Page 239 - Vitamin D and Cancer

226 C.M. Barnett and T.M. Beer

Specific to prostate cancer, multiple studies have shown the antiproliferative
effects of vitamin D on prostate cancer cells in cell lines, [17] human primary
culture, [52] and in rodent models [53].
While normal prostate cells express 1-alpha-hydroxylase, this activity can be
lost when prostate cancer develops, [3, 19, 54] perhaps reducing the cell’s ability to
produce 1,25-OH vitamin D from its circulating precursor, 25-OH vitamin D. Loss
2
of local 1-alpha-hydroxylase activity may render cancer cells dependent on circu-
lating 1,25-OH vitamin D for growth suppression activity. Indeed, restoring
2
LNCaP cells 1-alpha-hydroxylase activity with gene transfer [3, 54] has been
shown to restore effect of 25-OH vitamin D on cell proliferation. Interestingly,
colon cancer cells rarely lose 1-alpha-hydroxylase activity and sometimes even
have increased activity, [4] perhaps making colon cancer more responsive to the
effects of circulating 25-OH vitamin D than prostate cancer [21]. These biologic
differences may have significant clinical implications. Because circulating 1,25-
OH vitamin D levels are tightly regulated and remain relatively stable during mild
2
deficiency states, tissues that rely on renally activated vitamin D for VDR signaling
would remain relatively unaffected by vitamin D deficiency until it is severe. In
contrast, tissues with significant local production of 1,25-OH vitamin D would see
2
differences in VDR signaling with changes in circulating 25-OH vitamin D levels,
which more closely mirror the overall vitamin D status.
In animal models of cancer, the antineoplastic activity of vitamin D has been shown
to translate into a reduction in metastatic potential. In rodent models, there has been
demonstration of reduction in metastases with vitamin D therapy [55–57] and slowed
growth of the prostate cancer [58, 59]. Reduced prostate cancer cell invasiveness with
vitamin D therapy has been demonstrated in vitro by several investigators [37, 60–62].
1,25 Vitamin D also decreases IL-8 signaling in prostate cancer, thus inhibiting
endothelial migration and therefore inhibiting growth and invasion of the cancer [63].
In addition to growth inhibition, vitamin D induced apoptosis has been shown in
several prostate cancer cell culture models. To explain this, vitamin D has been shown
to down-regulate Bc1–2, [31] an important protein in anti-apoptotic pathways in
prostate cancer cells, and other cancer cell lines. Vitamin D also upregulates expres-
sion of pro-apoptotic proteins BAK and BAX [64]. Down-regulation of insulin-like
growth factor receptor in response to vitamin D has also been shown, [30] along with
up-regulation of TNF-alpha, [65] all important in apoptotic pathways.

10.5 Epidemiology

10.5.1 UV Exposure and Prostate Cancer Risk

The hypothesis that vitamin D plays a role in prostate cancer biology was formulated
after geographic studies showed that prostate cancer-related mortality was geo-
graphically dependent, with the greatest mortality in northern regions [66]. This
geographic distribution is consistent with an inverse relationship between prostate
cancer risk and UV exposure, and presumably, vitamin D levels [67]. After the initial