Vitamin D is a fat-soluble vitamin that regulates bone modeling and calcium metabolism. Although we absorb moderate amounts of the vitamin from foods such as milk and fatty fish, the majority of vitamin D is produced in the body when 7-dehydrocholesterol in the skin is exposed to ultraviolet UV B radiation to produce vitamin D3 cholecalciferol. Vitamin D3 then undergoes two hydroxylation steps: first in the liver to form dihydroxyvitamin D2, the major circulating metabolite, and then primarily in the kidney to produce 1,dihydroxyvitamin D3 1,25 OH 2D3 , the biologically active form.
Active vitamin D is produced in a number of tissues, including the breast, prostate, and colon. This activated vitamin D binds to the vitamin D receptor VDR to form a nuclear receptor-ligand complex. This forms a heterodimer with the retinoid-X-receptor RXR and can regulate the expression of up to genes, including p21, p27, c-fos, and c-myc. This prevents DNA synthesis and cell growth.
In this paper, we review the recent basic science and clinical research concerning vitamin D and the four most common malignancies: lung, breast, colorectal, and prostate cancer. NSCLC has three subtypes: squamous-cell carcinoma, adenocarcinoma, and large-cell lung cancer. Despite advances in early detection and standard treatment, NSCLC is often diagnosed at an advanced stage and has a poor prognosis.
Enough vitamin D may protect against some cancers
It is highly responsive to chemotherapy and radiotherapy but almost always relapses and is almost universally fatal. There have been multiple in vitro studies that have established 1,25 OH 2D3 as an inhibitor of lung cancer growth. Researchers have also demonstrated that 1,25 OH 2D3 inhibits squamous cell carcinoma SCC cell motility, invasion, and metastasis, partially through the promotion of E-cadherin-mediated cell—cell adhesion. Zhang et al. Given the in vitro and in vivo data, researchers have completed several observational trials that have explored the relationship between 1,25 OH 2D3 and lung cancer survival.
Srinivasan et al. Freedman et al. Given the intracellular effects of 1,25 OH 2D3, researchers have explored whether 1,25 OH 2D3 may have a synergistic effect with cytotoxic and targeted treatment. Several studies demonstrate that 1, OH 2D potentiates the cytotoxic effect of taxane and platinum-based chemotherapy in SCC murine models. Ultimately, while there is strong evidence that vitamin D has antineoplastic effects in vitro and in vivo, the epidemiologic evidence for improved survival is mixed.
Vitamin D could help cancer patients live longer -- ScienceDaily
Randomized clinical trials are needed to demonstrate whether vitamin D has a clinically significant benefit for lung cancer patients both for prevention and as an adjuvant treatment. Breast Cancer Aside from nonmelanoma skin cancer, breast cancer is the most common cancer among women in the US. In the most recent year for which statistics are available , , women in the US were diagnosed with breast cancer and 40, women died from the disease. There are several subtypes of breast cancer that affect both prognosis and treatment. These triple-negative cancers have a poorer prognosis compared with other types of breast cancer.
As discussed previously, multiple studies have found an in vitro effect of 1,25 OH 2D3 on breast cancer cell lines including cell-cycle arrest 31,32 and regulation of downstream signaling pathways. This suggests that 1,25 OH 2D3 may effect the bone microenvironment.
In , Garland et al. Subsequent studies have had mixed results. This relationship has also been explored in several large cohort studies. High vitamin D intake was associated with a statistically significant lower risk for premenopausal breast cancer odds ratio [OR] 0.
Higher intake of vitamin D was associated with a lower risk for breast cancer in premenopausal women OR 0. Researchers have also examined the relationship between serum 1,25 OH 2D3 levels and breast cancer risk, both in prospective cohort studies and case-control studies. The majority of case-control studies found a statistically significant lower risk for breast cancer among women with higher circulating vitamin D levels.
At this time, there have been only two randomized clinical trials exploring vitamin D levels and the risk of breast cancer.
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- Should I take a vitamin D supplement - Canadian Cancer Society?
In the WHI, there was no reduction in the risk for breast cancer in women randomly assigned to take calcium 1, mg and vitamin D3 IU daily versus placebo. Lastly, there is some data for utilizing vitamin D in breast cancer treatment. Colorectal Cancer Colorectal cancer is the third leading cause of cancer-related death in the US. It is the second leading cause when both sexes are combined. It is expected to cause about 50, deaths during In colorectal cancer cell lines, 1,25 OH 2D3 causes growth arrest of colorectal cancer cells. Vitamin D also modulates apoptosis in colorectal cancer cells.
Angiogenesis appears to be regulated by vitamin D in vitro. In colorectal carcinoma cultures, vitamin D has also been found to modify both phase I and II enzymes involved in reduction, oxidation, hydrolysis, and conjugation—all important for the removal of compounds that may contribute to the formation of cancer. There is a substantial amount of epidemiologic literature that examines the relationship between vitamin D and the risk for colorectal cancer.
Garland and Garland published a paper in that proposed an inverse relation between latitude and colorectal cancer mortality. They found an inverse association between both serum 25 OH D2 and vitamin D intake and the risk for developing colorectal cancer. There is some clinical trial data on vitamin D supplementation and colorectal cancer, albeit scarce. Trivedi et al. The largest clinical trial to date is the WHI. Initially, the results did not show a relationship between vitamin D supplementation and the incidence of colorectal cancer.
