2 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 1
Editorial
EDITORIAL Vitamin D and Cancer: Current Evidence and Future Perspective A potential association of vitamin D and cancer is an issue of great public health interest because vitamin D deficiency is common in general populations [1]. Many people are well aware that sunlight exposure is on the one hand required for endogenous vitamin D synthesis but may on the other hand cause skin cancer. By contrast, the observation that ultraviolet-B (UV-B) exposure is associated with reduced risk of overall cancer mortality is not so generally known although this UV-B cancer link was a starting point for vitamin D cancer research [2-4]. Numerous experimental and observational studies have meanwhile addressed the relationship of vitamin D and cancer and have, by the majority, supported the hypothesis that vitamin D might be useful for the prevention and treatment of cancer [5-7]. When discussing clinical use of vitamin D supplementation, the attention is often guided to past experiences with other micronutrients (e.g. vitamin E) that revealed promising anti-cancer properties in cell culture and observational studies but failed to show benefits or were even harmful in the clinical application. It should be underlined that vitamin D significantly differs from other micronutrients because vitamin D has a unique metabolism with endogenous UV-B induced vitamin D synthesis in the skin. Apart from this, vitamin D metabolites can be rather regarded as hormones than as vitamins and regulate approximately three percent of the human genome by binding to the almost ubiquitously expressed vitamin D receptor (VDR) [7]. While there is an ongoing debate on vitamin D status classification and optimal vitamin D dosing, it is widely accepted that vitamin D supplementation exerts beneficial effects on skeletal health [8-10]. These data were the basis for dietary reference intakes for vitamin D and for recommendations to supplement vitamin D in osteoporosis patients and in children for the prevention of rickets [8-10]. At present, there is no RCT published that was specifically designed and powered to study vitamin D effects on cancer. Interpretations of data on vitamin D supplementation and cancer as a secondary outcome are therefore limited but it should be acknowledged that available RCTs have largely failed to show significant anti-cancer effects of vitamin D whereas only some RCT data support the notion that vitamin D may significantly protect against cancer [6,9-13]. Therefore, we need further vitamin D RCTs, but after decades of research this should not be the only conclusion that we can draw from thousands of publications in this field. Rather than showing that there exists universal agreement it was an aim of this special issue to document that there exist different views, conclusions and recommendations of the experts regarding vitamin D and cancer. Given that some vitamin D RCTs are already ongoing we will have significantly more data within the next few years [14]. These RCTs will be essential for future vitamin D guidelines but we should also critically discuss the design of these RCTs and ask the question whether they have sufficiently considered the knowledge derived from previously published epidemiological studies [14]. In addition to RCTs among general populations it will therefore be important to study cohorts that are likewise particularly vitamin D sensitive, i.e. individuals suffering from overt vitamin D deficiency. Nevertheless, at present we have to deal with the currently available evidence when considering vitamin D treatment or vitamin D food fortification for our patients or for the general population. In this context, it should always be noted that vitamin D signalling is, beyond skeletal health, involved in the pathogenesis of many different diseases with a potential impact even on overall mortality [1,5,7,15-20]. However, whereas many data suggest beneficial effects of vitamin D for several health outcomes we must also pay particular attention to potentially harmful effects of vitamin D overdosing when discussing a general vitamin D supplementation or food fortification. This special issue aims to provide an overview of the current status and future perspective of vitamin D and cancer and covers topics related to basic as well as clinical research in order to give some guidance for future cancer research as well as for current considerations regarding the use of vitamin D treatment. Stefan Pilz et al. review data from prospective studies on 25hydroxyvitamin D and cancer mortality in their work. William B Grant highlights in his article that higher UV-B irradiance is associated with reduced risk of cancer. Julia Höbaus et al. summarize the important role of vitamin D metabolism (i.e. vitamin D hydroxylases) and its crosstalk with calcium in cancer pathogenesis and cancer prevention. Kun-Chun Chiang & Tai C Chen provide an overview of molecular anticancer actions of vitamin D in their article. Rebecca S Mason and Jörg Reichrath summarize the existing literature on the relationship of sunlight, vitamin D and skin cancer and discuss positive and negative effects of UV exposure with regard to skin cancer and overall health. Rowan T Chlebowski reviewed clinical data on vitamin D and breast cancer and concludes that current evidence does not support the use of high dose vitamin D supplementation in anticipation of benefit for breast cancer recurrence or breast cancer survival. Epidemiological data on vitamin D and colorectal cancer are summarized by Edward Giovannucci who underlines that the association of vitamin D deficiency and colorectal