Page 18 - Vitamin D and Cancer

1 Vitamin D: Synthesis and Catabolism 5

However, at low serum levels of 25-(OH)D , CYP27B1 activity in extrarenal
3
cells may be not high enough (in normal colonic mucosa without hyperproliferative
signaling, positivity for CYP27B1 is extremely low [26]) to achieve those steady-
state tissue concentrations of 1,25-(OH) D necessary to maintain normal cellular
2 3
growth and differentiation during hyperproliferation. In addition, 1,25-(OH) D
2 3
itself is an important regulator of CYP27B1 gene expression. Down-regulation of
the CYP27B1 gene involves a negative vitamin D response element and cell speci-
ficity for this could be due to differential expression of protein complexes associ-
ated with the CYP27B1 promoter [37, 38].

1.2.1 Expression of CYP27B1 and of VDR During
Hyperproliferation and Tumor Progression

The relevance of 1,25-(OH) D to maintain normal epithelial cell turnover in the
2
3
large intestine was demonstrated by studies with mice, which were genetically
altered to block 1,25-(OH) D /VDR signaling: The colon mucosa of VDR null
2
3
(VDR ) mice show a pattern of increased DNA damage and cell division, the for-
-/-
mer probably due to formation of reactive oxygen species [39]. Interestingly, the
large intestine reacts to inflammatory and hyperproliferative conditions with up-
regulation of the VDR and of its ligand-synthesizing enzyme, CYP27B1: Liu et al.
[40] reported that in a mouse model of ulcerative colitis, a disease considered to be
a precursor lesion to colorectal cancer, expression of CYP27B1 was increased four-
fold compared with controls. With respect to human colon cancer, we have shown
that expression of CYP27B1 rises about fourfold in the course of progression from
adenomas to well and moderately differentiated (G1 and G2) tumors, and then
substantially declines during further progression [41]. Expression of the VDR
showed the same dependence on tumor cell differentiation [41, 42]. However, cells
from poorly differentiated (G3) colonic lesions, are frequently devoid of immuno-
reactivity for VDR and CYP27B1, while, at the same time, epidermal growth factor
(EGF) receptor mRNA can be detected by in situ hybridization in almost any cancer
cell [43]. Statistical evaluation actually showed an inverse expression of EGF
receptor positivity compared to that of VDR. We suggested therefore that the
1,25-(OH) D /VDR system can be activated in colon epithelial cells in response to
2
3
mitogenic stimulation, e.g., by EGF, respectively, TGF-a [43, 44]. A strong auto-
crine/paracrine antimitogenic action of 1,25-(OH) D would retard further tumor
2
3
growth as long as cancer cells retain a certain degree of differentiation and high
levels of CYP27B1 activity and of VDR expression. However, during progression
to high grade malignancy, signaling from the 1,25-(OH) D /VDR system would be
3
2
too weak to effectively counteract proliferative effects from, e.g., EGF-R activation
[43]. We confirmed these hypotheses by demonstrating that, in differentiated colon
cell lines, EGF stimulates expression of VDR and CYP27B1, whereas in a primary
culture derived from a G2 tumor, expression of VDR and of CYP27B1 was actually
reduced [45]. Palmer et al. [46] demonstrated that induction of the adhesion protein