Page 46 - Vitamin D and Cancer

2 The Molecular Cancer Biology of the VDR 33

and may represent autocrine and non-calcemic actions. The animals became
growth-retarded, display alopecia, uterine hypoplasia, impaired ovarian follicu-
logenesis, reproductive dysfunction, cardiac hypertrophy, and enhanced
thrombogenicity.

2.2.2 Self-renewing Epithelial Systems

The sporadic, temporal acquisition of a cancer phenotype is compatible with
models of disruption of the self-renewal of epithelial tissues. It has become
increasingly clear that breast, colon, and prostate tissues, in common with other
epithelial tissues and many other cell types in the adult human, are self-renewing
and contain committed stem cell components [97–102].These stem cells are
slowly proliferating and are able to undergo asymmetric divisions to give rise
both to other stem cells and transiently amplifying (TA) populations of progenitor
cells, that in turn give rise to the differentiated cell types, which typify the func-
tions of these tissues and are subsequently lost through programmed cell death
processes and replaced by newly differentiated TA cells. The mechanisms that
control the intricate balance of these processes of division, differentiation, and
programmed cell death are subjects of significant investigations. These studies
have revealed common roles for Wnt and hedgehog signaling and the actions of
other signal transduction processes that govern cell cycle progression, with gene
targets such as the cyclin-dependent kinase inhibitor CDKN1A (which encodes
p21 (waf1/cip1) ) emerging as points of criticality upon which numerous signal path-
ways converge.
Against this backdrop, the Vdr operates in several self-renewing tissues. The
Vdr is readily detected in keratinocytes and co-treatment of calcium and
1a,25(OH) D decreases proliferation and promotes differentiation of cultured
2
3
keratinocytes [103]. The Vdr is also detected in outer root sheath and hair follicle
bulb, as well as in the sebaceous glands [104] and the Vdr -/- mice develop hair loss
and ultimately alopecia totalis, associated with large dermal cysts, that is not pre-
vented by the high calcium rescue diet. The alopecia arises due to a complete fail-
ure to initiate anagen, which is the first postnatal hair growth phase. Subsequently,
the hair follicles convert into epidermal cysts [105]. Hair follicle formation requires
highly coordinated signaling between different cell types including contributions
from the stem cells components and therefore the alopecia phenotype has attracted
significant research interest as it may represent a role for the VDR in stem cell
maintenance. Subsequent studies have demonstrated that a failure to maintain hair
follicles in Vdr -/- animals does not actually reflect a loss of follicle stem cells but
rather an inability of the primitive progenitor cells to migrate along the follicle at
the onset of anagen [106].
Interestingly, these effects appear independent of ligand binding, in that they
can be rescued even when Vdr is mutated in the LBD, but not completely if
the AF2 domain is interrupted, suggesting that the association with cofactors is