Page 118 - Vitamin D and Cancer

5 Vitamin D and Angiogenesis 105

1,25D or 1(OH)D inhibits tumor growth and prolongs the survival time in a
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murine renal cell carcinoma model [82]. Angiogenesis is also inhibited by either
agent as assessed by the blood volumes in the tumors. The number and size of
pulmonary and hepatic metastatic foci are reduced by either agent [82]. 1,25D and
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1(OH)D have also been shown to inhibit the development and angiogenesis in
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azoxymethane-induced colon cancer model in Wistar rats, which is associated with
reduced VEGF expression in tumors [83]. 1,25D or 22-oxa-1,25D inhibits angio-
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genesis in a mouse dorsal air sac model and an in vivo chamber angiogenesis
model, using Lewis lung carcinoma (LLC) tumor cells and bFGF as angiogenesis
activators, respectively [84]. 1,25D also shows an anti-angiogenic effect in a
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suture-induced cornea inflammation mouse model [85] and a mouse oxygen-
induced ischemic retinopathy model [77]. 1,25D and retinoids (all-trans retinoic
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acid, 13-cis retinoic, and 9-cis retinoic acid) synergistically inhibit tumor cell-
induced angiogenesis in vivo in mouse xenograft models [86, 87]. The same group
also reported that 1,25D potentiates the anti-angiogenic effects of IL-12 in the
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tumor cell-induced angiogenesis model, which may partially contribute to the anti-
tumor activity of 1,25D and IL-12 [88].
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Interestingly, vitamin D promotes angiogenesis in more physiological settings.
Vascular invasion of the chondro–osseous junction of growth plate, in which VEGF
plays an important role, is essential in endochondral bone formation. Mice treated
with 1,25D show enhanced vascularization of growth plate cartilage compared with
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vehicle-control-treated mice [89]. 1,25D enhances VEGF isoforms expression in
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CFK2 chondrogenic cell line in vitro and in growth plate chondrocytes and osteo-
blasts in the tibia and juvenile of mice in vivo [89]. 1,25D also stimulates osteoclasts
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in tibias to express MMP-9, which activates VEGF stored in the cartilage matrix [89].
Vitamin D analog ED-71 promotes blood vessel formation in bone marrow cavity
following bone marrow ablation in mice, which is associated with enhanced
VEGF120 expression in bone marrow cells [90]. It is beneficial that 1,25D differen-
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tially regulate angiogenesis in normal and tumor microenvironments.

5.2.4 Potential Mechanisms for the Effects of Vitamin D
on Angiogenesis

The mechanisms for anti-angiogenic effects of vitamin D remain unclear. 1,25D or
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22-oxa-1,25D suppresses the expression of MMP-2, MMP-9 and VEGF in Lewis
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lung carcinoma (LLC) cells, which may partially contribute to the anti-angiogenic
activity of the two agents in LLC-induced angiogenesis in vivo [84]. One study
indicates a role of interleukin-8 (IL-8) in the anti-angiogenic effect of vitamin D.
1,25D suppresses the secretion of IL-8 and TNF-induced IL-8, which is overex-
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pressed in prostate cancer development, in prostate cancer cell lines [91]. 1,25D also
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reduces the activation of nuclear factor-kB (NF-kB), which is a main regulator of
IL-8. 1,25D or IL-8-neutralizaing antibody inhibits prostate cancer cell conditioned
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media-induced HUVEC tube formation, migration, and MMP-9 expression [91].