Page 329 - Vitamin D and Cancer

316 R. Vieth

case-control studies have generally failed to demonstrate that a higher prediagnostic
serum 25(OH)D level lowers risk of cancer. The vitamin D relationship with cancer
is not a simple one, where more is better. As latitude increases, so does the seasonal
variability in UVB exposure and serum 25(OH)D of populations. Humans are a
tropical species for whom large seasonal fluctuations in serum 25(OH)D may not be
something for which their biology has been adapted. Metabolism within tissues
responsive to the paracrine synthesis of 1,25(OH) D needs to adapt to prevailing
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25(OH)D levels, through adjustments to the CYP27B1 and CYP24 that respectively
synthesize and catabolize 1,25(OH) D. These enzymes are unique in endocrinology,
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because their activity in vivo is a first-order relationship with substrate. Consequently,
so long as serum 25(OH)D levels are in a phase of decline, as they are during win-
ters, there will be a relative excess in tissue catabolism of 1,25(OH) D, lowering
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tissue 1,25(OH) D levels, and potentially affecting cancer risk and prognosis.
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14.1.1 Relationship Between Vitamin D and Prostate Cancer

Increased exposure to UVB light is associated with lower risk of internal cancers [1–3],
but those benefits are at the cost of higher risk of skin cancer [4, 5]. The benefits of a
high-UV environment are widely attributed to the vitamin D produced as a result of UVB
light. But for prostate cancer as well as cancer of the pancreas, there is much controversy
about whether higher vitamin D status (measured as serum 25-hydroxyvitamin D
[25(OH)D]) is beneficial or harmful [6–8]. One alternative to the vitamin D hypothesis
is that melatonin or lighting cycles themselves can moderate cellular biology to prevent
cancer [9, 10]; however, this speculation is not supported by direct evidence.
As an example, prostate cancer cells possess both of the enzymes needed to convert
vitamin D into the active paracrine hormone, 1,25-dihydroxyvitamin D3 (1,25(OH) D;
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calcitriol) [11]. In cultured prostate epithelial cells, a physiological level of vitamin D
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(the simple product of UV-exposed skin) inhibits growth, induces differentiation, and
up-regulates VDR, RXRs, and androgen receptors, suggesting that the observed
effects are receptor-mediated [11]. The vitamin D system targets many genes that can
play a cancer-preventive role, including genes involved in protection from oxidative
stress, and cell–cell and cell–matrix interactions [12, 13]. Anti-inflammatory effects
include the inhibition of tumor angiogenesis, invasion, and metastasis [14]. Calcitriol
inhibits stromal invasion of prostate cancer cells by modulation of protease activity
[15]. In xenograft mouse models, calcitriol and its analogs suppress the nuclear prolif-
eration marker MIB-1 (or Ki-67) in ovarian [16] and breast cancers [17]. Prostate
cancer LNCaP cells respond to calcitriol and its analogs with decreased MIB-1 expres-
sion [13, 18, 19] and when implanted into in vivo mouse models, they respond to
calcitriol with greatly diminished growth [20, 21]. In a mouse cancer model, the cal-
citriol precursor, calcidiol, slowed tumor growth and improved differentiation of ras-
transformed keratinocytes, confirming that in vivo, extrarenal 1-hydroxylase plays an
important role in paracrine/autocrine control of growth and differentiation [22].
The cellular mechanisms that explain why and how vitamin D can affect prostate
cancer have been studied thoroughly, but the practical question of whether vitamin