Page 17 - Vitamin D and Cancer

4 H.S. Cross

sunlight exposure is increased or whether there is increased oral uptake of vitamin
D [19], since its synthesis in renal cells is tightly regulated by PTH, calcium, and
phosphate.
As early as 1980, Garland et al. raised the question whether sunlight and vitamin
D can protect against colon cancer [20]. Strong support for this hypothesis was
obtained when Garland et al. [21] in 1985 published the results of a 19-year pro-
spective trial, showing that low dietary intakes of vitamin D and of calcium are
associated with a significant risk of colorectal cancer. In the following decades, a
compromised vitamin D status as indicated by low 25-(OH)D serum levels has
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been associated with pathogenesis of diverse types of malignancy (for review see,
e.g., [22, 23]). This, and the realization that there was vitamin D synthesis at extra-
renal sites potentially enhancing 1,25-(OH) D concentrations in certain tissues
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without contributing to serum levels of 1,25-(OH) D , suggested a hypothesis on
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how decreased sunlight exposure and low serum 25-(OH)D could contribute to
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tumor pathogenesis.

1.2 Regulation of 1,25-(OH) D Synthesis in Extrarenal Cells
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Regulation of 1,25-(OH) D production at multiple levels is a crucial determi-
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nant of nonclassical aspects of 1,25-(OH) D function. When we showed that
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normal and neoplastic human colon epithelial cells are endowed with a func-
tional 25-hydroxyvitamin D-1a-hydroxylase and can thus convert 25-(OH)D
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to 1,25-(OH) D [24–26], we hypothesized that adequate accumulation of the
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active metabolite could slow down or inhibit progression of malignant disease
by promoting differentiation and apoptosis and by suppressing antimitotic
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activity locally. Renal CYP27B1 activity is tightly regulated by serum Ca and
parathyroid hormone (PTH), as well as by feedback inhibition from
1,25-(OH) D . In contrast, CYP27B1 expression, at least in colonocytes and
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prostate cells, is relatively insensitive to modulation via the PTH/[Ca ] axis
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[27, 28]. Intracellular synthesis of 1,25-(OH) D at extrarenal sites depends
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largely on ambient 25-(OH)D levels and is not influenced by plasma levels of
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1,25-(OH) D [29]. This may explain why the incidence of vitamin D-dependent
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cancers, e.g., of the colorectum [30], breast [31], and prostate gland [32], is
correlated with low serum 25-(OH)D rather than with serum concentrations of
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1,25-(OH)D . Strong support for the importance of intracellularly produced
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over circulating 1,25-(OH) D for regulation of cell functions comes from a
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study by Rowling et al. [33] who have shown that in mammary gland cells
VDR-mediated actions depended more on megalin-mediated endocytosis of
25-(OH)D than on ambient 1,25-(OH) D . Also Lechner et al. [34] could
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induce the characteristic antimitogenic effect of 1,25-(OH) D when human
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colon carcinoma cells were treated with 25-(OH)D , though only when they
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were CYP27B1-positive. Similar observations were made in prostate [35] and
mammary cells [36].