Cancer stem cells and Vitamin D - many studies

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Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment – March 2019

Acta Pharmaceutica Sinica B, Vol 9, Issue 2, March 2019, Pages 203-219. https://doi.org/10.1016/j.apsb.2018.09.002
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Tumor cells along with a small proportion of cancer stem cells exist in a stromal microenvironment consisting of vasculature, cancer-associated fibroblasts, immune cells and extracellular components. Recent epidemiological and clinical studies strongly support that vitamin D supplementation is associated with reduced cancer risk and favorable prognosis. Experimental results suggest that vitamin D not only suppresses cancer cells, but also regulates tumor microenvironment to facilitate tumor repression. In this review, we have outlined the current knowledge on epidemiological studies and clinical trials of vitamin D. Notably, we summarized and discussed the anticancer action of vitamin D in cancer cells, cancer stem cells and stroma cells in tumor microenvironment, providing a better understanding of the role of vitamin D in cancer. We presently re-propose vitamin D to be a novel and economical anticancer agent.

Mechanisms of anticancer action of vitamin D within tumor microenvironment

“Supplementation of vitamin D is associated with reduced cancer risk and favorable prognosis. Vitamin D not only suppresses cancer cells and cancer stem cells, but also regulates tumor microenvironment, demonstrating the promise of the benefit of vitamin D in cancer prevention and treatment.”

3.2 Cancer stem cells

Cancer stem cells (CSCs) or tumor initiating cells (TICs) are critically responsible for tumorigenesis, progression, metastasis, and tumor recurrence, but they account for only a small proportion of cancer cells. Regarding the important role of the low-proportion CSCs in cancer microenvironment, targeting CSCs might be an efficient and promising method for cancer suppression. Recent studies have demonstrated that vitamin D may suppress cancer progression through targeting CSCs compartment. The role of vitamin D in regulating CSCs in gastrointestinal cancers has been thoroughly reviewed in our previous report179. Here we further summarized the suppressive action of vitamin D on CSCs in other cancers such as breast and prostate cancers.
In breast cancer, CD44 was identified as a breast cancer stem cell marker and CD44+/CD24-/low cells and CD49f+/CD24-/low were identified as tumor-initiating cells180. In MCF10A ductal carcinoma in situ (DCIS) cells, CD44 was significantly down-regulated by a Gemini vitamin D analog, BXL1024180. BXL1024 reduced the breast cancer stem-like cells population including CD44+/CD24-/low and CD49f+/CD24-/low subpopulation of MCF10A DCIS cells, and suppressed the stem cell markers expression (CD44 and CD49f)180. Further study has shown that the suppressive effect of 1,25(OH)2D3 or its analogue on breast CSCs in MCF10A DCIS was dependent in Hes1-mediated inhibition of Notch signaling181. In mammosphere, OCT4 and KLF4, which is associated with stem cell self-renewal and undifferentiated phenotype, were reduced by 1,25(OH)2D3 or BXL1024182. It is reported that another vitamin D analogue EB1089 in cooperation with BRAC1 exhibited anti-mammosphere formating ability in breast cancer cells183. Notably, Jeong et al.184 found that 1,25(OH)2D3 or oral administration with vitamin D could inhibit mouse TICs in MMTV-WNT1 mammary tumors through WNT//I- catenin signaling in vivo. 1,25(OH)2D3 inhibited spheroids formation of mouse TICs in 3D tumor spheroid culture assay in vitro1184. However, some studies showed that VDR was down-regulated in breast cancer mammosphere, potentially indicating less vitamin D action on breast CSCs183’185. Despite the controversy, the current findings still provided a new strategy for vitamin D targeting breast CSCs and give us a deeper understanding of vitamin D effect in cancer.

Although the anticancer effect of vitamin D on prostate cancer cells has been widely explored both in vitro and in vivo, the exact pharmacological action of vitamin D on prostate CSCs is not well understood. Existing evidence showed that the mechanism involved in the regulation of prostate CSCs by vitamin D was partly similar to that of prostate cancer cells. Maund et al.186 demonstrated that 1,25(OH)2D3 could induce p21 and p27 expression as well as cell cycle arrest in mouse prostate CSCs, and its anti-proliferative effect was mainly mediated by upregula- tion of IL-1a. In addition, the micro-array data indicated that the CSCs signaling (e.g., BMP and TGF-) participated in the regulatory action of 1,25(OH)2D3 on prostate CSCs186. Taken together, the mechanisms underlying vitamin D regulation of CSCs seem similar to that of normal cancer cells, i.e., mainly through WNT/-catenin, BMP, Notch and TGF- signaling mechanisms.

