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Vitamin D and neoplastic diseases

Because of the multiple effects of vitamin D on cell physiology and the vast range of affected tissues, a link with neoplastic diseases, typically characterized by a dysregulation of cell proliferation, differentiation and apoptosis, can be expected. Already in 1980 higher colon cancer mortality in geographic areas in the U.S. with low natural sunlight exposure was observed. A vitamin D related mechanism to explain this phenomenon was suggested. Additional support for the hypothesis that solar UV-B, through photosynthesis of vitamin D, is inversely-associated with cancer mortality rates is provided by studies from Grant et al. (1).


Today there is good evidence linking low blood levels of 25(OH)D with various cancer types. Results from the “Health Profession Follow-Up Study” allude to the spectrum of cancers that are potentially related to vitamin D (2). This spectrum goes well beyond colon cancer and includes esophagus, stomach, and pancreas cancer as well as hematologic diseases, such as leukemia. During an observation period of 14 years 4,286 incident cancers (excluding organ-confined prostate cancer and non-melanoma skin cancer) and 2,025 deaths from cancer were recorded in this study. Total cancer incidence decreased by 17% (multivariable relative risk = 0.83) and total cancer mortality by 29% (multivariable relative risk = 0.71), per 25 nmol/L increment in plasma 25(OH)D. Malignancies of the gastrointestinal tract (esophagus, stomach, pancreas, colon, and rectum) showed the strongest relationships with plasma 25(OH)D. A 25 nmol/L increment of plasma 25(OH)D lowers digestive cancer incidence by 46% and digestive cancer mortality by 49%.

Tumorprogression and survival

Numerous studies have reported an increased mortality in cancer patients with low serum/plasma 25(OH)D levels. For example, in the Norwegian JANUS study including 658 patients with breast cancer (n = 251), colon cancer (n = 52), lung cancer (n = 210), and lymphoma (n = 145), 343 (86%) died from cancer (3). Patients with 25(OH)D levels below 46 nmol/L at diagnosis had a shorter survival. Compared to patients in the lowest quartile of serum 25(OH)D, the risk of cancer death among patients in the highest quartile was significantly reduced (HR = 0.36). The association between 25(OH)D levels and survival was evident for all four cancers. In the “Third National Health and Nutrition Examination Survey" a total of 16,818 participants were followed from 1988-1994 through 2000 (4). A total of 536 cancer deaths were recorded whereby cancer mortality was unrelated to baseline vitamin D status in the entire population (4). A recent systematic review of existing prospective studies analyzed the relationship between 25(OH)D and cancer mortality as well as 25(OH)D and survival in cancer patients (5). Despite variable results the majority of studies in cancer patients showed an inverse relationship between circulating 25(OH)D and risk of mortality. So far there is no firm evidence that links high 25(OH)D levels to an increased mortality of any type of cancer.

Vitamin D supplementation for the prevention and treatment of cancer

Considering the link between vitamin D and various types of cancer, the question arises if supplementation of vitamin D has beneficial effects on tumor incidence, progression and survival. For example, in men with metastatic prostate cancer 2,000 IU of vitamin D per day decreased or maintained their prostate-specific antigen levels over a 21 months treatment period (6). Lappe et al. reported that women who ingested a daily amount of 1,100 IU of vitamin and 1,500 mg of calcium reduced the risk of developing all cancers by 66% after four years (7). So far, only very few randomized placebo controlled trials investigating the effect of vitamin D supplementation on cancer risk and mortality have been published. A problem of most vitamin D treatment studies is that vitamin D was administered together with calcium. Therefore, it is virtually impossible ascribing any potential effect to vitamin D. Studies with more adequate doses of vitamin D are needed for a better understanding of the effectiveness of vitamin D supplementation to prevent and treat malignant disease.

Vitamin D and specific cancer types

Colorectal cancer

Colorectal cancer was among the first solid organ cancer types that were associated with vitamin D status. A direct role of vitamin D in the pathophysiology of colon cancer has been hypothesized. However, “The Women´s Health Initiative”, a randomized double-blind placebo-controlled trial involving 36,282 postmenopausal women (8) who received either calcium plus vitamin D3 or placebo for an average of 7 years, could not document that the incidence of colorectal cancer differed significantly between patients and controls.


Prostate cancer

The World Health Organization indicates that prostate cancer is the second most frequently diagnosed cancer in men, 903,000 new cases annually. There is abundant laboratory evidence that vitamin D may have anti prostate cancer properties. Anticancer activities of vitamin D have been suggested to act mainly through its nuclear receptor or VDR. But in a recent meta-analysis of 11 observational studies prostate cancer was not associated with serum levels of 25(OH)D (9). However, a recently published large prospective study supports the hypothesis that higher plasma 25(OH)D levels are associated with lower risk of lethal prostate cancer. Furthermore, epidemiological studies have not shown consistently that vitamin D has anti prostate cancer activities as reviewed recently (10). Some studies indicated that high level of serum vitamin D may, instead of decrease, increase risk of prostate cancer development (11) which is possibly due to different prostatic expression levels of two vitamin D metabolizing enzymes (CYP27B1 and CYP24A1) which can be regulated by vitamin D, androgens, and other compounds (10). Recently some in vitro study reported the promising activity of novel vitamin D analogous in the inhibition of prostate cancer cell invasion. The use of vitamin D in prostate cancer therapy can cause hypercalcemia and the use of the analogous that are less calcemic show potential application in prostate cancer therapy.


