Commentary: Vitamin D and Pancreatic Cancer: A Pooled Analysis from the Pancreatic Cancer Case-Control Consortium

Waterhouse et al. criticized the association between vitamin D intake and the prevention of pancreatic cancer (1), an association that has been thoroughly reviewed in recent years (2, 3). Yet, randomized controlled clinical trials (RCTs) very rarely produced encouraging and reliable results on the field (4–7). Negative evidence in animal models and experimental studies (8, 9) should suggest that the chemopreventive role of 1,25(OH)2D3 deserve particular attention when dietary vitamin D3 is considered (10). Best correlations were reported on vitamin D3 deficiency and cancer malignancy (11–14) or on frequent dietary intake of vitamin D3 and tumor prevention (15). The chemopreventive role might closely depend on plasma bioavailability of 25(OH)D3 and genetic polymorphism of vitamin D receptor (VDR) (16, 17). Physicians are asking whether vitamin D3 supplementation may really contribute in preventing cancer (18, 19) and, at the same time, they suggested recommendations to fortify foods with supplemented vitamin D3, to achieve optimal levels of plasma 25(OH)D3 (20, 21). Waterhouse et al. showed that cancer risk increased with higher levels of vitamin D intake, although they did not exclude the possibility that vitamin D obtained through ultraviolet exposure has a beneficial effect (1). In the future, 25(OH)D3 may become ofmajor importance in assessing the role of the plasmatic content of vitamin D3 to prevent chronic diseases and cancer. Dietary vitamin D3 exhibited the same anti-cancer activity than 1,25(OH)2D3 in mice (9), a chemically modified form of 25(OH)vitD3 exerts a chemotherapeutic effect on neuroblastoma xenograft mouse model (22), an imbalance in plasma availability of 25(OH)D3 is considered a risk factor for carcinoma (23) and 25(OH)D3, likewise 1,25(OH)2D3, exerts an anti-inflammatory effect (24–26). Most of the recent evidence should suggest that plasma level of 25(OH)D3 has a fundamental role in warranting protection against chronic immune disorders and cancer (27). However, any approach to enhance 25(OH)D3 bioavailabilitywith diet does not appear sufficient to improve vitaminD3-related outcome, due to genetic variability within the population (28). This evidence may appear therefore quite discouraging. Physicians are wondering how to focus onto vitamin D3 dietary intake to prevent chronic immune disorders and cancer. Yet, a proper determination of plasmatic 25(OH)D3 metabolites is highly recommended (29, 30). Clinical chemists have some difficulty in evaluating plasmatic 1,25(OH)2D3, particularly because it is rapidly degraded by 24-hydroxylases. Conversely, 25(OH)D3 biochemical activity should be attributed fundamentally to the 1-α-hydroxylated form,