References

1. Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene 2008;27:5904-12.
2. Mlecnik B, Bindea G, Kirilovsky A, Angell HK, Obenauf AC, Tosolini M, et al. The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis. Sci Transl Med 2016;8:327ra26.
3. Albini A, Sporn MB. The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer 2007;7:139-47.
4. Pitt JM, Marabelle A, Eggermont A, Soria JC, Kroemer G, Zitvogel L. Targeting the tumor microenvironment: removing obstruction to anticancer immune responses and immunotherapy. Ann Oncol 2016;27:1482-92.
5. Zhao X, Chen R, Liu M, Feng J, Chen J, Hu K. Remodeling the blood-brain barrier microenvironment by natural products for brain tumor therapy. Acta Pharm Sin B 2017;7:541-53.
6. Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004;80:1678S-688SS.
7. Sun H, Wang C, Hao M, Sun R, Wang Y, Liu T, et al. CYP24A1 is a potential biomarker for the progression and prognosis of human colorectal cancer. Hum Pathol 2016;50:101-8.
8. Shiratsuchi H, Wang Z, Chen G, Ray P, Lin J, Zhang Z, et al. Oncogenic potential of CYP24A1 in lung adenocarcinoma. J Thorac Oncol 2017;12:269-80.
9. Luo W, Yu WD, Ma Y, Chernov M, Trump DL, Johnson CS. Inhibition of protein kinase CK2 reduces Cyp24a1 expression and enhances 1,25-dihydroxyvitamin D3 antitumor activity in human prostate cancer cells. Cancer Res 2013;73:2289-97.
10. Friedrich M, Axt-Fliedner R, Villena-Heinsen C, Tilgen W, Schmidt W, Reichrath J. Analysis of vitamin D-receptor (VDR) and retinoid X-receptor a in breast cancer. Histochem J 2002;34:35-40.
11. Izkhakov E, Somjen D, Sharon O, Knoll E, Aizic A, Fliss DM, et al. Vitamin D receptor expression is linked to potential markers of human thyroid papillary carcinoma. J Steroid Biochem Mol Biol 2016;159:26-30.
12. Khadzkou K, Buchwald P, Westin G, Dralle H, Akerstrom G, Hellman P. 25-hydroxyvitamin D3 1a-hydroxylase and vitamin D receptor expression in papillary thyroid carcinoma. J Histochem Cytochem 2006;54:355-61

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Role of vitamin D in targeting cancer and cancer stem cell populations and its therapeutic implications - Oct 2022

Med Oncol . 2022 Oct 29;40(1):2. doi: 10.1007/s12032-022-01855-0.
Jyoti Bharamgoud Marigoudar # 1 , Diptendu Sarkar 2 , Yakubu Magaji Yuguda # 3 , Reem Fawaz Abutayeh # 4 , Avneet Kaur 5 , Ankita Pati 6 , Disha Mitra 7 , Animikha Ghosh 8 , Debashis Banerjee 9 , Sudarshana Borah 10 , Kamallochan Barman 10 , Bhanita Das 10 , Shubham Jagdish Khairnar 11 , Emir Šehercehajic 12 , Shivam Kumar 13

Cancer is recognized globally as the second-most dominating and leading cause of morbidities. Fighting the global health epidemic threat posed by cancer requires progress and improvements in imaging techniques, surgical techniques, radiotherapy, and chemotherapy.

The existence of a small subpopulation of undifferentiated cells known as cancer stem cells has been supported by accumulating evidence and ongoing research. According to clinical data, cancer recurrence, tumor development, and metastasis are thought to be caused by CSCs.
Nutritional or dietary supplements can help you to fight against cancer and cope with the treatment side effects.

Vitamin D, sometimes known as the sunshine vitamin, is produced in the skin in reaction to sunlight. Vitamin D deficiency is hazardous to any degree, increasing the risk of diseases such as cancer and disorders like osteoporosis. Bioactive vitamin D, or calcitriol, regulates several biological pathways. Many modes of action of Vitamin D might be helpful in protecting somatic stem cells (e.g., DNA damage repair and oxidative stress protection) or restricting cancer stem cell growth (e.g., cell cycle arrest, cell apoptosis). Researchers have recently begun to investigate the inhibitory effects of dietary vitamin D on cancer stem cells. In this review, we investigated the therapeutic impact of vitamin D and its molecular processes to target cancer and cancer stem cells as well.

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A Guide to Cancer Stem Cell Markers (Gastric, Bladder. Brain, Liver, etc) - March 2022

BioCompare

"n fact, the glycoprotein CD44 has been detected on the stem cells of most cancers, including
   breast, pancreatic, prostate, colorectal, ovarian, lung, liver, head/neck, blood, bladder, gastric, brain, bone, and cervical cancers."