Breast cancer

The role of vitamin D in relation to breast cancer incidence and outcome is controversial. The variability of results can be partially attributed to the variability of breast cancer types. Several epidemiological studies have shown a link between low vitamin D levels and breast cancer. In one recent meta-analysis it was reported that the highest quintile of plasma vitamin D3 was found to be associated with a 45% decrease in breast cancer risk when compared with the lowest quintile (12) but no such inverse relationship is reported in another meta-analysis (9).


The potential role of treatment with vitamin D on inflammatory breast cancer, a highly aggressive form of breast cancer, is suggested also in another study (13). It is shown that although the vitamin D receptor is present in both inflammatory breast cancer and non-inflammatory breast cancer cell lines, the effect of vitamin D treatment is significant only on the inflammatory breast cancer cell lines. Furthermore, vitamin D treatment of this cell lines led to significantly fewer inflammatory breast cancer experimental metastases as compared to control. In a recent study (14) is reported that increased dietary intakes of vitamin D and calcium seem to be associated with decreased mammographic densities, one of the strongest breast cancer risk factor. It is suggested by a study that malignant breast tissue collectively responds to active 1,25(OH)2D but not to inactive pre-metabolite 25(OH)D which may have impact for vitamin D supplementation in breast cancer.

UV radiation and skin cancer

Solar and artificial UV radiation represents the most important environmental risk factor for the development of non-melanoma skin cancer, and UV protection is important to prevent these malignancies. However, approximately 90% of all vitamin D needed by the human body has to be formed in the skin through the action of UV-B radiation and it has been shown that strict sun protection causes vitamin D deficiency (15). These contrasting effects of sun light exposure represent a serious dilemma as a large number of experimental and epidemiologic studies have shown inverse associations between the body's vitamin D status and various diseases. At present most experts in the field recommend moderate sun exposure on a regular basis in order to balance adverse and beneficial effects of UV radiation.

There is no doubt that solar or artificial UV radiation is mutagenic and a main reason for the development of non-melanoma skin cancer. Therefore, excessive solar UV exposure has to be avoided, particularly burning in childhood (16). To reach this goal, the use of sunscreens as well as the wearing of protective clothes and glasses is decisive. However, it is important that recommendations of health campaigns on sun protection represent a balanced view of positive and negative effects of solar UV exposure. Exposure of the body in a bathing suit to one minimal erythemal dose (MED) of sunlight is equivalent to ingesting at least about 10,000 IU of vitamin D. Holick estimated that exposure of less than 18% of the body surface (hands, arms, and face) two to three times a week to a third to a half of an MED (about 5 min for a skin type 2 adult in Boston at noon in July) in the spring, summer, and autumn is more than adequate.

References

1.     Grant WB, Garland CF. The association of solar ultraviolet B (UVB) with reducing risk of cancer: multifactorial ecologic analysis of geographic variation in age-adjusted cancer mortality rates. Anticancer Res 2006;26:2687-99.
2.     Giovannucci E, Liu Y, Rimm EB, Hollis BW, Fuchs CS, Stampfer MJ, Willett WC. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 2006;98:451-9.
3.     Tretli S, Schwartz GG, Torjesen PA, Robsahm TE. Serum levels of 25-hydroxyvitamin D and survival in Norwegian patients with cancer of breast, colon, lung, and lymphoma: a population-based study. Cancer Causes Control 2012;23:363-70.
4.     Freedman DM, Looker AC, Chang SC, Graubard BI. Prospective study of serum vitamin D and cancer mortality in the United States. J Natl Cancer Inst 2007;99:1594-602.
5.     Pilz S, Kienreich K, Tomaschitz A, Ritz E, Lerchbaum E, Obermayer-Pietsch B et al. Vitamin D and cancer mortality: systematic review of prospective epidemiological studies. Anticancer Agents Med Chem 2013;13:107-17.
6.     Woo TC, Choo R, Jamieson M, Chander S, Vieth R. Pilot study: potential role of vitamin D (Cholecalciferol) in patients with PSA relapse after definitive therapy. Nutr Cancer 2005;51:32-6.
7.     Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007;85:1586-91.
8.     Wactawski-Wende J, Kotchen J, anderson G, Assaf A, Brunner R, O´Sullivan M, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684-94.
9.     Gandini S, Boniol M, Haukka J, Byrnes G, Cox B, Sneyd MJ et al. Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breat and prostate cancer and colorectal adenoma. Int J Cancer 2011;128:1414-24.
10.     Donkena KV, Young CY. Vitamin d, sunlight and prostate cancer risk. Adv Prev Med 2011;2011:281863.
11.     Albanes D, Mondul AM, Yu K, Parisi D, Horst RL, Virtamo J, Weinstein SJ. Serum 25-hydroxy vitamin D and prostate cancer risk in a large nested case-control study. Cancer Epidemiol Biomarkers Prev 2011;20:1850-60.
12.     Chen P, Hu P, Xie D, Qin Y, Wang F, Wang H. Meta-analysis of vitamin D, calcium and the prevention of breast cancer. Breast Cancer Res Treat 2010;121:469-77.
13.     Hillyer RL, Sirinvasin P, Joglekar M, Sikes RA, van Golen KL, Nohe A. Differential effects of vitamin D treatment on inflammatory and non-inflammatory breast cancer cell lines. Clin Exp Metastasis 2012;29:971-9.
14.     Berube S, Diorio C, Verhoek-Oftedahl W, Brisson J. Vitamin D, calcium, and mammographic breast densities. Cancer Epidemiol Biomarkers Prev 2004;13:1466-72.
15.     Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266-81.
16.     Reichrath J. The challenge resulting from positive and negative effects of sunlight: how much solar UV exposure is appropriate to balance between risks of vitamin D deficiency and skin cancer? Prog Biophys Mol Biol 2006;92:9-16.