Journal of Steroid Biochemistry & Molecular Biology 97 (2005) 121–128 The Vitamin D endocrine system of the gut—Its possible role in colorectal cancer prevention Heide S. Cross ∗ , Giovanna Bises, Daniel Lechner, Teresa Manhardt, Enik¨ o K´ allay Department of Pathophysiology, Center of Physiology and Pathophysiology, Medical University of Vienna, A-1090 Vienna, Waehringer Guertel 18-20, Austria Abstract While Vitamin D insufficiency in the US and European population is rising, epidemiological studies suggest an inverse correlation between low serum levels of 25-hydroxyvitamin D 3 (25-OH-D 3 ) and colorectal cancer incidence. The antimitotic, prodifferentiating and proapoptotic active metabolite 1,25-dihydroxyvitamin D 3 (1,25-(OH) 2 -D 3 ) is synthesized also by colonocytes, since these possess Vitamin D synthesizing (CYP27B1) and catabolic (CYP24) hydroxylases similar to the kidney. Early during colon tumor progression, expression of CYP27B1 and of the Vitamin D receptor increases, suggesting an autocrine/paracrine growth control in colon tissue as a physiological restriction against tumor progression. However, in human adenocarcinomas expression of the catabolic CYP24 is also enhanced when compared with adjacent normal mucosa. Therefore, to maintain colonic accumulation of 1,25-(OH) 2 -D 3 its catabolism needs to be restricted. Our studies in mice show that low nutritional calcium causes hyperproliferation of colon crypts and significant elevation of CYP24 expression, which can be completely abrogated by soy feeding. We suggest that phytoestrogens in soy, known to be estrogen receptor modulators, are responsible for decreased CYP24 expression. These results and our observation that 17-estradiol can elevate CYP27B1 expression in rectal tissue of postmenopausal women, may underlie the observed protective effect of estrogens against colorectal cancer in females. © 2005 Elsevier Ltd. All rights reserved. Keywords: Colonic 1,25-(OH) 2 -D 3 synthesis; CYP27B1; CYP24; Low and high grade tumors; Estrogens 1. Introduction Already in 1980 Garland and Garland [1] proposed that Vitamin D might be a protective factor against colorectal can- cer. They based this hypothesis on the observation that colon cancer mortality in the USA was highest in regions where the population was least exposed to solar radiation. UV-B is responsible for Vitamin D production in the skin and serum levels of 25-hydroxyvitamin D 3 (25-OH-D 3 ) are a direct reflection of sunlight exposure and of protective skin pig- mentation [2]. The latter could lead to enhanced incidence of colorectal, breast and prostate cancer that has been observed in African Americans [2]. The link between colorectal cancer incidence and solar radiation was later confirmed by several large studies comparing southern and northern parts of the USA (see, e.g. Ref. [3]). Recently, Grant and Garland sug- ∗ Corresponding author. Tel.: +431 40400 5123; fax: +431 40400 5130. E-mail address: heide.cross@meduniwien.ac.at (H.S. Cross). gested that actually 20–30% of colorectal cancer incidence is due to insufficient exposure to sunlight [4]. Such associations suggest that there is a correlation between reduced colorectal cancer incidence and sunlight exposure, low skin pigmentation, nutritional Vitamin D intake and high serum levels of 25-OH-D 3 . A recent meta- analysis demonstrated convincingly the beneficial effect of high 25-OH-D 3 serum levels with respect to colorectal cancer occurrence [5]. In a human pilot study, Holt et al. [6] demon- strated for the first time that rectal crypt proliferation was inversely correlated with 25-OH-D 3 levels in serum. 1,25- dihydroxyvitamin D 3 (1,25-(OH) 2 -D 3 ), however, which has been recognized as an antimitotic, prodifferentiating steroid hormone in in vitro (see, e.g. Ref. [7]) and also in very few in vivo animal studies [8], did not show a negative correlation with colorectal tumor incidence, not even at the highest physiological serum range. In 1997, we [9] demon- strated that conversion of the precursor 25-OH-D 3 into 1,25- (OH) 2 -D 3 occurs in human colon cancer cells. We found constitutive expression of the 25-hydroxyvitamin-D 3 -1- 0960-0760/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jsbmb.2005.06.005