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Vitamin D Compounds and Cancer Stem Cells in Cancer Prevention - April 2020

Chapter in Natural Products for Cancer Chemoprevention
https://doi.org/10.1007/978-3-030-39855-2_5
Nanjoo Suh, Hubert Maehr & David Augeri

Cancer is a disease process comprising distinct stages, from initiation to promotion and progression to metastasis, where multiple factors can enhance or delay each stage during the development. Cancer stem cells, a small subpopulation of cancer cells with self-renewal and differentiating capacity, have been suggested to be involved in initiation, progression, and recurrence of tumors. Thus, targeting cancer stem cells may be important for cancer prevention. Natural products, hormones, nutritional and dietary factors have the ability to change the fate of cancer stem cells. Revealing the effect of compounds on the regulation of self-renewal or differentiation of cancer stem cells in malignancies, including breast, colorectal, prostate, and pancreatic cancers, could be useful for implementing novel cancer preventive approaches. Vitamin D compounds are known to induce hematopoietic stem cells to become more functionally differentiated cells, and differentiation therapy has been well established in blood cancers. Based on the differentiating and anti-proliferating effects, targeting cancer stem cells by vitamin D compounds may potentially contribute to the inhibition of solid tumors. In this chapter, we review the role of vitamin D compounds in regulation of cancer stem cell markers such as CD44, ALDH1, CD24, CD133, EpCAM, CD49f, as well as cancer stem cell signaling pathways including Notch, Wnt or Hedgehog in cancer. Further, diverse structures of vitamin D compounds as well as combination strategies are considered for improving differentiating activities and cancer preventive effects. Understanding the role of vitamin D compounds targeting cancer stem cells may support their potential use as cancer preventive and therapeutic agents.

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Cancer stem cells revisited - Oct 2017

Nature Medicine volume 23, pages 1124–1134 (2017) https://doi.org/10.1038/nm.4409
Eduard Batlle & Hans Clevers

The cancer stem cell (CSC) concept was proposed four decades ago, and states that tumor growth, analogous to the renewal of healthy tissues, is fueled by small numbers of dedicated stem cells. It has gradually become clear that many tumors harbor CSCs in dedicated niches, and yet their identification and eradication has not been as obvious as was initially hoped. Recently developed lineage-tracing and cell-ablation strategies have provided insights into CSC plasticity, quiescence, renewal, and therapeutic response. Here we discuss new developments in the CSC field in relationship to changing insights into how normal stem cells maintain healthy tissues. Expectations in the field have become more realistic, and now, the first successes of therapies based on the CSC concept are emerging.
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Stem Cells - What are they and why are they important (to Multiple Sclerosis) 2019?

National MS Society
Many videos and studies

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Vitamin D can be used as a supplement_against cancer stem cells - Sept 2018

Cellular and Molecular Biology E-ISSN : 1165-158X / P-ISSN : 0145-5680 Doi: http://dx.doi.org/10.14715/cmb/2018.64.12.10
Nadir Koçak1*, Süleyman Nergiz1, Ibrahim Halil Yildinm2, Yagmur Duran1
1 Department of Medical, Medical Faculty, GeneticsSelcuk University, Konya, Turkiye
2 Department of Genetics, Faculty of Veterinary Medicine, Dicle University, Diyarbakir, Turkiye
Correspondence to: nadirkocak at yahoo.com

Cancer is standing like a bottomless pit or a black hole in front of mankind. Scientists are trying all possible ways to find a solution against to cancer. As known, cancer is a phenomenon fed from internal dynamics. One of internal dynamic is cancer stem cells that are involved in the formation and development of cancer. Because of these dynamics, scientists began to search solution inside of the body. Another internal dynamic is vitamin D and it is not only important in calcium homeostasis but also it is important for cell proliferation, differentiation, and apoptosis. In this study, we investigated the effect of vitamin D on cancer stem cells that sorted from MCF-7 cell line and on HEK293 cell line as control. Our results showed that calcitriol treatment reduced the number of CSC (Cancer Stem Cell) in the MCF-7 cell while increased in HEK293 cell population. Gene expression analyses showed that effect of calcitriol on apoptosis plays an important role in this reduction. Deficiency or unavailability of vitamin D may take a role in the pathogenesis of breast cancer.
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Boosting the effects of vitamin D to tackle diabetes - May 2018 Stem Cells Portal

• "In a paper published May 10 in Cell, researchers from the Salk Institute report a potential new approach for treating diabetes by protecting beta cells — the cells in the pancreas that produce, store and release the hormone insulin. When beta cells become dysfunctional, the body can't make insulin to control blood sugar (glucose) and levels of glucose can rise to dangerous, even fatal levels."
• "The investigators accomplished their goal by using an unexpected source: vitamin D. Vitamin D in cells and mouse models proved beneficial in treating damaged beta cells. It also provided new insights about gene regulation that could be applied to developing treatments for other diseases, including cancer."

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How Vitamin D Stops Cancer Stem Cells - 2016?

Dr. Jockers

It is interesting to notice that many of the nutrients activate the Vitamin D Receptor

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See also VitaminDWiki

• Active Vitamin D reduces Ovarian Cancer stem cells growth by 4X (via Vitamin D receptor in lab rat) – March 2018
• Metastatic Cancer probably reduced by vitamin D - many studies
• Cancer and Vitamin D - many studies
• Gastric Cancer, Vitamin D, VDR, UV - many studies

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