Biochimica et Biophysica Acta
Department of Oncological and Surgical Sciences, University ofPadova, Padova, Italy
Received 16 April 2011, Accepted 4 July 2011
Vitamin D is a hormone-like micronutrient involved not only in calcium metabolism but also in a variety of biological activities (e.g., cell proliferation, apoptosis, angiogenesis, inflammation) that makes it a candidate anticancer agent. Preclinical studies support the therapeutic potential of vitamin D both alone and in combination with other therapeutics. Overall, epidemiological data suggest the existence of a link between vitamin D and cancer risk, whereas the results of clinical trials are quite conflicting.
This article is a comprehensive and balanced overview of the current evidence in an attempt to critically interpret the wealth of scientific data thus far produced on this research field and to rationally envisage the next steps necessary to define the role of vitamin D in the therapeutic management of cancer.
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The above summary of the current evidence suggests that, overall, a relationship between vitamin D and cancer does exist, although its strength appears to weakens as we move from the preclinical to the clinical ground.
In fact, the ability of vitamin D to exert a variety of potential anticancer effects is quite uniformly reported in a wide range of in vitro and in vivo preclinical models. In particular, it is evident that different vitamin D derivatives can act as anticancer agents both as single agents and in association with conventional chemotherapeutics as well as molecularly targeted compounds, which is leading to test novel combinatorial regimens in the clinical setting . However, additional insights - possibly within the framework of a systems biology approach  - are eagerly needed to decipher the molecular network underlying sensitivity or resistance to vitamin D-based therapeutic strategies.
As regards epidemiological studies (Table 1 and 2), although the findings of single reports are sometimes conflicting, most pooled analyses do support a role of the vitamin D pathway in cancer development. The interpretation of these studies is complicated by several issues. One is the heterogeneity of the tumor types (and thus of the underlying biological behaviors) considered: in some studies the association is null when all tumors are considered, whereas it becomes significant if single histological types are considered  (Table 1). For other cancers the interaction between vitamin D and environmental factors adds further complexity: for instance, in cutaneous melanoma sun exposure can be both a protective factor (likely through the activation of vitamin D precursors in the skin) and a risk factor (due to the DNA damage by ultraviolet radiation from sunburns), which makes it difficult to separate the effects of vitamin D from those of (excessive) sun exposure .
Another issue is linked to the multigenic nature of cancer, which remains intrinsically unaddressed by studies dealing with genetic polymorphisms of single genes : in this regard, recently introduced genome wide association studies (GWAS)  will certainly accelerate the pace of discovery of germ-line genetic signatures explaining cancer predisposition/progression to a larger degree as compared to the small (sometime tiny) population attributable risks identified by single SNP.
Additionally, the meta-analyses on the relationship between vitamin D serum levels and cancer risk are not uniform (Table 2) and __single studies have even reported an adverse effect [80,81], which leads to advocate a U-shaped (instead of linear) association not only for cancer development but also progression _. Examination of the evidence for opposite effects of vitamin D on carcinogenesis in various tissues and among certain subgroups suggests a complex situation in which the potential for both harm and benefit may depend on dose, timing and duration of exposure, tissue specificity, lifestyle factors, and interaction with genetic background, all factors to be taken into consideration in multivariable models of cancer biology.
Finally, despite the wealth of clinical trials so far conducted to prove the therapeutic efficacy of vitamin D, the most reliable evidence - which comes from RCT - is again inconclusive, as above summarized. In view of the many unresolved questions regarding the optimal biological dose and schedule, as well as the pharmaceutical issues about the available vitamin D formulations, the lack of anticancer activity shown by some of these therapeutic trials cannot be taken as definitive. Furthermore, the lack of beneficial effects in arresting the progression of already established tumors does not rule out the possibility that vitamin D might be useful in preventing cancer development. In this regard, recent in vivo findings on the ability of vitamin D to reduce the DNA oxidative damage and promote colon epithelium differentiation in humans further strengthens this working hypothesis [83,84].
In conclusion, like most biological phenomena, the relationship between vitamin D and cancer is neither univocal nor easy to interpret, and any conclusion drawn on the basis of the existing evidence would probably be simplistic at this time.
More details are needed on the molecular network involved in the anticancer effects caused by vitamin D in preclinical models, which would enable researchers to fully exploit the therapeutic potential of this micronu-trient; on the other hand, appropriately designed clinical trials taking into consideration the already available knowledge (e.g., dose-effect relationship, synergism with molecularly targeted anticancer agents) are also warranted in order to test the therapeutic/preventive effect of vitamin D on the practical ground and ultimately define its role in the clinical setting. The above reported summary of the available evidence supports the belief that further investigation in this field is worthwhile in the fight against cancer, as witnessed by the large number of ongoing trials of vitamin D both in the therapeutic and preventive setting (see: http://www.clinicaltrials.gov).