UV exposure inhibits intestinal tumor growth and progression to malignancy in intestine-specific Apc mutant mice kept on low vitamin D diet Heggert Rebel 1 , Celia Dingemanse-van der Spek 2 , Daniela Salvatori 3,4 , Johannes P.T.M. van Leeuwen 5 , Els C. Robanus-Maandag 2 and Frank R. de Gruijl 1 1 Department of Dermatology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands 2 Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands 3 Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands 4 Central Animal Facility, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands 5 Department of Internal Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands Mortality from colorectal cancer increases with latitude and decreases with ambient UV radiation. We investigated whether moderate UV dosages could inhibit intestinal tumor development and whether this corresponded with UV-induced vitamin D. FabplCre;Apc 15lox/1 mice, which develop intestinal tumors, and their parents were put on a vitamin D-deficient diet. Next to a control group, one group was vitamin D supplemented and another one group was daily UV irradiated from 6 weeks of age. Vitamin D statuses after 6 weeks of treatment were markedly increased: mean 6 SD from 7.7 6 1.9 in controls to 75 6 15 nmol/l with vitamin D supplementation (no gender difference), and to 31 6 13 nmol/l in males and 85 6 17 nmol/l in females upon UV irradiation. The tumor load (area covered by tumors) at 7.5 months of age was significantly reduced in both the vita- min D-supplemented group (130 6 25 mm 2 , p 5 0.018) and the UV-exposed group (88 6 9 mm 2 , p < 0.0005; no gender differ- ences) compared to the control group (202 6 23 mm 2 ). No reductions in tumor numbers were found. Only UV exposure appeared to reduce progression to malignancy (p 5 0.014). Our experiments clearly demonstrate for the first time an inhibitory effect of moderate UV exposure on outgrowth and malignant progression of primary intestinal tumors, which at least in part can be attributed to vitamin D. Introduction In 1980, the brothers Garland proposed that the observed lat- itudinal gradient in mortality from colon cancer over the USA might be explained by variation in solar UV radiation, through cutaneous vitamin D production. 1 More recently, a pooled US study 2 and a pan-European study 3 showed that increased risk of colon cancer was indeed significantly associ- ated with a prediagnostic low vitamin D status [serum level of 25-hydroxyvitamin D 3 , 25(OH)D 3 , calcidiol]. The 25(OH)D 3 level varies widely over the year in apparent dependence of the ambient UV levels: low in winter and high in summer. It is estimated that most of the calcidiol supply (>70% over the year) stems from UV-driven production in the skin, while a minor part is of dietary origin (<30%). 3,4 Vitamin D is an important prohormone playing a crucial role in the maintenance of calcium homeostasis. The primary role of vitamin D is to facilitate absorption of calcium and phosphate in the intestine. The kidney is responsible for maintaining proper blood levels of the active metabolite, the hormone, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 , calcitriol) by hydroxylation of serum 25(OH)D 3 . Extrarenal hydroxyla- tion, like in the colon, has been implicated to regulate local processes in various tissues. 5,6 In this way, 1,25(OH) 2 D 3 lev- els can be increased locally above blood levels without adding substantially to the quantity in circulation and, thus, without calciotropic effects. Most experimental studies indicate that vitamin D protects against colon cancer mainly through the local production of 1,25(OH) 2 D 3 . 7–10 Vitamin D receptor (VDR)-deficient APC- Min/1 mice develop colon cancers larger in size than APC Min/1 control mice. 11 In vitro data indicate that 1,25(OH) 2 D 3 inhibits proliferation and promotes epithelial differentiation of human colon cancer cells by inducing the expression of E-cadherin and by antagonizing the Wnt/b-catenin pathway. 12–17 Addi- tionally, 1,25(OH) 2 D 3 and VDR regulate the c-MYC/MXD1 Key words: intestinal cancer, UV exposure, vitamin D, adenoma, adenocarcinoma, Apc mutant mice Additional Supporting Information may be found in the online version of this article. Grant sponsors: Sunlight Research Forum (pilot study not reported here); Foundation for General Light Therapy (Stichting Algemeene Lichttherapie); Valorisation Fund DOI: 10.1002/ijc.29002 History: Received 23 Dec 2013; Accepted 12 May 2014; Online 29 May 2014 Correspondence to: Frank R. de Gruijl, Department of Dermatology, Leiden University of Medicine, Ctr./LUMC- S2P, PO Box 9300, 2300 RC Leiden, The Netherlands, Tel.: 131 71 526 9363, Fax: 131 71 5248106, E-mail: f.r.de_gruijl@lumc.nl Carcinogenesis Int. J. Cancer: 00, 00–00 (2014) V C 2014 UICC International Journal of Cancer IJC