A recent animated discussion within the research group where I was working suggested for the existence of a great concern about who and how may be the principal expert in the field, an expert able to fulfill the expectation coming from the most common people whether really vitamin D supplementation exerts wondrous properties on human health or not. (Table 1) summarizes how many fundamental research teams are endeavoured with vitamin D in the medical field within the University where I am working. This overview should shed a light on how this topic is inflated in medical science, even offering a limited example such this. Therefore, this may suggest that experts in the field about vitamin D are really biochemists, physicians or other graduated and postgraduated professionals who are endeavored to demonstrate the role of vitamin D in many inflammatory disorders. Yet, at the same time, this should even suggest that there is not any particular intellectual property aside from that one coming from a general, shared interest in the issue as related to other specific areas, such as cancer, rheumatology, allergy, endocrinology, internal medicine. Therefore, the question is: why so much people is investigating the role of vitamin D in medicine?

A recent communication held by Professor William Grant from the Sunlight Nutrition and Health Research Center, San Francisco, CA, USA, concluded that solar UVB geographical exposure and 25(OH)vitD₃ (calcifediol or calcidiol) bioavailability, are causally linked in the presumptive reduction of cancer incidence and that an increase in plasma bioavailability up to 100 nmol/L 25(OH)vitD₃ should reduce notably cancer risk [1]. Vitamin D went in the spotlight because of its wondrous potential to prevent cancer onset, or even fight it. Interestingly, very few papers dealing with vitamin D in cancer have never reported in my University, despite the fact that some research teams (Table 1) would be pleased to test vitamin D on pancreas cancer, though they never published on pancreas oncology and have an ongoing expertise in adipose tissue and aging. An eclecticism, somewhat, in medical science, arouses researchers' curiosity on vitamin D, most probably because this vitamin exerts a particular appeal in clinical pathology. Sincerely, I think that vitamin D, particularly its main circulating form 25(OH)vitD₃, actually possesses many interesting properties but most probably they were overrated or, more simply, excessively simplified at the most common view.

The role of vitamin D in cancer prevention and treatment is yet a puzzling issue.

While an extensive, thorough scientific literature exists about the role of vitamin D in muscle and bone physiology, its latest emerging role as an anti-inflammatory agent suggested for a major role in chronic inflammatory pathologies, such as tumors [2]. The effect of calcidiol on tumors yet depends on a huge deal of factors, of which the availability and metabolism of calcitriol (1α, 25(OH)2vit D3) is probably the main item [3]. Calcitriol is the active form of vitamin D, is the major ligand of the vitamin D receptor (VDR) and is rapidly degraded by 24-hydroxylases. To date, due to its very short plasma half-life, its analytical determination is particularly cumbersome and time expensive, so the activity of calcitriol is closely related to the bioavailability of its main precursor, 25(OH)vitD₃. However, the ability of calcidiol to exert its action as the dihydroxylated form, depends by VDR response in different cells, particularly in immune and cancer cells [3] [4]. Genetics of VDR in human population, such as Cdx2 (breast cancer), Fok1 (prostate cancer), BsmI, TaqI, Apal, EcoRV VDR polymorphisms, has been reported to affect cancer onset and progression, when related to vitamin D availability and supplementation [5] [6] [7]. VDR polymorphism influences any vitamin D-mediated response in metabolic syndrome [8], islet autoimmunity and type 1 diabetes [9], gynecological malignancies [10], Th1 cell immunity [11], although association with VDR SNPs and type 1 diabetes at the genomic level showed also some contradictory evidence [12] [13]. If calcitriol acts as a hormonal and immunomodulating activity targeting VDR, its efficiency level in tumors should depend on VDR polymorphism, besides to any nutritional intake [3] and actually VDR polymorphism is a major issue to address cancer prevention and therapy [14].

Moreover, VDR is expressed also by immune cells and both calcidiol and calcitriol are able to modulate gene transcription in leukocytes, mainly T-helper and NK cells [15]. To date, no reports were published trying to address the complex relationship between VDR polymorphism and circulating levels of calcidiol, while this issue should be investigated in order to elucidate the apparently contradictory evidence coming from the employment of dietary-derived substances in cancer research [16] [17].

The fact that calcitriol is both a cytokine-like molecule and a hormone, should hamper any naïve approach taking into account vitamin D supplementation in cancer prevention or even treatment, even by arranging in vitro studies aiming at elucidating this relationship [18]. The relationship of circulating calcidiol and bioactive calcitriol appears to be the only mechanism to which any effort appears to be moved on, as a simplistic view considering that calcidiol is quite perfectly transformed in calcitriol, leads people to believe that a linear relationship between circulating calcidiol and active calcitriol can be reported. This might be quite far from the truth, although plasma level of calcidiol should give a "signal" of the individual endowment in active vitamin D₃. The question of how much plasma circulating calcidiol should warrant for a good prevention of chronic diseases, yet remains.

A more complex approach on vitamin D in cancer should involve issues such as (a) dietary habits in the studied/enrolled population, (b) lifestyles, (c) geographical area, (d) genetic polymorphism for VDR and P450 cytochromes, (e) gut microflora and gut microbiome (genomics).

Although this suggestion may be considered cumbersome for any good laboratory research on vitamin D, the simplest approach to test commercial colecalciferol or calcidiol on cancer cell lines cannot give important insights on the actual activity of calcidiol in people affected by tumors, particularly if research teams do not possess an excellent expertise in clinical oncology. Epidemiological investigations trying to highlight the relationship between plasma vitamin D levels and cancer onset and/or progression, are welcome but they must be read and understood at the light of differential dietary habits and geographical areas and furthermore an international consensus about the best plasma circulating calcidiol levels should be fitted to different geographical regions and/or different diet regimens and lifestyles, besides to age and sex.

Laboratories are hindered in their attempt to evaluate calcitriol dosage in biological fluids and therefore calcidiol, which accounts for a simplest way to evaluate its concentration, is quite the only reliable plasmatic parameter used to study vitamin D availability in humans. Any effort to relate clinical outcome to this marker does not take into consideration the fact that plasma calcidiol is in an homeostatic equilibrium with other forms and metabolites of vitamin D, particularly in chronic or immune degenerative disorders, although reports were published showing a certain linearity between calcidiol and calcitriol, which represents the current major prejudice [19] [20]. Furthermore, its relationship with innate and acquired immunity is yet highly complex [3] [4]. Whether vitamin D, in its active form, is either a protolerogenic or anti-inflammatory molecule, depends on its relationship with adipose tissue, muscle, bone and gut [3][4], making a scenario that should render more complicated to ascertain the effect of vitamin D supplementation on cancer.

Therefore, maybe it is time at last to build up a multidisciplinar laboratory or research center in our University focused quite exclusively on vitamin D related disorders and translational medicine, based on vitamin D target, as the interest on the role exerted by vitamin D in the human health is greatly increasing in recent years.

Vitamin D probably does not heal people from cancer but, as many other natural-derived molecule, may greatly contribute to prevent its malignancy.

Keywords: Vitamin D, cancer, Verona University, pancreas

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