Biomedical Engineering Reference
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The Wnt pathway is also associated with development of bone metastases
associated with prostate cancer (reviewed by Hall and Keller 2006). Data
indicate that the Wnt antagonist DKK-1 is a switch that controls bone metas-
tases from osteolytic to osteoblastic in a manner depending on the tumor
microenvironment. While it is largely unknown what role, if any, that Wnt
signaling plays in normal prostate development, recent data support its role in
prostate CSCs. Two independent studies demonstrated increased b-catenin
gene expression in cell line-derived CD44 + CSCs relative to the non-stem cell
population (Patrawala et al. 2006; Hurt et al. 2008). In addition, the Wnt
pathway antagonist DKK1 is downregulated in the CD44 + CSCs (EMH
unpublished observations). Though these data suggest that Wnt signaling is
increased, it was not determined whether b-catenin was localized in the nucleus,
where it is required for TCF/LEF activation. Additional studies are needed to
determine how upregulated Wnt signaling contributes to the CSC phenotype.
4.2 Hedgehog Signaling
The hedgehog gene family encodes several secreted glycoproteins such as Indian
hedgehog (IHh), desert hedgehog (DHh), and sonic hedgehog (SHh). These
serve to mediate signaling in embryogenesis and development through activa-
tion of the GLI family of transcription factors (reviewed in Taipale and Beachy
2001; Liu et al. 2005) The Hh pathway is somewhat unique in that the signals
serve to relieve a series of repressive interactions. The receptor for Hh, the
transmembrane protein patched 1 (PTCH), normally binds and inhibits
smoothened (SMOH), a G-protein-coupled receptor that is related to FRZ.
When secreted Hh binds both PTCH and hedgehog-interacting protein (HIP),
SMOH initiates a transcriptional response. Specifically, SMOH activates the
serine/threonine kinase Fused (Fu) to release GLI from the sequestration by
Suppressor of Fused (SuFu). Subsequently GLI proteins are able to translocate
to the nucleus and regulate transcription of cyclin D and E, c-myc, and other
genes involved in cell proliferation and differentiation (reviewed in Nybakken
and Perrimon 2002; Pasca di Magliano and Hebrok 2003).
Normal mammalian prostate development requires functional Hh signaling
(Berman et al. 2004; Freestone et al. 2003). In rodent models, SHh is expressed
during formation of prostate ducts and branches from epithelial buds (Lamm
et al. 2002; Berman et al. 2004). Recently, Hh expression was confirmed in human
fetal prostate development (Zhu et al. 2007). In mature prostate cells, Hh expres-
sion is low (Zhu et al. 2007), which suggests that it is only during development and
differentiation, steps that involve stem or TA cells, that Hh is required. In
addition, SHh and IHh expression increases in prostate cancer cells (Sanchez
et al. 2004; reviewed in Anton Aparicio et al. 2007), and the Hh targets of PTCH
and GLIare upregulated in human prostate cancer cells but not in normal samples
(Karhadkar et al. 2004). Thus, activation of the Hh pathway is an important
component in the unregulated growth of prostate cancer cells.
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