Page 119 - Vitamin D and Cancer

106 Y. Ma et al.

These results indicate that 1,25D -mediated interruption of IL-8 signaling may
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prevent the progression of prostate cancer. Hypoxia is a pathophysiologic condition
that promotes angiogenesis, and is mediated by transcription factor HIF-1. HIF-1 is
overexpressed in many cancer cells and is positively related to disease progression
[92]. 1,25D suppresses the expression of HIF-1a and VEGF in human prostate and
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colorectal cancer cells [93]. 1,25D also inhibits HIF-1 transcriptional activity and
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reduces the transcript levels of HIF-1 target genes including VEGF, ET-1, Glut-1.
1,25D -mediated suppression of hypoxia-induced VEGF expression is HIF-pathway-
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dependent as studied in HIF-1a knockout colon cancer cells [93]. HIF-1 pathway
may also be involved in 1,25D anti-angiogenic effects.
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5.2.5 Effect on VSMC

Endothelial cells alone cannot complete angiogenesis nor maintain the newly
formed vessels. Peri endothelial cells, including smooth muscle cells and pericytes,
play an essential role in vessel maturation and stabilization [4].
Vitamin D has a variety of effects on the function and pathology of VSMCs,
including cell growth, contractility, migration, and the evolution of vascular calcifi-
cations [72, 94–100]. VSMCs have been shown to express an enzymatically active
1a-hydroxylase, which can be increased by parathyroid hormone (PTH) and native
and synthetic phytoestrogens [101]. 1,25D inhibits the DNA synthesis and thus
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proliferation of VSMC, but increases metabolic turnover as assessed by creatine
kinase activity, suggesting a potential role of the 1,25D synthesized intracellularly
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in these cells [101, 102]. 1,25D also inhibits epidermal growth factor (EGF)-
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induced VSMC proliferation [102]. In contrast, other studies support a role of
1,25D in promoting VSMC proliferation [71, 73] by upregulating VEGF expression
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[73]. VEGF receptor antagonist or VEGF-neutralizing antibody abrogates the effect
of 1,25D on VSMC proliferation [73]. In fact, 1,25D may inhibit or promote the
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growth of VSMC, depending on the underling culture conditions [72]. In nonquies-
cent cells, 1,25D inhibits thrombin or PDGF-induced VSMC growth, as well as
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thrombin-mediated induction of c-myc RNA. While in quiescent cells, 1,25D pro-
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motes the cell growth and the induction of c-myc RNA by thrombin [72].
The role of vitamin D in vascular calcification and cardiovascular disease is
controversial. Epidemiological data show that there is correlation between ischemic
heart disease mortality rate and geographic latitude for several European and
Western countries [103]. High latitude has been shown to associate with low serum
vitamin D levels [104]. In addition, an inverse association between coronary heart
disease mortality rate in males and altitude was observed [105]. It is a fact that the
intensity of UVB radiation increases exponentially at higher altitude. The mortality
rate of coronary heart disease also displays seasonal variation. Multiple studies
show that ischemic heart disease death rate is low in summer and high in winter
[106–108]. Serum levels of 1,25D show the opposite pattern with a peak in
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summer and a nadir in winter [109–111]. These studies suggest that lower level of
serum vitamin D is associated with higher ischemic heart disease mortality rate.