cancer is strongly suggestive of a causal association. Gary G Schwartz presents an overview on vitamin D, UV exposure and prostate cancer and points out that these relationships may be modulated according to the prevailing calcium intake. Kathy J Helzlsouer & Lisa Gallicchio summarize clinical data on vitamin D and rare cancer sites and conclude that while there is little evidence that higher vitamin D status may be protective for some rare cancer sites there exist conflicting results regarding increased pancreatic cancer risk at very high vitamin D levels. Matteo Lazzeroni et al. review RCTs on vitamin D supplementation and cancer and discuss the conclusions that can be drawn from published RCTs and what can be expected from ongoing vitamin D RCTs. Heike Bischoff-Ferrari summarizes beneficial musculoskeletal effects of vitamin D supplementation in cancer patients. Jean-Claude Souberbielle and Etienne Cavalier provide an overview on vitamin D status assessment and give some practical guidance for vitamin D testing and supplementation. Armin Zittermann et al. highlight pathophysiological and clinical data regarding safety issues of vitamin D supplementation. Finally, Michael F Holick summarizes current knowledge on the vitamin D, sunlight and cancer connection and gives some advice for clinical vitamin D treatment. In conclusion, this special issue gives an up to date overview on almost all aspects regarding vitamin D and cancer. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8]
Holick, M.F. Vitamin D deficiency. N. Engl. J. Med., 2007, 357(3), 266-283. Garland, C.F.; Garland, F.C. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int. J. Epidemiol., 1980, 9(3), 227-31. Apperly, F.L. The Relation of Solar Radiation to Cancer Mortality in North America. Cancer. Res., 1941, 1(3), 191-195. Grant, W.B.; Mohr, S.B. Ecological studies of ultraviolet B, vitamin D and cancer since 2000. Ann. Epidemiol., 2009, 19(7), 446-54. Deeb, K.K.; Trump, D.L.; Johnson, C.S. Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat. Rev. Cancer., 2007, 7(9), 684-700. Pilz, S.; Tomaschitz, A.; Obermayer-Pietsch, B.; Dobnig, H.; Pieber, T.R. Epidemiology of vitamin D insufficiency and cancer mortality. Anticancer Res., 2009, 29(9), 3699-704. Bouillon, R.; Carmeliet, G.; Verlinden, L.; van Etten, E.; Verstuyf, A.; Luderer, H.F.; Lieben, L.; Mathieu, C.; Demay, M. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr. Rev., 2008, 29(6), 726-76. Bischoff-Ferrari, H.A.; Willett, W.C.; Wong, J.B.; Stuck, A.E.; Staehelin, H.B.; Orav, E.J.; Thoma, A.; Kiel, D.P.; Henschkowski, J. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch. Intern. Med., 2009, 169(6), 551-61.
Editorial [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20]
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Ross, A.C.; Manson, J.E.; Abrams, S.A.; Aloia, J.F.; Brannon, P.M.; Clinton, S.K.; Durazo-Arvizu, R.A.; Gallagher, J.C.; Gallo, R.L.; Jones, G.; Kovacs, C.S.; Mayne, S.T.; Rosen, C.J.; Shapses, S.A. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J. Clin. Endocrinol. Metab., 2011, 96(1), 53-8. Holick, M.F.; Binkley, N.C.; Bischoff-Ferrari, H.A.; Gordon, C.M.; Hanley, D.A.; Heaney, R.P.; Murad, M.H.; Weaver, C.M.; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab., 2011, 96(7), 1911-30. Bolland, M.J.; Grey, A.; Gamble, G.D.; Reid, I.R. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am. J. Clin. Nutr., 2011, 94(4), 1144-9. Brunner, R.L.; Wactawski-Wende, J.; Caan, B.J.; Cochrane, B.B.; Chlebowski, R.T.; Gass, M.L.; Jacobs, E.T.; LaCroix, A.Z.; Lane, D.; Larson, J.; Margolis, K.L.; Millen, A.E.; Sarto, G.E.; Vitolins, M.Z.; Wallace, R.B. The effect of calcium plus vitamin D on risk for invasive cancer: results of the Women's Health Initiative (WHI) calcium plus vitamin D randomized clinical trial. Nutr. Cancer., 2011, 63(6), 827-41. Lappe, J.M.; Travers-Gustafson, D.; Davies, K.M.; Recker, R.R.; Heaney, R.P. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am. J. Clin. Nutr., 2007, 85(6), 1586-91. Manson, J.E.; Bassuk, S.S.; Lee, I.M.; Cook, N.R.; Albert, M.A.; Gordon, D.; Zaharris, E.; Macfadyen, J.G.; Danielson, E.; Lin, J.; Zhang, S.M.; Buring, J.E. The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp. Clin. Trials., 2012, 33(1), 159-71. Pilz, S.; Tomaschitz, A.; März, W.; Drechsler, C.; Ritz, E.; Zittermann, A.; Cavalier, E.; Pieber, T.R.; Lappe, J.M.; Grant, W.B.; Holick, M.F.; Dekker, J.M. Vitamin D, cardiovascular disease and mortality. Clin. Endocrinol. (Oxf.), 2011, 75(5), 575-84. Lips, P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr. Rev., 2001, 22(4), 477-501. Pilz, S.; Tomaschitz, A.; Drechsler, C.; Zittermann, A.; Dekker, J.M.; März, W. Vitamin D supplementation: a promising approach for the prevention and treatment of strokes. Curr. Drug Targets, 2011, 12(1), 88-96. Zittermann, A.; Iodice, S.; Pilz, S.; Grant, W.B.; Bagnardi, V.; Gandini, S. Vitamin D deficiency and mortality risk in the general population: a metaanalysis of prospective cohort studies. Am. J. Clin. Nutr., 2012, 95(1), 91-100. Pilz, S.; Iodice, S.; Zittermann, A.; Grant, W.B.; Gandini, S. Vitamin D status and mortality risk in CKD: a meta-analysis of prospective studies. Am. J. Kidney Dis., 2011, 58(3), 374-82. Bjelakovic, G.; Gluud, L.L.; Nikolova, D.; Whitfield, K.; Wetterslev, J.; Simonetti, R.G.; Bjelakovic, M.; Gluud, C. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst. Rev., 2011, (7), CD007470.
Stefan Pilz (Guest Editor) Department of Internal Medicine Division of Endocrinology and Metabolism Medical University of Graz Auenbruggerplatz 15, 8036 Graz Austria Tel: ++43 650 9103667 Fax: ++43 316 673216 E-mail:
[email protected] 