There is a lot of evidence implicating a role for vitamin D in colorectal cancer in vitro and in epidemiologic studies. Give vitamin D 3 doses high enough to raise 25 OH D concentrations to the upper part of the relationship. Measure 25 OH D concentration again during the trial to determine the success of the dosing and assess compliance Guidelines for designing vitamin D trials more likely to find beneficial effects were outlined in two recent papers 5 , It was suggested that all trial outcomes be related to 25 OH D concentrations, measured several times during the trial, with adjustments in dosing to produce desired achieved concentrations Comparing cancer survival between black and white Americans.
Another way to assess vitamin D's role in cancer is to examine the disparity in cancer survival rates between black and white Americans. According to a review of the journal literature, disparities are evident for 13 cancers after consideration of socioeconomic status, stage at diagnosis, and treatment in most cases: bladder, breast, colon, endometrial, lung, ovarian, pancreatic, prostate, rectal, testicular, and vaginal cancer; Hodgkin's lymphoma; and melanoma Of course, other lifestyle factors could also be involved.
One concern is that black Americans have a different biologically available 25 OH D concentration. That effect was believed to be a result of a different relation between total and free 25 OH D due to a different effect of the vitamin D—binding protein But a recent study dispelled that concern by showing nearly identical odds ratios for free and total 25 OH D concentrations for colorectal cancer incidence for black Americans Summary table.
Table V presents findings of ecological and observational studies regarding cancer incidence, survival, and mortality rates with respect to indices of solar UVB or 25 OH D concentration, as well as results regarding disparities in cancer-specific survival rates between black and white Americans. The ecological study findings are taken from the review in 2. The occupational exposure results are primarily from an analysis of SIRs by occupation The observational results for 25 OH D concentrations are generally the latest meta-analysis.
If no meta-analysis has been published, the most recent paper is used. The results for African Americans are from 11 along with results from later papers. The cancers are grouped into epithelial or hematopoietic hematological categories and arranged in descending order according to estimated incidences in That order is used because the likelihood of finding effects of UVB or vitamin D is expected to increase with the annual number of cases.
Summary table of significant inverse relationships regarding UVB dose, 25 OH D concentration, on cancer incidence, survival, mortality rate or survival disparities for African Americans compared to white Americans. In addition, seven of those 17 also have studies reporting significantly poorer survival rates for black Americans than white Americans. The findings are less robust for hematological cancers, with little support for protective effects against cancer incidence.
However, some studies report inverse correlations between serum 25 OH D concentration at time of diagnosis and progression or survival. Hill ' s criteria for causality. Another way to assess causality is to apply A. Bradford Hill's criteria for causality in a biological system The criteria appropriate for vitamin D include strength of association, consistency, temporality, biological gradient dose—response relationship , plausibility e. Later authors added two more criteria: account for confounding factors and eliminate bias Not all criteria need be satisfied, but the more that are, the stronger the case for causality.
Hill's criteria have been applied to cancer for cancer in general and breast cancer Because several years have passed since those two analyses, a brief update is worthwhile. Table VI summarizes how the criteria are satisfied. Assessing the UVB—vitamin D—cancer hypothesis by using Hill's criteria for causality in biological systems The way forward.
The authors of several recent papers suggest how that can be done 5 , In addition, the results of several large-scale vitamin D clinical trials should be available in the next year or two. Although they may not have been ideally designed, they should nonetheless report reduced risk for cancer, especially among the black Americans in the Vitamin D and OmegA-3 VITAL trial Another factor to consider is more widespread use of CC studies in which 25 OH D concentrations are measured near time of cancer diagnosis along with taking a recent history of supplement intake, dietary sources including meat 35 , and sun exposure.
Controls should be matched as well as possible, including time of blood draw. That concentration was associated with significantly reduced cancer incidence in a clinical trial in Nebraska Most other studies reporting J- or U-shaped 25 OH D concentration—health outcome relationships did not obtain a vitamin D supplementation history of the participants, and most participants with high 25 OH D concentrations higher than expected from solar UVB exposure were probably taking vitamin D supplements, many starting only recently, perhaps because of osteoporosis concerns.
Many other health benefits are associated with higher 25 OH D concentrations, including reduced risk of autoimmune diseases , diabetes mellitus type 2 , adverse pregnancy and birth outcomes , respiratory tract infections , and all-cause mortality rate Whether vitamin D reduces risk of cardiovascular disease is still uncertain based on support from observational studies but not clinical trials Thus, raising 25 OH D concentrations in an effort to reduce cancer risk will yield additional benefits.
The only way to ensure reaching the desired concentration is to have serum 25 OH D concentration measured 18 , The UVB—vitamin D—cancer hypothesis has considerable supporting scientific evidence from a variety of study types: geographical ecological, observational, and laboratory studies of mechanisms, as well as several clinical trials. At this time, the general public and individual physicians can spend more reasonable time in the sun and use vitamin D 3 to prevent and treat many cancers. Hopefully soon, the clinical evidence will be strong enough that health care systems and agencies will endorse vitamin D 3 supplementation as a way to prevent and treat cancer.
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