Page 165 - Vitamin D and Cancer

152 E. Gocek and G.P. Studzinski

?
GF A E 2
1,25D

GFR

Ras

PI3K Raf-1 VDR AR ER

PIP 3 MEK 1/2

Erk 1/2
AKT

? VDR NR Differentiation-
related gene
DIFFERENTIATION transcription
+
SURVIVAL PROLIFERATION
Fig. 7.2 Signaling of differentiation by 1,25D in hormone-dependent cancer cells. This schematic
illustrates the hypothesis that in normal breast or prostate cells, estrogen (E ) or androgen (A) is
2
sufficient to induce differentiation, respectively. In cancer cells, the differentiation signal provided
by the hormone-liganded nuclear receptor (NR) may need to be amplified by cooperation with
1,25D-activated VDR to induce differentiation. Since cells also receive signals from growth fac-
tors (GF), several of which activate Ras, the presence of a Ras-activated signaling pathways is
exemplified by the AKT and extracellular-signal regulated kinase (ERK) cascades, though the role
of these pathways in the differentiation of hormone-dependent cells is uncertain

7.2.4 Keratinocytes and Squamous Cell Carcinoma Cells

While there is extensive evidence of 1,25D-induced differentiation in normal kera-
tinocytes, the studies of the induction of differentiation in squamous cell carcino-
mas (SCC), composed essentially of neoplastic keratinocytes, are less conclusive.
Differentiation can be detected by the presence of various components of the kera-
tinizing cells, such as cytokeratins K1 and K10, cornifin beta, involucrin, and
transglutaminase, considered to be a late marker of squamous cell differentiation to
normal epidermal keratinocytes [88]. The expression of target genes of 1,25D and
analogs can also be taken as evidence that SCC cell lines can be driven to differen-
tiation by these compounds [89]. Such genes include N-cadherin, which when
overexpressed restores the epithelial phenotype also in prostate cancer cells [90],
cystatin M, protease M, type XIII collagen, and desmoglein 3 [89]. Bikle and col-
leagues have presented persuasive models for induction of keratinocyte differentia-
tion by increased calcium levels and by calcium-1,25D interactions [91, 92]. The key
features of calcium-induced human keratinocyte differentiation appear to include the