, and an innate resistance to cytotoxic therapeutics 41. Wnt, Notch, Hh, and/or TGF-β signaling pathways are involved in proliferation and maintenance of CSCs, and dysregulation of these pathways might cause the development of CRC 42–45. Despite the advancements in diagnosis and targeted and combined treatment, the advanced and metastatic stage of CRC still remains untreatable.…”

Section: Hh Signaling Pathwaymentioning

confidence: 99%

Hedgehog signaling pathway in colorectal cancer: function, mechanism, and therapy

Zhu

Liu

et al. 2017

OTT

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Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide. It is a complicated and often fatal cancer, and is related to a high disease-related mortality. Around 90% of mortalities are caused by the metastasis of CRC. Current treatment statistics shows a less than 5% 5-year survival for patients with metastatic disease. The development and metastasis of CRC involve multiple factors and mechanisms. The Hedgehog (Hh) signaling plays an important role in embryogenesis and somatic development. Abnormal activation of the Hh pathway has been proven to be related to several types of human cancers. The role of Hh signaling in CRC, however, remains controversial. In this review, we will go through previous literature on the Hh signaling and its functions in the formation, proliferation, and metastasis of CRC. We will also discuss the potential of targeting Hh signaling pathway in the treatment, prognosis, and prevention of CRC.

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“…We and others have shown that supplementation with dietary vitamin D or treatment with its active hormonal form calcitriol [1,25(OH) 2 D 3 ] exhibits multiple actions to inhibit BCa growth as demonstrated in cultured BCa cells and in lean mouse models of BCa (Deeb, et al 2007; Feldman, et al 2014; Rossdeutscher, et al 2015; Shui and Giovannucci 2014; So and Suh 2015; Welsh 2012). These vitamin D actions include the transcriptional repression of aromatase ( Cyp19 ) (Krishnan, et al 2010; Swami, et al 2011), inhibition of Er expression (Swami, et al 2000; Swami, et al 2013), and suppression of cyclooxygenase-2 (COX-2) expression (Moreno, et al 2005) leading to the reduction in the synthesis of pro-inflammatory mediators such as PGE 2 that are major stimulators of aromatase transcription in BCa (Brown and Simpson 2010; Simpson and Brown 2013a).…”

Section: Introductionmentioning

confidence: 99%

Vitamin D mitigates the adverse effects of obesity on breast cancer in mice

Swami

Krishnan

Williams

et al. 2016

Endocrine-Related Cancer

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Obesity is an established risk factor for postmenopausal breast cancer (BCa), insulin resistance and vitamin D deficiency, and all contribute to increased synthesis of mammary estrogens, the drivers of estrogen receptor-positive (ER+) BCa growth. Since both dietary vitamin D and calcitriol treatments inhibit breast estrogen synthesis and signaling, we hypothesized that vitamin D would be especially beneficial in mitigating the adverse effects of obesity on ER+ BCa. To assess whether obesity exerted adverse effects on BCa growth and whether vitamin D compounds could reduce these unfavorable effects, we employed a diet-induced obesity (DIO) model in ovariectomized C57BL/6 mice. Breast tumor cells originally from syngeneic Mmtv-wnt1 transgenic mice were then implanted into the mammary fat pads of lean and obese mice. DIO accelerated the initiation and progression of the mammary tumors. Treatments with either calcitriol or dietary vitamin D reduced the adverse effects of obesity causing a delay in tumor appearance and inhibiting continued tumor growth. Beneficial actions of treatments with vitamin D or calcitriol on BCa and surrounding adipose tissue included: repressed Er, aromatase and Cox-2 expression, decreased tumor derived estrogen and PGE2 and reduced expression of leptin receptors and increased adiponectin receptors. We demonstrate that vitamin D treatments decreased insulin resistance, reduced leptin and increased adiponectin signaling and also regulated the LKB1/AMPK pathway contributing to an overall decrease in local estrogen synthesis in the obese mice. We conclude that calcitriol and dietary vitamin D, acting by multiple interrelated pathways, mitigate obesity enhanced BCa growth in a postmenopausal setting.

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Targeting cancer stem cells in solid tumors by vitamin D

Cited by 48 publications

References 104 publications

Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer

Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer

Hedgehog signaling pathway in colorectal cancer: function, mechanism, and therapy

Vitamin D mitigates the adverse effects of obesity on breast cancer in mice

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